Hyman Research Publications
Featured Publications
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2023. Shifting the trajectory of therapeutic development for neurological and psychiatric disorders. Science translational medicine. 15(720):eadg4775. Pubmed: 38190501 DOI:10.1126/scitranslmed.adg4775 Krainc D, Martin WJ, Casey B, Jensen FE, Tishkoff S, Potter WZ, Hyman SE. 2023. Shifting the trajectory of therapeutic development for neurological and psychiatric disorders. Science translational medicine. 15(720):eadg4775. Pubmed: 38190501 DOI:10.1126/scitranslmed.adg4775 Clinical trials for central nervous system disorders often enroll patients with unrecognized heterogeneous diseases, leading to costly trials that have high failure rates. Here, we discuss the potential of emerging technologies and datasets to elucidate disease mechanisms and identify biomarkers to improve patient stratification and monitoring of disease progression in clinical trials for neuropsychiatric disorders. Greater efforts must be centered on rigorously standardizing data collection and sharing of methods, datasets, and analytical tools across sectors. To address health care disparities in clinical trials, diversity of genetic ancestries and environmental exposures of research participants and associated biological samples must be prioritized. -
Lähteenvuo M, Ahola-Olli A, Suokas K, Holm M, Misiewicz Z, Jukuri T, Männynsalo T, Wegelius A, Haaki W, Kajanne R, Kyttälä A, Tuulio-Henriksson A, Lahdensuo K, Häkkinen K, Hietala J, Paunio T, Niemi-Pynttäri J, Kieseppä T, Veijola J, Lönnqvist J, Isometsä E, Kampman O, Tiihonen J, Hyman S, Neale B, Daly M, Suvisaari J, Palotie A. 2023. Cohort profile: SUPER-Finland - the Finnish study for hereditary mechanisms of psychotic disorders. BMJ open. 13(4):e070710. Pubmed: 37045567 DOI:10.1136/bmjopen-2022-070710 Lähteenvuo M, Ahola-Olli A, Suokas K, Holm M, Misiewicz Z, Jukuri T, Männynsalo T, Wegelius A, Haaki W, Kajanne R, Kyttälä A, Tuulio-Henriksson A, Lahdensuo K, Häkkinen K, Hietala J, Paunio T, Niemi-Pynttäri J, Kieseppä T, Veijola J, Lönnqvist J, Isometsä E, Kampman O, Tiihonen J, Hyman S, Neale B, Daly M, Suvisaari J, Palotie A. 2023. Cohort profile: SUPER-Finland - the Finnish study for hereditary mechanisms of psychotic disorders. BMJ open. 13(4):e070710. Pubmed: 37045567 DOI:10.1136/bmjopen-2022-070710 Array© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. -
Trubetskoy V, Pardiñas AF, Qi T, Panagiotaropoulou G, Awasthi S, Bigdeli TB, Bryois J, Chen CY, Dennison CA, Hall LS, Lam M, Watanabe K, Frei O, Ge T, Harwood JC, Koopmans F, Magnusson S, Richards AL, Sidorenko J, Wu Y, Zeng J, Grove J, Kim M, Li Z, Voloudakis G, Zhang W, Adams M, Agartz I, Atkinson EG, Agerbo E, Al Eissa M, Albus M, Alexander M, Alizadeh BZ, Alptekin K, Als TD, Amin F, Arolt V, Arrojo M, Athanasiu L, Azevedo MH, Bacanu SA, Bass NJ, Begemann M, Belliveau RA, Bene J, Benyamin B, Bergen SE, Blasi G, Bobes J, Bonassi S, Braun A, Bressan RA, Bromet EJ, Bruggeman R, Buckley PF, Buckner RL, Bybjerg-Grauholm J, Cahn W, Cairns MJ, Calkins ME, Carr VJ, Castle D, Catts SV, Chambert KD, Chan RCK, Chaumette B, Cheng W, Cheung EFC, Chong SA, Cohen D, Consoli A, Cordeiro Q, Costas J, Curtis C, Davidson M, Davis KL, de Haan L, Degenhardt F, DeLisi LE, Demontis D, Dickerson F, Dikeos D, Dinan T, Djurovic S, Duan J, Ducci G, Dudbridge F, Eriksson JG, Fañanás L, Faraone SV, Fiorentino A, Forstner A, Frank J, Freimer NB, Fromer M, Frustaci A, Gadelha A, Genovese G, Gershon ES, Giannitelli M, Giegling I, Giusti-Rodríguez P, Godard S, Goldstein JI, González Peñas J, González-Pinto A, Gopal S, Gratten J, Green MF, Greenwood TA, Guillin O, Gülöksüz S, Gur RE, Gur RC, Gutiérrez B, Hahn E, Hakonarson H, Haroutunian V, Hartmann AM, Harvey C, Hayward C, Henskens FA, Herms S, Hoffmann P, Howrigan DP, Ikeda M, Iyegbe C, Joa I, Julià A, Kähler AK, Kam-Thong T, Kamatani Y, Karachanak-Yankova S, Kebir O, Keller MC, Kelly BJ, Khrunin A, Kim SW, Klovins J, Kondratiev N, Konte B, Kraft J, Kubo M, Kučinskas V, Kučinskiene ZA, Kusumawardhani A, Kuzelova-Ptackova H, Landi S, Lazzeroni LC, Lee PH, Legge SE, Lehrer DS, Lencer R, Lerer B, Li M, Lieberman J, Light GA, Limborska S, Liu CM, Lönnqvist J, Loughland CM, Lubinski J, Luykx JJ, Lynham A, Macek M, Mackinnon A, Magnusson PKE, Maher BS, Maier W, Malaspina D, Mallet J, Marder SR, Marsal S, Martin AR, Martorell L, Mattheisen M, McCarley RW, McDonald C, McGrath JJ, Medeiros H, Meier S, Melegh B, Melle I, Mesholam-Gately RI, Metspalu A, Michie PT, Milani L, Milanova V, Mitjans M, Molden E, Molina E, Molto MD, Mondelli V, Moreno C, Morley CP, Muntané G, Murphy KC, Myin-Germeys I, Nenadić I, Nestadt G, Nikitina-Zake L, Noto C, Nuechterlein KH, O'Brien NL, O'Neill FA, Oh SY, Olincy A, Ota VK, Pantelis C, Papadimitriou GN, Parellada M, Paunio T, Pellegrino R, Periyasamy S, Perkins DO, Pfuhlmann B, Pietiläinen O, Pimm J, Porteous D, Powell J, Quattrone D, Quested D, Radant AD, Rampino A, Rapaport MH, Rautanen A, Reichenberg A, Roe C, Roffman JL, Roth J, Rothermundt M, Rutten BPF, Saker-Delye S, Salomaa V, Sanjuan J, Santoro ML, Savitz A, Schall U, Scott RJ, Seidman LJ, Sharp SI, Shi J, Siever LJ, Sigurdsson E, Sim K, Skarabis N, Slominsky P, So HC, Sobell JL, Söderman E, Stain HJ, Steen NE, Steixner-Kumar AA, Stögmann E, Stone WS, Straub RE, Streit F, Strengman E, Stroup TS, Subramaniam M, Sugar CA, Suvisaari J, Svrakic DM, Swerdlow NR, Szatkiewicz JP, Ta TMT, Takahashi A, Terao C, Thibaut F, Toncheva D, Tooney PA, Torretta S, Tosato S, Tura GB, Turetsky BI, Üçok A, Vaaler A, van Amelsvoort T, van Winkel R, Veijola J, Waddington J, Walter H, Waterreus A, Webb BT, Weiser M, Williams NM, Witt SH, Wormley BK, Wu JQ, Xu Z, Yolken R, Zai CC, Zhou W, Zhu F, Zimprich F, Atbaşoğlu EC, Ayub M, Benner C, Bertolino A, Black DW, Bray NJ, Breen G, Buccola NG, Byerley WF, Chen WJ, Cloninger CR, Crespo-Facorro B, Donohoe G, Freedman R, Galletly C, Gandal MJ, Gennarelli M, Hougaard DM, Hwu HG, Jablensky AV, McCarroll SA, Moran JL, Mors O, Mortensen PB, Müller-Myhsok B, Neil AL, Nordentoft M, Pato MT, Petryshen TL, Pirinen M, Pulver AE, Schulze TG, Silverman JM, Smoller JW, Stahl EA, Tsuang DW, Vilella E, Wang SH, Xu S, Adolfsson R, Arango C, Baune BT, Belangero SI, Børglum AD, Braff D, Bramon E, Buxbaum JD, Campion D, Cervilla JA, Cichon S, Collier DA, Corvin A, Curtis D, Forti MD, Domenici E, Ehrenreich H, Escott-Price V, Esko T, Fanous AH, Gareeva A, Gawlik M, Gejman PV, Gill M, Glatt SJ, Golimbet V, Hong KS, Hultman CM, Hyman SE, Iwata N, Jönsson EG, Kahn RS, Kennedy JL, Khusnutdinova E, Kirov G, Knowles JA, Krebs MO, Laurent-Levinson C, Lee J, Lencz T, Levinson DF, Li QS, Liu J, Malhotra AK, Malhotra D, McIntosh A, McQuillin A, Menezes PR, Morgan VA, Morris DW, Mowry BJ, Murray RM, Nimgaonkar V, Nöthen MM, Ophoff RA, Paciga SA, Palotie A, Pato CN, Qin S, Rietschel M, Riley BP, Rivera M, Rujescu D, Saka MC, Sanders AR, Schwab SG, Serretti A, Sham PC, Shi Y, St Clair D, Stefánsson H, Stefansson K, Tsuang MT, van Os J, Vawter MP, Weinberger DR, Werge T, Wildenauer DB, Yu X, Yue W, Holmans PA, Pocklington AJ, Roussos P, Vassos E, Verhage M, Visscher PM, Yang J, Posthuma D, Andreassen OA, Kendler KS, Owen MJ, Wray NR, Daly MJ, Huang H, Neale BM, Sullivan PF, Ripke S, Walters JTR, O'Donovan MC. 2022. Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature. 604(7906):502-508. Pubmed: 35396580 DOI:10.1038/s41586-022-04434-5 Trubetskoy V, Pardiñas AF, Qi T, Panagiotaropoulou G, Awasthi S, Bigdeli TB, Bryois J, Chen CY, Dennison CA, Hall LS, Lam M, Watanabe K, Frei O, Ge T, Harwood JC, Koopmans F, Magnusson S, Richards AL, Sidorenko J, Wu Y, Zeng J, Grove J, Kim M, Li Z, Voloudakis G, Zhang W, Adams M, Agartz I, Atkinson EG, Agerbo E, Al Eissa M, Albus M, Alexander M, Alizadeh BZ, Alptekin K, Als TD, Amin F, Arolt V, Arrojo M, Athanasiu L, Azevedo MH, Bacanu SA, Bass NJ, Begemann M, Belliveau RA, Bene J, Benyamin B, Bergen SE, Blasi G, Bobes J, Bonassi S, Braun A, Bressan RA, Bromet EJ, Bruggeman R, Buckley PF, Buckner RL, Bybjerg-Grauholm J, Cahn W, Cairns MJ, Calkins ME, Carr VJ, Castle D, Catts SV, Chambert KD, Chan RCK, Chaumette B, Cheng W, Cheung EFC, Chong SA, Cohen D, Consoli A, Cordeiro Q, Costas J, Curtis C, Davidson M, Davis KL, de Haan L, Degenhardt F, DeLisi LE, Demontis D, Dickerson F, Dikeos D, Dinan T, Djurovic S, Duan J, Ducci G, Dudbridge F, Eriksson JG, Fañanás L, Faraone SV, Fiorentino A, Forstner A, Frank J, Freimer NB, Fromer M, Frustaci A, Gadelha A, Genovese G, Gershon ES, Giannitelli M, Giegling I, Giusti-Rodríguez P, Godard S, Goldstein JI, González Peñas J, González-Pinto A, Gopal S, Gratten J, Green MF, Greenwood TA, Guillin O, Gülöksüz S, Gur RE, Gur RC, Gutiérrez B, Hahn E, Hakonarson H, Haroutunian V, Hartmann AM, Harvey C, Hayward C, Henskens FA, Herms S, Hoffmann P, Howrigan DP, Ikeda M, Iyegbe C, Joa I, Julià A, Kähler AK, Kam-Thong T, Kamatani Y, Karachanak-Yankova S, Kebir O, Keller MC, Kelly BJ, Khrunin A, Kim SW, Klovins J, Kondratiev N, Konte B, Kraft J, Kubo M, Kučinskas V, Kučinskiene ZA, Kusumawardhani A, Kuzelova-Ptackova H, Landi S, Lazzeroni LC, Lee PH, Legge SE, Lehrer DS, Lencer R, Lerer B, Li M, Lieberman J, Light GA, Limborska S, Liu CM, Lönnqvist J, Loughland CM, Lubinski J, Luykx JJ, Lynham A, Macek M, Mackinnon A, Magnusson PKE, Maher BS, Maier W, Malaspina D, Mallet J, Marder SR, Marsal S, Martin AR, Martorell L, Mattheisen M, McCarley RW, McDonald C, McGrath JJ, Medeiros H, Meier S, Melegh B, Melle I, Mesholam-Gately RI, Metspalu A, Michie PT, Milani L, Milanova V, Mitjans M, Molden E, Molina E, Molto MD, Mondelli V, Moreno C, Morley CP, Muntané G, Murphy KC, Myin-Germeys I, Nenadić I, Nestadt G, Nikitina-Zake L, Noto C, Nuechterlein KH, O'Brien NL, O'Neill FA, Oh SY, Olincy A, Ota VK, Pantelis C, Papadimitriou GN, Parellada M, Paunio T, Pellegrino R, Periyasamy S, Perkins DO, Pfuhlmann B, Pietiläinen O, Pimm J, Porteous D, Powell J, Quattrone D, Quested D, Radant AD, Rampino A, Rapaport MH, Rautanen A, Reichenberg A, Roe C, Roffman JL, Roth J, Rothermundt M, Rutten BPF, Saker-Delye S, Salomaa V, Sanjuan J, Santoro ML, Savitz A, Schall U, Scott RJ, Seidman LJ, Sharp SI, Shi J, Siever LJ, Sigurdsson E, Sim K, Skarabis N, Slominsky P, So HC, Sobell JL, Söderman E, Stain HJ, Steen NE, Steixner-Kumar AA, Stögmann E, Stone WS, Straub RE, Streit F, Strengman E, Stroup TS, Subramaniam M, Sugar CA, Suvisaari J, Svrakic DM, Swerdlow NR, Szatkiewicz JP, Ta TMT, Takahashi A, Terao C, Thibaut F, Toncheva D, Tooney PA, Torretta S, Tosato S, Tura GB, Turetsky BI, Üçok A, Vaaler A, van Amelsvoort T, van Winkel R, Veijola J, Waddington J, Walter H, Waterreus A, Webb BT, Weiser M, Williams NM, Witt SH, Wormley BK, Wu JQ, Xu Z, Yolken R, Zai CC, Zhou W, Zhu F, Zimprich F, Atbaşoğlu EC, Ayub M, Benner C, Bertolino A, Black DW, Bray NJ, Breen G, Buccola NG, Byerley WF, Chen WJ, Cloninger CR, Crespo-Facorro B, Donohoe G, Freedman R, Galletly C, Gandal MJ, Gennarelli M, Hougaard DM, Hwu HG, Jablensky AV, McCarroll SA, Moran JL, Mors O, Mortensen PB, Müller-Myhsok B, Neil AL, Nordentoft M, Pato MT, Petryshen TL, Pirinen M, Pulver AE, Schulze TG, Silverman JM, Smoller JW, Stahl EA, Tsuang DW, Vilella E, Wang SH, Xu S, Adolfsson R, Arango C, Baune BT, Belangero SI, Børglum AD, Braff D, Bramon E, Buxbaum JD, Campion D, Cervilla JA, Cichon S, Collier DA, Corvin A, Curtis D, Forti MD, Domenici E, Ehrenreich H, Escott-Price V, Esko T, Fanous AH, Gareeva A, Gawlik M, Gejman PV, Gill M, Glatt SJ, Golimbet V, Hong KS, Hultman CM, Hyman SE, Iwata N, Jönsson EG, Kahn RS, Kennedy JL, Khusnutdinova E, Kirov G, Knowles JA, Krebs MO, Laurent-Levinson C, Lee J, Lencz T, Levinson DF, Li QS, Liu J, Malhotra AK, Malhotra D, McIntosh A, McQuillin A, Menezes PR, Morgan VA, Morris DW, Mowry BJ, Murray RM, Nimgaonkar V, Nöthen MM, Ophoff RA, Paciga SA, Palotie A, Pato CN, Qin S, Rietschel M, Riley BP, Rivera M, Rujescu D, Saka MC, Sanders AR, Schwab SG, Serretti A, Sham PC, Shi Y, St Clair D, Stefánsson H, Stefansson K, Tsuang MT, van Os J, Vawter MP, Weinberger DR, Werge T, Wildenauer DB, Yu X, Yue W, Holmans PA, Pocklington AJ, Roussos P, Vassos E, Verhage M, Visscher PM, Yang J, Posthuma D, Andreassen OA, Kendler KS, Owen MJ, Wray NR, Daly MJ, Huang H, Neale BM, Sullivan PF, Ripke S, Walters JTR, O'Donovan MC. 2022. Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature. 604(7906):502-508. Pubmed: 35396580 DOI:10.1038/s41586-022-04434-5 Schizophrenia has a heritability of 60-80%, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.© 2022. The Author(s), under exclusive licence to Springer Nature Limited. -
Nehme R, Pietiläinen O, Artomov M, Tegtmeyer M, Valakh V, Lehtonen L, Bell C, Singh T, Trehan A, Sherwood J, Manning D, Peirent E, Malik R, Guss EJ, Hawes D, Beccard A, Bara AM, Hazelbaker DZ, Zuccaro E, Genovese G, Loboda AA, Neumann A, Lilliehook C, Kuismin O, Hamalainen E, Kurki M, Hultman CM, Kähler AK, Paulo JA, Ganna A, Madison J, Cohen B, McPhie D, Adolfsson R, Perlis R, Dolmetsch R, Farhi S, McCarroll S, Hyman S, Neale B, Barrett LE, Harper W, Palotie A, Daly M, Eggan K. 2022. The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia. Nature communications. 13(1):3690. Pubmed: 35760976 DOI:10.1038/s41467-022-31436-8 Nehme R, Pietiläinen O, Artomov M, Tegtmeyer M, Valakh V, Lehtonen L, Bell C, Singh T, Trehan A, Sherwood J, Manning D, Peirent E, Malik R, Guss EJ, Hawes D, Beccard A, Bara AM, Hazelbaker DZ, Zuccaro E, Genovese G, Loboda AA, Neumann A, Lilliehook C, Kuismin O, Hamalainen E, Kurki M, Hultman CM, Kähler AK, Paulo JA, Ganna A, Madison J, Cohen B, McPhie D, Adolfsson R, Perlis R, Dolmetsch R, Farhi S, McCarroll S, Hyman S, Neale B, Barrett LE, Harper W, Palotie A, Daly M, Eggan K. 2022. The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia. Nature communications. 13(1):3690. Pubmed: 35760976 DOI:10.1038/s41467-022-31436-8 It is unclear how the 22q11.2 deletion predisposes to psychiatric disease. To study this, we generated induced pluripotent stem cells from deletion carriers and controls and utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Here, we show that upon differentiation into neural progenitor cells, the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including autism. In excitatory neurons, altered transcripts encoded presynaptic factors and were associated with genetic risk for schizophrenia, including common and rare variants. To understand how the deletion contributed to these changes, we defined the minimal protein-protein interaction network that best explains gene expression alterations. We found that many genes in 22q11.2 interact in presynaptic, proteasome, and JUN/FOS transcriptional pathways. Our findings suggest that the 22q11.2 deletion impacts genes that may converge with psychiatric risk loci to influence disease manifestation in each deletion carrier.© 2022. The Author(s). -
Hyman, SE. 2021. Psychiatric disorders: Grounded in human biology but not natural kinds. Perspectives in Biology and Medicine. 64(1):6-28. DOI:10.1353/pbm.2021.0002 Hyman, SE. 2021. Psychiatric disorders: Grounded in human biology but not natural kinds. Perspectives in Biology and Medicine. 64(1):6-28. DOI:10.1353/pbm.2021.0002 The third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III) and its descriptive psychiatry-based intellectual antecedents imagined psychiatric disorders as discontinuous categories, presumably natural kinds, that would be empirically validated based on future scientific studies. Validation would emerge from a predicted convergence of clinical descriptions (symptom clusters that could be shown to be stable over the lifespan), laboratory results, and family studies. That future science is now arriving, but rather than validating the categorical DSM approach, large-scale genetics along with modern neurobiology and epidemiology have emphatically undercut it. Clinical description, laboratory studies, and family (now genetic) studies do not converge at all on distinct categories. Rather, modern studies are consistent with psychiatric disorders as heterogeneous quantitative deviations from health. The characteristics of these disorders have proven to be discoverable rather than invented and thus are grounded in nature. However, scientific results demonstrate that psychiatric disorders cannot reasonably be understood as discrete categories-and certainly not as natural kinds. -
Turley P, Meyer MN, Wang N, Cesarini D, Hammonds E, Martin AR, Neale BM, Rehm HL, Wilkins-Haug L, Benjamin DJ, Hyman S, Laibson D, Visscher PM. 2021. Problems with Using Polygenic Scores to Select Embryos. The New England journal of medicine. 385(1):78-86. Pubmed: 34192436 DOI:10.1056/NEJMsr2105065 Turley P, Meyer MN, Wang N, Cesarini D, Hammonds E, Martin AR, Neale BM, Rehm HL, Wilkins-Haug L, Benjamin DJ, Hyman S, Laibson D, Visscher PM. 2021. Problems with Using Polygenic Scores to Select Embryos. The New England journal of medicine. 385(1):78-86. Pubmed: 34192436 DOI:10.1056/NEJMsr2105065 Companies have recently begun to sell a new service to patients considering in vitro fertilization: embryo selection based on polygenic scores (ESPS). These scores represent individualized predictions of health and other outcomes derived from genomewide association studies in adults to partially predict these outcomes. This article includes a discussion of many factors that lower the predictive power of polygenic scores in the context of embryo selection and quantifies these effects for a variety of clinical and nonclinical traits. Also discussed are potential unintended consequences of ESPS (including selecting for adverse traits, altering population demographics, exacerbating inequalities in society, and devaluing certain traits). Recommendations for the responsible communication about ESPS by practitioners are provided, and a call for a society-wide conversation about this technology is made. (Funded by the National Institute on Aging and others.).Copyright © 2021 Massachusetts Medical Society.
All Publications
2024
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Hyman SE. 2024. Philosophy of psychiatry can gain greater vitality by engaging the implications of new science. World psychiatry : official journal of the World Psychiatric Association (WPA). 23(2):235-237. Pubmed: 38727055 DOI:10.1002/wps.21197 Hyman SE. 2024. Philosophy of psychiatry can gain greater vitality by engaging the implications of new science. World psychiatry : official journal of the World Psychiatric Association (WPA). 23(2):235-237. Pubmed: 38727055 DOI:10.1002/wps.21197 2023
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Krainc D, Martin WJ, Casey B, Jensen FE, Tishkoff S, Potter WZ, Hyman SE. 2023. Shifting the trajectory of therapeutic development for neurological and psychiatric disorders. Science translational medicine. 15(720):eadg4775. Pubmed: 38190501 DOI:10.1126/scitranslmed.adg4775 Krainc D, Martin WJ, Casey B, Jensen FE, Tishkoff S, Potter WZ, Hyman SE. 2023. Shifting the trajectory of therapeutic development for neurological and psychiatric disorders. Science translational medicine. 15(720):eadg4775. Pubmed: 38190501 DOI:10.1126/scitranslmed.adg4775 Clinical trials for central nervous system disorders often enroll patients with unrecognized heterogeneous diseases, leading to costly trials that have high failure rates. Here, we discuss the potential of emerging technologies and datasets to elucidate disease mechanisms and identify biomarkers to improve patient stratification and monitoring of disease progression in clinical trials for neuropsychiatric disorders. Greater efforts must be centered on rigorously standardizing data collection and sharing of methods, datasets, and analytical tools across sectors. To address health care disparities in clinical trials, diversity of genetic ancestries and environmental exposures of research participants and associated biological samples must be prioritized. -
Lähteenvuo M, Ahola-Olli A, Suokas K, Holm M, Misiewicz Z, Jukuri T, Männynsalo T, Wegelius A, Haaki W, Kajanne R, Kyttälä A, Tuulio-Henriksson A, Lahdensuo K, Häkkinen K, Hietala J, Paunio T, Niemi-Pynttäri J, Kieseppä T, Veijola J, Lönnqvist J, Isometsä E, Kampman O, Tiihonen J, Hyman S, Neale B, Daly M, Suvisaari J, Palotie A. 2023. Cohort profile: SUPER-Finland - the Finnish study for hereditary mechanisms of psychotic disorders. BMJ open. 13(4):e070710. Pubmed: 37045567 DOI:10.1136/bmjopen-2022-070710 Lähteenvuo M, Ahola-Olli A, Suokas K, Holm M, Misiewicz Z, Jukuri T, Männynsalo T, Wegelius A, Haaki W, Kajanne R, Kyttälä A, Tuulio-Henriksson A, Lahdensuo K, Häkkinen K, Hietala J, Paunio T, Niemi-Pynttäri J, Kieseppä T, Veijola J, Lönnqvist J, Isometsä E, Kampman O, Tiihonen J, Hyman S, Neale B, Daly M, Suvisaari J, Palotie A. 2023. Cohort profile: SUPER-Finland - the Finnish study for hereditary mechanisms of psychotic disorders. BMJ open. 13(4):e070710. Pubmed: 37045567 DOI:10.1136/bmjopen-2022-070710 Array© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. 2022
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Kotov R, Cicero DC, Conway CC, DeYoung CG, Dombrovski A, Eaton NR, First MB, Forbes MK, Hyman SE, Jonas KG, Krueger RF, Latzman RD, Li JJ, Nelson BD, Regier DA, Rodriguez-Seijas C, Ruggero CJ, Simms LJ, Skodol AE, Waldman ID, Waszczuk MA, Watson D, Widiger TA, Wilson S, Wright AGC. 2022. The Hierarchical Taxonomy of Psychopathology (HiTOP) in psychiatric practice and research. Psychological medicine. 52(9):1666-1678. Pubmed: 35650658 DOI:10.1017/S0033291722001301 Kotov R, Cicero DC, Conway CC, DeYoung CG, Dombrovski A, Eaton NR, First MB, Forbes MK, Hyman SE, Jonas KG, Krueger RF, Latzman RD, Li JJ, Nelson BD, Regier DA, Rodriguez-Seijas C, Ruggero CJ, Simms LJ, Skodol AE, Waldman ID, Waszczuk MA, Watson D, Widiger TA, Wilson S, Wright AGC. 2022. The Hierarchical Taxonomy of Psychopathology (HiTOP) in psychiatric practice and research. Psychological medicine. 52(9):1666-1678. Pubmed: 35650658 DOI:10.1017/S0033291722001301 The Hierarchical Taxonomy of Psychopathology (HiTOP) has emerged out of the quantitative approach to psychiatric nosology. This approach identifies psychopathology constructs based on patterns of co-variation among signs and symptoms. The initial HiTOP model, which was published in 2017, is based on a large literature that spans decades of research. HiTOP is a living model that undergoes revision as new data become available. Here we discuss advantages and practical considerations of using this system in psychiatric practice and research. We especially highlight limitations of HiTOP and ongoing efforts to address them. We describe differences and similarities between HiTOP and existing diagnostic systems. Next, we review the types of evidence that informed development of HiTOP, including populations in which it has been studied and data on its validity. The paper also describes how HiTOP can facilitate research on genetic and environmental causes of psychopathology as well as the search for neurobiologic mechanisms and novel treatments. Furthermore, we consider implications for public health programs and prevention of mental disorders. We also review data on clinical utility and illustrate clinical application of HiTOP. Importantly, the model is based on measures and practices that are already used widely in clinical settings. HiTOP offers a way to organize and formalize these techniques. This model already can contribute to progress in psychiatry and complement traditional nosologies. Moreover, HiTOP seeks to facilitate research on linkages between phenotypes and biological processes, which may enable construction of a system that encompasses both biomarkers and precise clinical description. -
Trubetskoy V, Pardiñas AF, Qi T, Panagiotaropoulou G, Awasthi S, Bigdeli TB, Bryois J, Chen CY, Dennison CA, Hall LS, Lam M, Watanabe K, Frei O, Ge T, Harwood JC, Koopmans F, Magnusson S, Richards AL, Sidorenko J, Wu Y, Zeng J, Grove J, Kim M, Li Z, Voloudakis G, Zhang W, Adams M, Agartz I, Atkinson EG, Agerbo E, Al Eissa M, Albus M, Alexander M, Alizadeh BZ, Alptekin K, Als TD, Amin F, Arolt V, Arrojo M, Athanasiu L, Azevedo MH, Bacanu SA, Bass NJ, Begemann M, Belliveau RA, Bene J, Benyamin B, Bergen SE, Blasi G, Bobes J, Bonassi S, Braun A, Bressan RA, Bromet EJ, Bruggeman R, Buckley PF, Buckner RL, Bybjerg-Grauholm J, Cahn W, Cairns MJ, Calkins ME, Carr VJ, Castle D, Catts SV, Chambert KD, Chan RCK, Chaumette B, Cheng W, Cheung EFC, Chong SA, Cohen D, Consoli A, Cordeiro Q, Costas J, Curtis C, Davidson M, Davis KL, de Haan L, Degenhardt F, DeLisi LE, Demontis D, Dickerson F, Dikeos D, Dinan T, Djurovic S, Duan J, Ducci G, Dudbridge F, Eriksson JG, Fañanás L, Faraone SV, Fiorentino A, Forstner A, Frank J, Freimer NB, Fromer M, Frustaci A, Gadelha A, Genovese G, Gershon ES, Giannitelli M, Giegling I, Giusti-Rodríguez P, Godard S, Goldstein JI, González Peñas J, González-Pinto A, Gopal S, Gratten J, Green MF, Greenwood TA, Guillin O, Gülöksüz S, Gur RE, Gur RC, Gutiérrez B, Hahn E, Hakonarson H, Haroutunian V, Hartmann AM, Harvey C, Hayward C, Henskens FA, Herms S, Hoffmann P, Howrigan DP, Ikeda M, Iyegbe C, Joa I, Julià A, Kähler AK, Kam-Thong T, Kamatani Y, Karachanak-Yankova S, Kebir O, Keller MC, Kelly BJ, Khrunin A, Kim SW, Klovins J, Kondratiev N, Konte B, Kraft J, Kubo M, Kučinskas V, Kučinskiene ZA, Kusumawardhani A, Kuzelova-Ptackova H, Landi S, Lazzeroni LC, Lee PH, Legge SE, Lehrer DS, Lencer R, Lerer B, Li M, Lieberman J, Light GA, Limborska S, Liu CM, Lönnqvist J, Loughland CM, Lubinski J, Luykx JJ, Lynham A, Macek M, Mackinnon A, Magnusson PKE, Maher BS, Maier W, Malaspina D, Mallet J, Marder SR, Marsal S, Martin AR, Martorell L, Mattheisen M, McCarley RW, McDonald C, McGrath JJ, Medeiros H, Meier S, Melegh B, Melle I, Mesholam-Gately RI, Metspalu A, Michie PT, Milani L, Milanova V, Mitjans M, Molden E, Molina E, Molto MD, Mondelli V, Moreno C, Morley CP, Muntané G, Murphy KC, Myin-Germeys I, Nenadić I, Nestadt G, Nikitina-Zake L, Noto C, Nuechterlein KH, O'Brien NL, O'Neill FA, Oh SY, Olincy A, Ota VK, Pantelis C, Papadimitriou GN, Parellada M, Paunio T, Pellegrino R, Periyasamy S, Perkins DO, Pfuhlmann B, Pietiläinen O, Pimm J, Porteous D, Powell J, Quattrone D, Quested D, Radant AD, Rampino A, Rapaport MH, Rautanen A, Reichenberg A, Roe C, Roffman JL, Roth J, Rothermundt M, Rutten BPF, Saker-Delye S, Salomaa V, Sanjuan J, Santoro ML, Savitz A, Schall U, Scott RJ, Seidman LJ, Sharp SI, Shi J, Siever LJ, Sigurdsson E, Sim K, Skarabis N, Slominsky P, So HC, Sobell JL, Söderman E, Stain HJ, Steen NE, Steixner-Kumar AA, Stögmann E, Stone WS, Straub RE, Streit F, Strengman E, Stroup TS, Subramaniam M, Sugar CA, Suvisaari J, Svrakic DM, Swerdlow NR, Szatkiewicz JP, Ta TMT, Takahashi A, Terao C, Thibaut F, Toncheva D, Tooney PA, Torretta S, Tosato S, Tura GB, Turetsky BI, Üçok A, Vaaler A, van Amelsvoort T, van Winkel R, Veijola J, Waddington J, Walter H, Waterreus A, Webb BT, Weiser M, Williams NM, Witt SH, Wormley BK, Wu JQ, Xu Z, Yolken R, Zai CC, Zhou W, Zhu F, Zimprich F, Atbaşoğlu EC, Ayub M, Benner C, Bertolino A, Black DW, Bray NJ, Breen G, Buccola NG, Byerley WF, Chen WJ, Cloninger CR, Crespo-Facorro B, Donohoe G, Freedman R, Galletly C, Gandal MJ, Gennarelli M, Hougaard DM, Hwu HG, Jablensky AV, McCarroll SA, Moran JL, Mors O, Mortensen PB, Müller-Myhsok B, Neil AL, Nordentoft M, Pato MT, Petryshen TL, Pirinen M, Pulver AE, Schulze TG, Silverman JM, Smoller JW, Stahl EA, Tsuang DW, Vilella E, Wang SH, Xu S, Adolfsson R, Arango C, Baune BT, Belangero SI, Børglum AD, Braff D, Bramon E, Buxbaum JD, Campion D, Cervilla JA, Cichon S, Collier DA, Corvin A, Curtis D, Forti MD, Domenici E, Ehrenreich H, Escott-Price V, Esko T, Fanous AH, Gareeva A, Gawlik M, Gejman PV, Gill M, Glatt SJ, Golimbet V, Hong KS, Hultman CM, Hyman SE, Iwata N, Jönsson EG, Kahn RS, Kennedy JL, Khusnutdinova E, Kirov G, Knowles JA, Krebs MO, Laurent-Levinson C, Lee J, Lencz T, Levinson DF, Li QS, Liu J, Malhotra AK, Malhotra D, McIntosh A, McQuillin A, Menezes PR, Morgan VA, Morris DW, Mowry BJ, Murray RM, Nimgaonkar V, Nöthen MM, Ophoff RA, Paciga SA, Palotie A, Pato CN, Qin S, Rietschel M, Riley BP, Rivera M, Rujescu D, Saka MC, Sanders AR, Schwab SG, Serretti A, Sham PC, Shi Y, St Clair D, Stefánsson H, Stefansson K, Tsuang MT, van Os J, Vawter MP, Weinberger DR, Werge T, Wildenauer DB, Yu X, Yue W, Holmans PA, Pocklington AJ, Roussos P, Vassos E, Verhage M, Visscher PM, Yang J, Posthuma D, Andreassen OA, Kendler KS, Owen MJ, Wray NR, Daly MJ, Huang H, Neale BM, Sullivan PF, Ripke S, Walters JTR, O'Donovan MC. 2022. Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature. 604(7906):502-508. Pubmed: 35396580 DOI:10.1038/s41586-022-04434-5 Trubetskoy V, Pardiñas AF, Qi T, Panagiotaropoulou G, Awasthi S, Bigdeli TB, Bryois J, Chen CY, Dennison CA, Hall LS, Lam M, Watanabe K, Frei O, Ge T, Harwood JC, Koopmans F, Magnusson S, Richards AL, Sidorenko J, Wu Y, Zeng J, Grove J, Kim M, Li Z, Voloudakis G, Zhang W, Adams M, Agartz I, Atkinson EG, Agerbo E, Al Eissa M, Albus M, Alexander M, Alizadeh BZ, Alptekin K, Als TD, Amin F, Arolt V, Arrojo M, Athanasiu L, Azevedo MH, Bacanu SA, Bass NJ, Begemann M, Belliveau RA, Bene J, Benyamin B, Bergen SE, Blasi G, Bobes J, Bonassi S, Braun A, Bressan RA, Bromet EJ, Bruggeman R, Buckley PF, Buckner RL, Bybjerg-Grauholm J, Cahn W, Cairns MJ, Calkins ME, Carr VJ, Castle D, Catts SV, Chambert KD, Chan RCK, Chaumette B, Cheng W, Cheung EFC, Chong SA, Cohen D, Consoli A, Cordeiro Q, Costas J, Curtis C, Davidson M, Davis KL, de Haan L, Degenhardt F, DeLisi LE, Demontis D, Dickerson F, Dikeos D, Dinan T, Djurovic S, Duan J, Ducci G, Dudbridge F, Eriksson JG, Fañanás L, Faraone SV, Fiorentino A, Forstner A, Frank J, Freimer NB, Fromer M, Frustaci A, Gadelha A, Genovese G, Gershon ES, Giannitelli M, Giegling I, Giusti-Rodríguez P, Godard S, Goldstein JI, González Peñas J, González-Pinto A, Gopal S, Gratten J, Green MF, Greenwood TA, Guillin O, Gülöksüz S, Gur RE, Gur RC, Gutiérrez B, Hahn E, Hakonarson H, Haroutunian V, Hartmann AM, Harvey C, Hayward C, Henskens FA, Herms S, Hoffmann P, Howrigan DP, Ikeda M, Iyegbe C, Joa I, Julià A, Kähler AK, Kam-Thong T, Kamatani Y, Karachanak-Yankova S, Kebir O, Keller MC, Kelly BJ, Khrunin A, Kim SW, Klovins J, Kondratiev N, Konte B, Kraft J, Kubo M, Kučinskas V, Kučinskiene ZA, Kusumawardhani A, Kuzelova-Ptackova H, Landi S, Lazzeroni LC, Lee PH, Legge SE, Lehrer DS, Lencer R, Lerer B, Li M, Lieberman J, Light GA, Limborska S, Liu CM, Lönnqvist J, Loughland CM, Lubinski J, Luykx JJ, Lynham A, Macek M, Mackinnon A, Magnusson PKE, Maher BS, Maier W, Malaspina D, Mallet J, Marder SR, Marsal S, Martin AR, Martorell L, Mattheisen M, McCarley RW, McDonald C, McGrath JJ, Medeiros H, Meier S, Melegh B, Melle I, Mesholam-Gately RI, Metspalu A, Michie PT, Milani L, Milanova V, Mitjans M, Molden E, Molina E, Molto MD, Mondelli V, Moreno C, Morley CP, Muntané G, Murphy KC, Myin-Germeys I, Nenadić I, Nestadt G, Nikitina-Zake L, Noto C, Nuechterlein KH, O'Brien NL, O'Neill FA, Oh SY, Olincy A, Ota VK, Pantelis C, Papadimitriou GN, Parellada M, Paunio T, Pellegrino R, Periyasamy S, Perkins DO, Pfuhlmann B, Pietiläinen O, Pimm J, Porteous D, Powell J, Quattrone D, Quested D, Radant AD, Rampino A, Rapaport MH, Rautanen A, Reichenberg A, Roe C, Roffman JL, Roth J, Rothermundt M, Rutten BPF, Saker-Delye S, Salomaa V, Sanjuan J, Santoro ML, Savitz A, Schall U, Scott RJ, Seidman LJ, Sharp SI, Shi J, Siever LJ, Sigurdsson E, Sim K, Skarabis N, Slominsky P, So HC, Sobell JL, Söderman E, Stain HJ, Steen NE, Steixner-Kumar AA, Stögmann E, Stone WS, Straub RE, Streit F, Strengman E, Stroup TS, Subramaniam M, Sugar CA, Suvisaari J, Svrakic DM, Swerdlow NR, Szatkiewicz JP, Ta TMT, Takahashi A, Terao C, Thibaut F, Toncheva D, Tooney PA, Torretta S, Tosato S, Tura GB, Turetsky BI, Üçok A, Vaaler A, van Amelsvoort T, van Winkel R, Veijola J, Waddington J, Walter H, Waterreus A, Webb BT, Weiser M, Williams NM, Witt SH, Wormley BK, Wu JQ, Xu Z, Yolken R, Zai CC, Zhou W, Zhu F, Zimprich F, Atbaşoğlu EC, Ayub M, Benner C, Bertolino A, Black DW, Bray NJ, Breen G, Buccola NG, Byerley WF, Chen WJ, Cloninger CR, Crespo-Facorro B, Donohoe G, Freedman R, Galletly C, Gandal MJ, Gennarelli M, Hougaard DM, Hwu HG, Jablensky AV, McCarroll SA, Moran JL, Mors O, Mortensen PB, Müller-Myhsok B, Neil AL, Nordentoft M, Pato MT, Petryshen TL, Pirinen M, Pulver AE, Schulze TG, Silverman JM, Smoller JW, Stahl EA, Tsuang DW, Vilella E, Wang SH, Xu S, Adolfsson R, Arango C, Baune BT, Belangero SI, Børglum AD, Braff D, Bramon E, Buxbaum JD, Campion D, Cervilla JA, Cichon S, Collier DA, Corvin A, Curtis D, Forti MD, Domenici E, Ehrenreich H, Escott-Price V, Esko T, Fanous AH, Gareeva A, Gawlik M, Gejman PV, Gill M, Glatt SJ, Golimbet V, Hong KS, Hultman CM, Hyman SE, Iwata N, Jönsson EG, Kahn RS, Kennedy JL, Khusnutdinova E, Kirov G, Knowles JA, Krebs MO, Laurent-Levinson C, Lee J, Lencz T, Levinson DF, Li QS, Liu J, Malhotra AK, Malhotra D, McIntosh A, McQuillin A, Menezes PR, Morgan VA, Morris DW, Mowry BJ, Murray RM, Nimgaonkar V, Nöthen MM, Ophoff RA, Paciga SA, Palotie A, Pato CN, Qin S, Rietschel M, Riley BP, Rivera M, Rujescu D, Saka MC, Sanders AR, Schwab SG, Serretti A, Sham PC, Shi Y, St Clair D, Stefánsson H, Stefansson K, Tsuang MT, van Os J, Vawter MP, Weinberger DR, Werge T, Wildenauer DB, Yu X, Yue W, Holmans PA, Pocklington AJ, Roussos P, Vassos E, Verhage M, Visscher PM, Yang J, Posthuma D, Andreassen OA, Kendler KS, Owen MJ, Wray NR, Daly MJ, Huang H, Neale BM, Sullivan PF, Ripke S, Walters JTR, O'Donovan MC. 2022. Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature. 604(7906):502-508. Pubmed: 35396580 DOI:10.1038/s41586-022-04434-5 Schizophrenia has a heritability of 60-80%, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.© 2022. The Author(s), under exclusive licence to Springer Nature Limited. -
Johnson MB, Hyman SE. 2022. A Critical Perspective on the Synaptic Pruning Hypothesis of Schizophrenia Pathogenesis. Biological psychiatry. 92(6):440-442. Pubmed: 35105471 DOI:S0006-3223(21)01873-4 Johnson MB, Hyman SE. 2022. A Critical Perspective on the Synaptic Pruning Hypothesis of Schizophrenia Pathogenesis. Biological psychiatry. 92(6):440-442. Pubmed: 35105471 DOI:S0006-3223(21)01873-4 -
Nehme R, Pietiläinen O, Artomov M, Tegtmeyer M, Valakh V, Lehtonen L, Bell C, Singh T, Trehan A, Sherwood J, Manning D, Peirent E, Malik R, Guss EJ, Hawes D, Beccard A, Bara AM, Hazelbaker DZ, Zuccaro E, Genovese G, Loboda AA, Neumann A, Lilliehook C, Kuismin O, Hamalainen E, Kurki M, Hultman CM, Kähler AK, Paulo JA, Ganna A, Madison J, Cohen B, McPhie D, Adolfsson R, Perlis R, Dolmetsch R, Farhi S, McCarroll S, Hyman S, Neale B, Barrett LE, Harper W, Palotie A, Daly M, Eggan K. 2022. The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia. Nature communications. 13(1):3690. Pubmed: 35760976 DOI:10.1038/s41467-022-31436-8 Nehme R, Pietiläinen O, Artomov M, Tegtmeyer M, Valakh V, Lehtonen L, Bell C, Singh T, Trehan A, Sherwood J, Manning D, Peirent E, Malik R, Guss EJ, Hawes D, Beccard A, Bara AM, Hazelbaker DZ, Zuccaro E, Genovese G, Loboda AA, Neumann A, Lilliehook C, Kuismin O, Hamalainen E, Kurki M, Hultman CM, Kähler AK, Paulo JA, Ganna A, Madison J, Cohen B, McPhie D, Adolfsson R, Perlis R, Dolmetsch R, Farhi S, McCarroll S, Hyman S, Neale B, Barrett LE, Harper W, Palotie A, Daly M, Eggan K. 2022. The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia. Nature communications. 13(1):3690. Pubmed: 35760976 DOI:10.1038/s41467-022-31436-8 It is unclear how the 22q11.2 deletion predisposes to psychiatric disease. To study this, we generated induced pluripotent stem cells from deletion carriers and controls and utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Here, we show that upon differentiation into neural progenitor cells, the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including autism. In excitatory neurons, altered transcripts encoded presynaptic factors and were associated with genetic risk for schizophrenia, including common and rare variants. To understand how the deletion contributed to these changes, we defined the minimal protein-protein interaction network that best explains gene expression alterations. We found that many genes in 22q11.2 interact in presynaptic, proteasome, and JUN/FOS transcriptional pathways. Our findings suggest that the 22q11.2 deletion impacts genes that may converge with psychiatric risk loci to influence disease manifestation in each deletion carrier.© 2022. The Author(s). 2021
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Hyman SE. 2021. Wringing Biological Insight From Polygenic Signals. Biological psychiatry. 89(1):8-10. Pubmed: 33272363 DOI:S0006-3223(20)31845-X Hyman SE. 2021. Wringing Biological Insight From Polygenic Signals. Biological psychiatry. 89(1):8-10. Pubmed: 33272363 DOI:S0006-3223(20)31845-X -
Hyman SE. 2021. PANDAS: Too Narrow a View of the Neuroimmune Landscape. The American journal of psychiatry. 178(1):5-7. Pubmed: 33384008 DOI:10.1176/appi.ajp.2020.20111598 Hyman SE. 2021. PANDAS: Too Narrow a View of the Neuroimmune Landscape. The American journal of psychiatry. 178(1):5-7. Pubmed: 33384008 DOI:10.1176/appi.ajp.2020.20111598 -
Hyman SE. 2021. Use of mouse models to investigate the contributions of CNVs associated with schizophrenia and autism to disease mechanisms. Current opinion in genetics & development. 68:99-105. Pubmed: 33957550 DOI:S0959-437X(21)00046-0 Hyman SE. 2021. Use of mouse models to investigate the contributions of CNVs associated with schizophrenia and autism to disease mechanisms. Current opinion in genetics & development. 68:99-105. Pubmed: 33957550 DOI:S0959-437X(21)00046-0 Human genetics is providing much needed clues to mechanisms underlying neuropsychiatric disorders. Highly penetrant copy number variants (CNVs) were among the first genetic variants confidently associated with schizophrenia and autism spectrum disorders (ASDs). Despite their structural complexity, the high penetrance of CNVs associated with neuropsychiatric disorders suggested utility for construction of cellular and animal models. Human cellular models that carry disease associated alleles have the advantage of human genetic backgrounds against which to study the effects of CNVs. However, investigation of the effects of disease-associated alleles on the structure and function of living brains requires genome engineering of model organisms or introduction of genetic material into their brains by viral vectors. Here I focus on the translational utility of transgenic mice that carry models of human neuropsychiatric CNVs, while recognizing their limitations as veridical models of complex human brain disorders. In order to improve translational utility and avoid the intellectual cul-de-sacs that often bedevil interpretation of neuropsychiatric disease models, I conclude with a 'draft' proposal to replace current concepts of construct and face validity with more nuanced and contextually relevant judgments.Copyright © 2021 The Author. Published by Elsevier Ltd.. All rights reserved. -
Hyman SE. 2021. The familiar dialectic between overclaiming and moral outrage over brain biology: disconnected from what matters. Psychological medicine. 51(16):2776-2777. Pubmed: 34399865 DOI:10.1017/S0033291721003184 Hyman SE. 2021. The familiar dialectic between overclaiming and moral outrage over brain biology: disconnected from what matters. Psychological medicine. 51(16):2776-2777. Pubmed: 34399865 DOI:10.1017/S0033291721003184 -
Hyman, SE. 2021. Psychiatric disorders: Grounded in human biology but not natural kinds. Perspectives in Biology and Medicine. 64(1):6-28. DOI:10.1353/pbm.2021.0002 Hyman, SE. 2021. Psychiatric disorders: Grounded in human biology but not natural kinds. Perspectives in Biology and Medicine. 64(1):6-28. DOI:10.1353/pbm.2021.0002 The third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III) and its descriptive psychiatry-based intellectual antecedents imagined psychiatric disorders as discontinuous categories, presumably natural kinds, that would be empirically validated based on future scientific studies. Validation would emerge from a predicted convergence of clinical descriptions (symptom clusters that could be shown to be stable over the lifespan), laboratory results, and family studies. That future science is now arriving, but rather than validating the categorical DSM approach, large-scale genetics along with modern neurobiology and epidemiology have emphatically undercut it. Clinical description, laboratory studies, and family (now genetic) studies do not converge at all on distinct categories. Rather, modern studies are consistent with psychiatric disorders as heterogeneous quantitative deviations from health. The characteristics of these disorders have proven to be discoverable rather than invented and thus are grounded in nature. However, scientific results demonstrate that psychiatric disorders cannot reasonably be understood as discrete categories-and certainly not as natural kinds. -
Turley P, Meyer MN, Wang N, Cesarini D, Hammonds E, Martin AR, Neale BM, Rehm HL, Wilkins-Haug L, Benjamin DJ, Hyman S, Laibson D, Visscher PM. 2021. Problems with Using Polygenic Scores to Select Embryos. The New England journal of medicine. 385(1):78-86. Pubmed: 34192436 DOI:10.1056/NEJMsr2105065 Turley P, Meyer MN, Wang N, Cesarini D, Hammonds E, Martin AR, Neale BM, Rehm HL, Wilkins-Haug L, Benjamin DJ, Hyman S, Laibson D, Visscher PM. 2021. Problems with Using Polygenic Scores to Select Embryos. The New England journal of medicine. 385(1):78-86. Pubmed: 34192436 DOI:10.1056/NEJMsr2105065 Companies have recently begun to sell a new service to patients considering in vitro fertilization: embryo selection based on polygenic scores (ESPS). These scores represent individualized predictions of health and other outcomes derived from genomewide association studies in adults to partially predict these outcomes. This article includes a discussion of many factors that lower the predictive power of polygenic scores in the context of embryo selection and quantifies these effects for a variety of clinical and nonclinical traits. Also discussed are potential unintended consequences of ESPS (including selecting for adverse traits, altering population demographics, exacerbating inequalities in society, and devaluing certain traits). Recommendations for the responsible communication about ESPS by practitioners are provided, and a call for a society-wide conversation about this technology is made. (Funded by the National Institute on Aging and others.).Copyright © 2021 Massachusetts Medical Society. 2020
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Waszczuk MA, Eaton NR, Krueger RF, Shackman AJ, Waldman ID, Zald DH, Lahey BB, Patrick CJ, Conway CC, Ormel J, Hyman SE, Fried EI, Forbes MK, Docherty AR, Althoff RR, Bach B, Chmielewski M, DeYoung CG, Forbush KT, Hallquist M, Hopwood CJ, Ivanova MY, Jonas KG, Latzman RD, Markon KE, Mullins-Sweatt SN, Pincus AL, Reininghaus U, South SC, Tackett JL, Watson D, Wright AGC, Kotov R. 2020. Redefining phenotypes to advance psychiatric genetics: Implications from hierarchical taxonomy of psychopathology. Journal of abnormal psychology. 129(2):143-161. Pubmed: 31804095 DOI:10.1037/abn0000486 Waszczuk MA, Eaton NR, Krueger RF, Shackman AJ, Waldman ID, Zald DH, Lahey BB, Patrick CJ, Conway CC, Ormel J, Hyman SE, Fried EI, Forbes MK, Docherty AR, Althoff RR, Bach B, Chmielewski M, DeYoung CG, Forbush KT, Hallquist M, Hopwood CJ, Ivanova MY, Jonas KG, Latzman RD, Markon KE, Mullins-Sweatt SN, Pincus AL, Reininghaus U, South SC, Tackett JL, Watson D, Wright AGC, Kotov R. 2020. Redefining phenotypes to advance psychiatric genetics: Implications from hierarchical taxonomy of psychopathology. Journal of abnormal psychology. 129(2):143-161. Pubmed: 31804095 DOI:10.1037/abn0000486 Genetic discovery in psychiatry and clinical psychology is hindered by suboptimal phenotypic definitions. We argue that the hierarchical, dimensional, and data-driven classification system proposed by the Hierarchical Taxonomy of Psychopathology (HiTOP) consortium provides a more effective approach to identifying genes that underlie mental disorders, and to studying psychiatric etiology, than current diagnostic categories. Specifically, genes are expected to operate at different levels of the HiTOP hierarchy, with some highly pleiotropic genes influencing higher order psychopathology (e.g., the general factor), whereas other genes conferring more specific risk for individual spectra (e.g., internalizing), subfactors (e.g., fear disorders), or narrow symptoms (e.g., mood instability). We propose that the HiTOP model aligns well with the current understanding of the higher order genetic structure of psychopathology that has emerged from a large body of family and twin studies. We also discuss the convergence between the HiTOP model and findings from recent molecular studies of psychopathology indicating broad genetic pleiotropy, such as cross-disorder SNP-based shared genetic covariance and polygenic risk scores, and we highlight molecular genetic studies that have successfully redefined phenotypes to enhance precision and statistical power. Finally, we suggest how to integrate a HiTOP approach into future molecular genetic research, including quantitative and hierarchical assessment tools for future data-collection and recommendations concerning phenotypic analyses. (PsycINFO Database Record (c) 2020 APA, all rights reserved). -
Cline H, Coolen L, de Vries S, Hyman S, Segal R, Steward O. 2020. Recognizing Team Science Contributions in Academic Hiring, Promotion, and Tenure. The Journal of neuroscience : the official journal of the Society for Neuroscience. 40(35):6662-6663. Pubmed: 32847999 DOI:10.1523/JNEUROSCI.1139-20.2020 Cline H, Coolen L, de Vries S, Hyman S, Segal R, Steward O. 2020. Recognizing Team Science Contributions in Academic Hiring, Promotion, and Tenure. The Journal of neuroscience : the official journal of the Society for Neuroscience. 40(35):6662-6663. Pubmed: 32847999 DOI:10.1523/JNEUROSCI.1139-20.2020 2019
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Ramos KM, Grady C, Greely HT, Chiong W, Eberwine J, Farahany NA, Johnson LSM, Hyman BT, Hyman SE, Rommelfanger KS, Serrano EE, Churchill JD, Gordon JA, Koroshetz WJ. 2019. The NIH BRAIN Initiative: Integrating Neuroethics and Neuroscience. Neuron. 101(3):394-398. Pubmed: 30731065 DOI:S0896-6273(19)30051-0 Ramos KM, Grady C, Greely HT, Chiong W, Eberwine J, Farahany NA, Johnson LSM, Hyman BT, Hyman SE, Rommelfanger KS, Serrano EE, Churchill JD, Gordon JA, Koroshetz WJ. 2019. The NIH BRAIN Initiative: Integrating Neuroethics and Neuroscience. Neuron. 101(3):394-398. Pubmed: 30731065 DOI:S0896-6273(19)30051-0 The NIH Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative is focused on developing new tools and neurotechnologies to transform our understanding of the brain, and neuroethics is an essential component of this research effort. Coordination with other brain projects around the world will help maximize success.Published by Elsevier Inc. -
Hyman SE. 2019. New Evidence for Shared Risk Architecture of Mental Disorders. JAMA psychiatry. 76(3):235-236. Pubmed: 30649144 DOI:10.1001/jamapsychiatry.2018.4269 Hyman SE. 2019. New Evidence for Shared Risk Architecture of Mental Disorders. JAMA psychiatry. 76(3):235-236. Pubmed: 30649144 DOI:10.1001/jamapsychiatry.2018.4269 -
Reed GM, First MB, Kogan CS, Hyman SE, Gureje O, Gaebel W, Maj M, Stein DJ, Maercker A, Tyrer P, Claudino A, Garralda E, Salvador-Carulla L, Ray R, Saunders JB, Dua T, Poznyak V, Medina-Mora ME, Pike KM, Ayuso-Mateos JL, Kanba S, Keeley JW, Khoury B, Krasnov VN, Kulygina M, Lovell AM, de Jesus Mari J, Maruta T, Matsumoto C, Rebello TJ, Roberts MC, Robles R, Sharan P, Zhao M, Jablensky A, Udomratn P, Rahimi-Movaghar A, Rydelius PA, Bährer-Kohler S, Watts AD, Saxena S. 2019. Innovations and changes in the ICD-11 classification of mental, behavioural and neurodevelopmental disorders. World psychiatry : official journal of the World Psychiatric Association (WPA). 18(1):3-19. Pubmed: 30600616 DOI:10.1002/wps.20611 Reed GM, First MB, Kogan CS, Hyman SE, Gureje O, Gaebel W, Maj M, Stein DJ, Maercker A, Tyrer P, Claudino A, Garralda E, Salvador-Carulla L, Ray R, Saunders JB, Dua T, Poznyak V, Medina-Mora ME, Pike KM, Ayuso-Mateos JL, Kanba S, Keeley JW, Khoury B, Krasnov VN, Kulygina M, Lovell AM, de Jesus Mari J, Maruta T, Matsumoto C, Rebello TJ, Roberts MC, Robles R, Sharan P, Zhao M, Jablensky A, Udomratn P, Rahimi-Movaghar A, Rydelius PA, Bährer-Kohler S, Watts AD, Saxena S. 2019. Innovations and changes in the ICD-11 classification of mental, behavioural and neurodevelopmental disorders. World psychiatry : official journal of the World Psychiatric Association (WPA). 18(1):3-19. Pubmed: 30600616 DOI:10.1002/wps.20611 Following approval of the ICD-11 by the World Health Assembly in May 2019, World Health Organization (WHO) member states will transition from the ICD-10 to the ICD-11, with reporting of health statistics based on the new system to begin on January 1, 2022. The WHO Department of Mental Health and Substance Abuse will publish Clinical Descriptions and Diagnostic Guidelines (CDDG) for ICD-11 Mental, Behavioural and Neurodevelopmental Disorders following ICD-11's approval. The development of the ICD-11 CDDG over the past decade, based on the principles of clinical utility and global applicability, has been the most broadly international, multilingual, multidisciplinary and participative revision process ever implemented for a classification of mental disorders. Innovations in the ICD-11 include the provision of consistent and systematically characterized information, the adoption of a lifespan approach, and culture-related guidance for each disorder. Dimensional approaches have been incorporated into the classification, particularly for personality disorders and primary psychotic disorders, in ways that are consistent with current evidence, are more compatible with recovery-based approaches, eliminate artificial comorbidity, and more effectively capture changes over time. Here we describe major changes to the structure of the ICD-11 classification of mental disorders as compared to the ICD-10, and the development of two new ICD-11 chapters relevant to mental health practice. We illustrate a set of new categories that have been added to the ICD-11 and present the rationale for their inclusion. Finally, we provide a description of the important changes that have been made in each ICD-11 disorder grouping. This information is intended to be useful for both clinicians and researchers in orienting themselves to the ICD-11 and in preparing for implementation in their own professional contexts.© 2019 World Psychiatric Association. -
Martin AR, Daly MJ, Robinson EB, Hyman SE, Neale BM. 2019. Predicting Polygenic Risk of Psychiatric Disorders. Biological psychiatry. 86(2):97-109. Pubmed: 30737014 DOI:S0006-3223(18)32119-X Martin AR, Daly MJ, Robinson EB, Hyman SE, Neale BM. 2019. Predicting Polygenic Risk of Psychiatric Disorders. Biological psychiatry. 86(2):97-109. Pubmed: 30737014 DOI:S0006-3223(18)32119-X Genetics provides two major opportunities for understanding human disease-as a transformative line of etiological inquiry and as a biomarker for heritable diseases. In psychiatry, biomarkers are very much needed for both research and treatment, given the heterogenous populations identified by current phenomenologically based diagnostic systems. To date, however, useful and valid biomarkers have been scant owing to the inaccessibility and complexity of human brain tissue and consequent lack of insight into disease mechanisms. Genetic biomarkers are therefore especially promising for psychiatric disorders. Genome-wide association studies of common diseases have matured over the last decade, generating the knowledge base for increasingly informative individual-level genetic risk prediction. In this review, we discuss fundamental concepts involved in computing genetic risk with current methods, strengths and weaknesses of various approaches, assessments of utility, and applications to various psychiatric disorders and related traits. Although genetic risk prediction has become increasingly straightforward to apply and common in published studies, there are important pitfalls to avoid. At present, the clinical utility of genetic risk prediction is still low; however, there is significant promise for future clinical applications as the ancestral diversity and sample sizes of genome-wide association studies increase. We discuss emerging data and methods aimed at improving the value of genetic risk prediction for disentangling disease mechanisms and stratifying subjects for epidemiological and clinical studies. For all applications, it is absolutely critical that polygenic risk prediction is applied with appropriate methodology and control for confounding to avoid repeating some mistakes of the candidate gene era.Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved. -
Koopmans F, van Nierop P, Andres-Alonso M, Byrnes A, Cijsouw T, Coba MP, Cornelisse LN, Farrell RJ, Goldschmidt HL, Howrigan DP, Hussain NK, Imig C, de Jong APH, Jung H, Kohansalnodehi M, Kramarz B, Lipstein N, Lovering RC, MacGillavry H, Mariano V, Mi H, Ninov M, Osumi-Sutherland D, Pielot R, Smalla KH, Tang H, Tashman K, Toonen RFG, Verpelli C, Reig-Viader R, Watanabe K, van Weering J, Achsel T, Ashrafi G, Asi N, Brown TC, De Camilli P, Feuermann M, Foulger RE, Gaudet P, Joglekar A, Kanellopoulos A, Malenka R, Nicoll RA, Pulido C, de Juan-Sanz J, Sheng M, Südhof TC, Tilgner HU, Bagni C, Bayés À, Biederer T, Brose N, Chua JJE, Dieterich DC, Gundelfinger ED, Hoogenraad C, Huganir RL, Jahn R, Kaeser PS, Kim E, Kreutz MR, McPherson PS, Neale BM, O'Connor V, Posthuma D, Ryan TA, Sala C, Feng G, Hyman SE, Thomas PD, Smit AB, Verhage M. 2019. SynGO: An Evidence-Based, Expert-Curated Knowledge Base for the Synapse. Neuron. 103(2):217-234.e4. Pubmed: 31171447 DOI:S0896-6273(19)30427-1 Koopmans F, van Nierop P, Andres-Alonso M, Byrnes A, Cijsouw T, Coba MP, Cornelisse LN, Farrell RJ, Goldschmidt HL, Howrigan DP, Hussain NK, Imig C, de Jong APH, Jung H, Kohansalnodehi M, Kramarz B, Lipstein N, Lovering RC, MacGillavry H, Mariano V, Mi H, Ninov M, Osumi-Sutherland D, Pielot R, Smalla KH, Tang H, Tashman K, Toonen RFG, Verpelli C, Reig-Viader R, Watanabe K, van Weering J, Achsel T, Ashrafi G, Asi N, Brown TC, De Camilli P, Feuermann M, Foulger RE, Gaudet P, Joglekar A, Kanellopoulos A, Malenka R, Nicoll RA, Pulido C, de Juan-Sanz J, Sheng M, Südhof TC, Tilgner HU, Bagni C, Bayés À, Biederer T, Brose N, Chua JJE, Dieterich DC, Gundelfinger ED, Hoogenraad C, Huganir RL, Jahn R, Kaeser PS, Kim E, Kreutz MR, McPherson PS, Neale BM, O'Connor V, Posthuma D, Ryan TA, Sala C, Feng G, Hyman SE, Thomas PD, Smit AB, Verhage M. 2019. SynGO: An Evidence-Based, Expert-Curated Knowledge Base for the Synapse. Neuron. 103(2):217-234.e4. Pubmed: 31171447 DOI:S0896-6273(19)30427-1 Synapses are fundamental information-processing units of the brain, and synaptic dysregulation is central to many brain disorders ("synaptopathies"). However, systematic annotation of synaptic genes and ontology of synaptic processes are currently lacking. We established SynGO, an interactive knowledge base that accumulates available research about synapse biology using Gene Ontology (GO) annotations to novel ontology terms: 87 synaptic locations and 179 synaptic processes. SynGO annotations are exclusively based on published, expert-curated evidence. Using 2,922 annotations for 1,112 genes, we show that synaptic genes are exceptionally well conserved and less tolerant to mutations than other genes. Many SynGO terms are significantly overrepresented among gene variations associated with intelligence, educational attainment, ADHD, autism, and bipolar disorder and among de novo variants associated with neurodevelopmental disorders, including schizophrenia. SynGO is a public, universal reference for synapse research and an online analysis platform for interpretation of large-scale -omics data (https://syngoportal.org and http://geneontology.org).Copyright © 2019 Elsevier Inc. All rights reserved. -
Lam M, Chen CY, Li Z, Martin AR, Bryois J, Ma X, Gaspar H, Ikeda M, Benyamin B, Brown BC, Liu R, Zhou W, Guan L, Kamatani Y, Kim SW, Kubo M, Kusumawardhani AAAA, Liu CM, Ma H, Periyasamy S, Takahashi A, Xu Z, Yu H, Zhu F, Chen WJ, Faraone S, Glatt SJ, He L, Hyman SE, Hwu HG, McCarroll SA, Neale BM, Sklar P, Wildenauer DB, Yu X, Zhang D, Mowry BJ, Lee J, Holmans P, Xu S, Sullivan PF, Ripke S, O'Donovan MC, Daly MJ, Qin S, Sham P, Iwata N, Hong KS, Schwab SG, Yue W, Tsuang M, Liu J, Ma X, Kahn RS, Shi Y, Huang H. 2019. Comparative genetic architectures of schizophrenia in East Asian and European populations. Nature genetics. 51(12):1670-1678. Pubmed: 31740837 DOI:10.1038/s41588-019-0512-x Lam M, Chen CY, Li Z, Martin AR, Bryois J, Ma X, Gaspar H, Ikeda M, Benyamin B, Brown BC, Liu R, Zhou W, Guan L, Kamatani Y, Kim SW, Kubo M, Kusumawardhani AAAA, Liu CM, Ma H, Periyasamy S, Takahashi A, Xu Z, Yu H, Zhu F, Chen WJ, Faraone S, Glatt SJ, He L, Hyman SE, Hwu HG, McCarroll SA, Neale BM, Sklar P, Wildenauer DB, Yu X, Zhang D, Mowry BJ, Lee J, Holmans P, Xu S, Sullivan PF, Ripke S, O'Donovan MC, Daly MJ, Qin S, Sham P, Iwata N, Hong KS, Schwab SG, Yue W, Tsuang M, Liu J, Ma X, Kahn RS, Shi Y, Huang H. 2019. Comparative genetic architectures of schizophrenia in East Asian and European populations. Nature genetics. 51(12):1670-1678. Pubmed: 31740837 DOI:10.1038/s41588-019-0512-x Schizophrenia is a debilitating psychiatric disorder with approximately 1% lifetime risk globally. Large-scale schizophrenia genetic studies have reported primarily on European ancestry samples, potentially missing important biological insights. Here, we report the largest study to date of East Asian participants (22,778 schizophrenia cases and 35,362 controls), identifying 21 genome-wide-significant associations in 19 genetic loci. Common genetic variants that confer risk for schizophrenia have highly similar effects between East Asian and European ancestries (genetic correlation = 0.98 ± 0.03), indicating that the genetic basis of schizophrenia and its biology are broadly shared across populations. A fixed-effect meta-analysis including individuals from East Asian and European ancestries identified 208 significant associations in 176 genetic loci (53 novel). Trans-ancestry fine-mapping reduced the sets of candidate causal variants in 44 loci. Polygenic risk scores had reduced performance when transferred across ancestries, highlighting the importance of including sufficient samples of major ancestral groups to ensure their generalizability across populations. 2018
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Farahany NA, Greely HT, Hyman S, Koch C, Grady C, Pașca SP, Sestan N, Arlotta P, Bernat JL, Ting J, Lunshof JE, Iyer EPR, Hyun I, Capestany BH, Church GM, Huang H, Song H. 2018. The ethics of experimenting with human brain tissue. Nature. 556(7702):429-432. Pubmed: 29691509 DOI:10.1038/d41586-018-04813-x Farahany NA, Greely HT, Hyman S, Koch C, Grady C, Pașca SP, Sestan N, Arlotta P, Bernat JL, Ting J, Lunshof JE, Iyer EPR, Hyun I, Capestany BH, Church GM, Huang H, Song H. 2018. The ethics of experimenting with human brain tissue. Nature. 556(7702):429-432. Pubmed: 29691509 DOI:10.1038/d41586-018-04813-x -
Greely HT, Grady C, Ramos KM, Chiong W, Eberwine J, Farahany NA, Johnson LSM, Hyman BT, Hyman SE, Rommelfanger KS, Serrano EE. 2018. Neuroethics Guiding Principles for the NIH BRAIN Initiative. The Journal of neuroscience : the official journal of the Society for Neuroscience. 38(50):10586-10588. Pubmed: 30541767 DOI:10.1523/JNEUROSCI.2077-18.2018 Greely HT, Grady C, Ramos KM, Chiong W, Eberwine J, Farahany NA, Johnson LSM, Hyman BT, Hyman SE, Rommelfanger KS, Serrano EE. 2018. Neuroethics Guiding Principles for the NIH BRAIN Initiative. The Journal of neuroscience : the official journal of the Society for Neuroscience. 38(50):10586-10588. Pubmed: 30541767 DOI:10.1523/JNEUROSCI.2077-18.2018 -
Hyman SE. 2018. The importance of true collaboration in efforts to increase diversity in genetic analyses. Current biology : CB. 28(10):R598. Pubmed: 29787720 DOI:S0960-9822(18)30467-6 Hyman SE. 2018. The importance of true collaboration in efforts to increase diversity in genetic analyses. Current biology : CB. 28(10):R598. Pubmed: 29787720 DOI:S0960-9822(18)30467-6 In Michael Gross's recent article ('Mind the genome diversity gap'), he rightly states that global health equity demands an overhaul of the current approach to genetic analysis of psychiatric conditions, which relies heavily on European sample collections. Unfortunately, the article missed the mark in its description of work undertaken by the Broad Institute of MIT and Harvard, the Harvard T.H. Chan School of Public Health, and collaborative partners in Africa and Asia that aims to change the status quo.Copyright © 2018 The Author. Published by Elsevier Ltd.. All rights reserved. -
Hyman SE. 2018. The daunting polygenicity of mental illness: making a new map. Philosophical transactions of the Royal Society of London. Series B, Biological sciences. 373(1742). Pubmed: 29352030 DOI:10.1098/rstb.2017.0031 Hyman SE. 2018. The daunting polygenicity of mental illness: making a new map. Philosophical transactions of the Royal Society of London. Series B, Biological sciences. 373(1742). Pubmed: 29352030 DOI:10.1098/rstb.2017.0031 An epochal opportunity to elucidate the pathogenic mechanisms of psychiatric disorders has emerged from advances in genomic technology, new computational tools and the growth of international consortia committed to data sharing. The resulting large-scale, unbiased genetic studies have begun to yield new biological insights and with them the hope that a half century of stasis in psychiatric therapeutics will come to an end. Yet a sobering picture is coming into view; it reveals daunting genetic and phenotypic complexity portending enormous challenges for neurobiology. Successful exploitation of results from genetics will require eschewal of long-successful reductionist approaches to investigation of gene function, a commitment to supplanting much research now conducted in model organisms with human biology, and development of new experimental systems and computational models to analyse polygenic causal influences. In short, psychiatric neuroscience must develop a new scientific map to guide investigation through a polygenic This article is part of a discussion meeting issue 'Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists'.© 2018 The Authors. -
Hyman SE. 2018. Steven E. Hyman. Current biology : CB. 28(1):R6-R8. Pubmed: 29414131 DOI:S0960-9822(17)31536-1 Hyman SE. 2018. Steven E. Hyman. Current biology : CB. 28(1):R6-R8. Pubmed: 29414131 DOI:S0960-9822(17)31536-1 Interview with Steven Hyman, Director of the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard.Copyright © 2017. -
Sanders SJ, Neale BM, Huang H, Werling DM, An JY, Dong S, Abecasis G, Arguello PA, Blangero J, Boehnke M, Daly MJ, Eggan K, Geschwind DH, Glahn DC, Goldstein DB, Gur RE, Handsaker RE, McCarroll SA, Ophoff RA, Palotie A, Pato CN, Sabatti C, State MW, Willsey AJ, Hyman SE, Addington AM, Lehner T, Freimer NB. 2018. Publisher Correction: Whole genome sequencing in psychiatric disorders: the WGSPD consortium. Nature neuroscience. 21(7):1017. Pubmed: 29549319 DOI:10.1038/s41593-018-0102-8 Sanders SJ, Neale BM, Huang H, Werling DM, An JY, Dong S, Abecasis G, Arguello PA, Blangero J, Boehnke M, Daly MJ, Eggan K, Geschwind DH, Glahn DC, Goldstein DB, Gur RE, Handsaker RE, McCarroll SA, Ophoff RA, Palotie A, Pato CN, Sabatti C, State MW, Willsey AJ, Hyman SE, Addington AM, Lehner T, Freimer NB. 2018. Publisher Correction: Whole genome sequencing in psychiatric disorders: the WGSPD consortium. Nature neuroscience. 21(7):1017. Pubmed: 29549319 DOI:10.1038/s41593-018-0102-8 In the version of this article initially published, the consortium authorship and corresponding authors were not presented correctly. In the PDF and print versions, the Whole Genome Sequencing for Psychiatric Disorders (WGSPD) consortium was missing from the author list at the beginning of the paper, where it should have appeared as the seventh author; it was present in the author list at the end of the paper, but the footnote directing readers to the Supplementary Note for a list of members was missing. In the HTML version, the consortium was listed as the last author instead of as the seventh, and the line directing readers to the Supplementary Note for a list of members appeared at the end of the paper under Author Information but not in association with the consortium name itself. Also, this line stated that both member names and affiliations could be found in the Supplementary Note; in fact, only names are given. In all versions of the paper, the corresponding author symbols were attached to A. Jeremy Willsey, Steven E. Hyman, Anjene M. Addington and Thomas Lehner; they should have been attached, respectively, to Steven E. Hyman, Anjene M. Addington, Thomas Lehner and Nelson B. Freimer. As a result of this shift, the respective contact links in the HTML version did not lead to the indicated individuals. The errors have been corrected in the HTML and PDF versions of the article. 2017
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Hyman S. 2017. Biology needs more staff scientists. Nature. 545(7654):283-284. Pubmed: 28516936 DOI:10.1038/545283a Hyman S. 2017. Biology needs more staff scientists. Nature. 545(7654):283-284. Pubmed: 28516936 DOI:10.1038/545283a -
Hyman SE. 2017. A Valuable New Direction in Ethical Analysis of Psychiatric Genetics. The American journal of bioethics : AJOB. 17(4):13-15. Pubmed: 28328368 DOI:10.1080/15265161.2017.1285145 Hyman SE. 2017. A Valuable New Direction in Ethical Analysis of Psychiatric Genetics. The American journal of bioethics : AJOB. 17(4):13-15. Pubmed: 28328368 DOI:10.1080/15265161.2017.1285145 -
Hyman SE. 2017. A New Hope for Biological Insights Into Depression. Biological psychiatry. 81(4):280-281. Pubmed: 28089024 DOI:S0006-3223(16)33056-6 Hyman SE. 2017. A New Hope for Biological Insights Into Depression. Biological psychiatry. 81(4):280-281. Pubmed: 28089024 DOI:S0006-3223(16)33056-6 -
Sanders SJ, Neale BM, Huang H, Werling DM, An JY, Dong S, Abecasis G, Arguello PA, Blangero J, Boehnke M, Daly MJ, Eggan K, Geschwind DH, Glahn DC, Goldstein DB, Gur RE, Handsaker RE, McCarroll SA, Ophoff RA, Palotie A, Pato CN, Sabatti C, State MW, Willsey AJ, Hyman SE, Addington AM, Lehner T, Freimer NB. 2017. Whole genome sequencing in psychiatric disorders: the WGSPD consortium. Nature neuroscience. 20(12):1661-1668. Pubmed: 29184211 DOI:10.1038/s41593-017-0017-9 Sanders SJ, Neale BM, Huang H, Werling DM, An JY, Dong S, Abecasis G, Arguello PA, Blangero J, Boehnke M, Daly MJ, Eggan K, Geschwind DH, Glahn DC, Goldstein DB, Gur RE, Handsaker RE, McCarroll SA, Ophoff RA, Palotie A, Pato CN, Sabatti C, State MW, Willsey AJ, Hyman SE, Addington AM, Lehner T, Freimer NB. 2017. Whole genome sequencing in psychiatric disorders: the WGSPD consortium. Nature neuroscience. 20(12):1661-1668. Pubmed: 29184211 DOI:10.1038/s41593-017-0017-9 As technology advances, whole genome sequencing (WGS) is likely to supersede other genotyping technologies. The rate of this change depends on its relative cost and utility. Variants identified uniquely through WGS may reveal novel biological pathways underlying complex disorders and provide high-resolution insight into when, where, and in which cell type these pathways are affected. Alternatively, cheaper and less computationally intensive approaches may yield equivalent insights. Understanding the role of rare variants in the noncoding gene-regulating genome, through pilot WGS projects, will be critical to determine which of these two extremes best represents reality. With large cohorts, well-defined risk loci, and a compelling need to understand the underlying biology, psychiatric disorders have a role to play in this preliminary WGS assessment. The WGSPD consortium will integrate data for 18,000 individuals with psychiatric disorders, beginning with autism spectrum disorder, schizophrenia, bipolar disorder, and major depressive disorder, along with over 150,000 controls. 2016
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Hyman SE, Landis SC, Leshner AI. 2016. Research Into Brain Disorders as an Example of Targeted Science. JAMA. 316(16):1673-1674. Pubmed: 27668392 DOI:10.1001/jama.2016.12412 Hyman SE, Landis SC, Leshner AI. 2016. Research Into Brain Disorders as an Example of Targeted Science. JAMA. 316(16):1673-1674. Pubmed: 27668392 DOI:10.1001/jama.2016.12412 -
Hyman SE. 2016. Back to basics: luring industry back into neuroscience. Nature neuroscience. 19(11):1383-1384. Pubmed: 27786185 DOI:10.1038/nn.4429 Hyman SE. 2016. Back to basics: luring industry back into neuroscience. Nature neuroscience. 19(11):1383-1384. Pubmed: 27786185 DOI:10.1038/nn.4429 -
Ransom RC, Hunter DJ, Hyman S, Singh G, Ransom SC, Shen EZ, Perez KC, Gillette M, Li J, Liu B, Brunski JB, Helms JA. 2016. Axin2-expressing cells execute regeneration after skeletal injury. Scientific reports. 6:36524. Pubmed: 27853243 DOI:10.1038/srep36524 Ransom RC, Hunter DJ, Hyman S, Singh G, Ransom SC, Shen EZ, Perez KC, Gillette M, Li J, Liu B, Brunski JB, Helms JA. 2016. Axin2-expressing cells execute regeneration after skeletal injury. Scientific reports. 6:36524. Pubmed: 27853243 DOI:10.1038/srep36524 The mammalian skeleton performs a diverse range of vital functions, requiring mechanisms of regeneration that restore functional skeletal cell populations after injury. We hypothesized that the Wnt pathway specifies distinct functional subsets of skeletal cell types, and that lineage tracing of Wnt-responding cells (WRCs) using the Axin2 gene in mice identifies a population of long-lived skeletal cells on the periosteum of long bone. Ablation of these WRCs disrupts healing after injury, and three-dimensional finite element modeling of the regenerate delineates their essential role in functional bone regeneration. These progenitor cells in the periosteum are activated upon injury and give rise to both cartilage and bone. Indeed, our findings suggest that WRCs may serve as a therapeutic target in the setting of impaired skeletal regeneration. 2015
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First MB, Reed GM, Hyman SE, Saxena S. 2015. The development of the ICD-11 Clinical Descriptions and Diagnostic Guidelines for Mental and Behavioural Disorders. World psychiatry : official journal of the World Psychiatric Association (WPA). 14(1):82-90. Pubmed: 25655162 DOI:10.1002/wps.20189 First MB, Reed GM, Hyman SE, Saxena S. 2015. The development of the ICD-11 Clinical Descriptions and Diagnostic Guidelines for Mental and Behavioural Disorders. World psychiatry : official journal of the World Psychiatric Association (WPA). 14(1):82-90. Pubmed: 25655162 DOI:10.1002/wps.20189 The World Health Organization is in the process of preparing the eleventh revision of the International Classification of Diseases (ICD-11), scheduled for presentation to the World Health Assembly for approval in 2017. The International Advisory Group for the Revision of the ICD-10 Mental and Behavioural Disorders made improvement in clinical utility an organizing priority for the revision. The uneven nature of the diagnostic information included in the ICD-10 Clinical Descriptions and Diagnostic Guidelines (CDDG), especially with respect to differential diagnosis, is a major shortcoming in terms of its usefulness to clinicians. Consequently, ICD-11 Working Groups were asked to collate diagnostic information about the disorders under their purview using a standardized template (referred to as a "Content Form"). Using the information provided in the Content Forms as source material, the ICD-11 CDDG are being developed with a uniform structure. The effectiveness of this format in producing more consistent clinical judgments in ICD-11 as compared to ICD-10 is currently being tested in a series of Internet-based field studies using standardized case material, and will also be tested in clinical settings.© 2015 World Psychiatric Association. -
Hyman SE, Goldberg ME. 2015. Protect researchers from harassment. Science (New York, N.Y.). 348(6240):1216-7. Pubmed: 26068840 DOI:10.1126/science.348.6240.1216-c Hyman SE, Goldberg ME. 2015. Protect researchers from harassment. Science (New York, N.Y.). 348(6240):1216-7. Pubmed: 26068840 DOI:10.1126/science.348.6240.1216-c -
Hyman SE. 2015. Enlisting hESCs to Interrogate Genetic Variants Associated with Neuropsychiatric Disorders. Cell stem cell. 17(3):253-4. Pubmed: 26340523 DOI:S1934-5909(15)00368-9 Hyman SE. 2015. Enlisting hESCs to Interrogate Genetic Variants Associated with Neuropsychiatric Disorders. Cell stem cell. 17(3):253-4. Pubmed: 26340523 DOI:S1934-5909(15)00368-9 Connecting rare genetic variants to neuropsychiatric disease mechanisms remains a significant challenge. In this issue of Cell Stem Cell, Pak et al. (2015) combine gene targeting and stem cell technologies to identify a significant cellular effect of rare penetrant NRXN1 mutations in human neurons, which was found to cause a defect in neurotransmitter release.Copyright © 2015 Elsevier Inc. All rights reserved. -
Robinson EB, Neale BM, Hyman SE. 2015. Genetic research in autism spectrum disorders. Current opinion in pediatrics. 27(6):685-91. Pubmed: 26371945 DOI:10.1097/MOP.0000000000000278 Robinson EB, Neale BM, Hyman SE. 2015. Genetic research in autism spectrum disorders. Current opinion in pediatrics. 27(6):685-91. Pubmed: 26371945 DOI:10.1097/MOP.0000000000000278 Array 2014
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Hyman SE. 2014. Perspective: Revealing molecular secrets. Nature. 508(7494):S20. Pubmed: 24695333 DOI:10.1038/508S20a Hyman SE. 2014. Perspective: Revealing molecular secrets. Nature. 508(7494):S20. Pubmed: 24695333 DOI:10.1038/508S20a -
Hyman SE. 2014. The unconscionable gap between what we know and what we do. Science translational medicine. 6(253):253cm9. Pubmed: 25210058 DOI:10.1126/scitranslmed.3010312 Hyman SE. 2014. The unconscionable gap between what we know and what we do. Science translational medicine. 6(253):253cm9. Pubmed: 25210058 DOI:10.1126/scitranslmed.3010312 Mental disorders have high aggregate prevalence, are responsible globally for nearly a quarter of all years lived with disability, and represent the largest cause of lost economic output among all classes of noncommunicable disease worldwide. Cost-effective treatments, including both generic drugs and brief, manualized cognitive therapies are available to address this burden. Nonetheless, treatment of mental disorders remains a low priority worldwide-disproportionately so in low- and middle-income countries. Here, I focus on possible reasons for the failure of policy-makers to respond effectively, and I suggest corrective approaches.Copyright © 2014, American Association for the Advancement of Science. -
Choi DW, Armitage R, Brady LS, Coetzee T, Fisher W, Hyman S, Pande A, Paul S, Potter W, Roin B, Sherer T. 2014. Medicines for the mind: policy-based "pull" incentives for creating breakthrough CNS drugs. Neuron. 84(3):554-63. Pubmed: 25442934 DOI:S0896-6273(14)00947-7 Choi DW, Armitage R, Brady LS, Coetzee T, Fisher W, Hyman S, Pande A, Paul S, Potter W, Roin B, Sherer T. 2014. Medicines for the mind: policy-based "pull" incentives for creating breakthrough CNS drugs. Neuron. 84(3):554-63. Pubmed: 25442934 DOI:S0896-6273(14)00947-7 Several large pharmaceutical companies have selectively downsized their neuroscience research divisions, reflecting a growing view that developing drugs to treat brain diseases is more difficult and often more time-consuming and expensive than developing drugs for other therapeutic areas, and thus represents a weak area for investment. These withdrawals reduce global neuroscience translational capabilities and pose a serious challenge to society's interests in ameliorating the impact of nervous system diseases. While the path forward ultimately lies in improving understandings of disease mechanisms, many promising therapeutic approaches have already been identified, and rebalancing the underlying risk/reward calculus could help keep companies engaged in making CNS drugs. One way to do this that would not require upfront funding is to change the policies that regulate market returns for the most-needed breakthrough drugs. The broader neuroscience community including clinicians and patients should convene to develop and advocate for such policy changes.Copyright © 2014 Elsevier Inc. All rights reserved. -
Pankevich DE, Altevogt BM, Dunlop J, Gage FH, Hyman SE. 2014. Improving and accelerating drug development for nervous system disorders. Neuron. 84(3):546-53. Pubmed: 25442933 DOI:S0896-6273(14)00905-2 Pankevich DE, Altevogt BM, Dunlop J, Gage FH, Hyman SE. 2014. Improving and accelerating drug development for nervous system disorders. Neuron. 84(3):546-53. Pubmed: 25442933 DOI:S0896-6273(14)00905-2 Advances in the neurosciences have placed the field in the position where it is poised to significantly reduce the burden of nervous system disorders. However, drug discovery, development, and translation for nervous system disorders still pose many unique challenges. The key scientific challenges can be summarized as follows: mechanisms of disease, target identification and validation, predictive models, biomarkers for patient stratification and as endpoints for clinical trials, clear regulatory pathways, reliability and reproducibility of published data, and data sharing and collaboration. To accelerate nervous system drug development, the Institute of Medicine's Forum on Neuroscience and Nervous System Disorders has hosted a series of public workshops that brought together representatives of industry, government (including both research funding and regulatory agencies), academia, and patient groups to discuss these challenges and offer potential strategies to improve the translational neuroscience.Copyright © 2014 Elsevier Inc. All rights reserved. -
De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, Kou Y, Liu L , Fromer M, Walker S, Singh T, Klei L, Kosmicki J, Shih-Chen F, Aleksic B, Biscaldi M, Bolton PF, Brownfeld JM, Cai J, Campbell NG, Carracedo A, Chahrour MH, Chiocchetti AG, Coon H, Crawford EL, Curran SR, Dawson G, Duketis E, Fernandez BA, Gallagher L, Geller E, Guter SJ, Hill RS, Ionita-Laza J, Jimenz Gonzalez P, Kilpinen H, Klauck SM, Kolevzon A, Lee I, Lei I, Lei J, Lehtimäki T, Lin CF, Ma'ayan A, Marshall CR, McInnes AL, Neale B, Owen MJ, Ozaki N, Parellada M, Parr JR, Purcell S, Puura K, Rajagopalan D, Rehnström K, Reichenberg A, Sabo A, Sachse M, Sanders SJ, Schafer C, Schulte-Rüther M, Skuse D, Stevens C, Szatmari P, Tammimies K, Valladares O, Voran A, Li-San W, Weiss LA, Willsey AJ, Yu TW, Yuen RK, DDD Study, Homozygosity Mapping Collaborative for Autism, UK10K Consortium, Cook EH, Freitag CM, Gill M, Hultman CM, Lehner T, Palotie A, Schellenberg GD, Sklar P, State MW, Sutcliffe JS, Walsh CA, Scherer SW, Zwick ME, Barett JC, Cutler DJ, Roeder K, Devlin B, Daly MJ, Buxbaum JD. 2014. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature. 515(7526):209-215. DOI:10.1038/nature13772 De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, Kou Y, Liu L , Fromer M, Walker S, Singh T, Klei L, Kosmicki J, Shih-Chen F, Aleksic B, Biscaldi M, Bolton PF, Brownfeld JM, Cai J, Campbell NG, Carracedo A, Chahrour MH, Chiocchetti AG, Coon H, Crawford EL, Curran SR, Dawson G, Duketis E, Fernandez BA, Gallagher L, Geller E, Guter SJ, Hill RS, Ionita-Laza J, Jimenz Gonzalez P, Kilpinen H, Klauck SM, Kolevzon A, Lee I, Lei I, Lei J, Lehtimäki T, Lin CF, Ma'ayan A, Marshall CR, McInnes AL, Neale B, Owen MJ, Ozaki N, Parellada M, Parr JR, Purcell S, Puura K, Rajagopalan D, Rehnström K, Reichenberg A, Sabo A, Sachse M, Sanders SJ, Schafer C, Schulte-Rüther M, Skuse D, Stevens C, Szatmari P, Tammimies K, Valladares O, Voran A, Li-San W, Weiss LA, Willsey AJ, Yu TW, Yuen RK, DDD Study, Homozygosity Mapping Collaborative for Autism, UK10K Consortium, Cook EH, Freitag CM, Gill M, Hultman CM, Lehner T, Palotie A, Schellenberg GD, Sklar P, State MW, Sutcliffe JS, Walsh CA, Scherer SW, Zwick ME, Barett JC, Cutler DJ, Roeder K, Devlin B, Daly MJ, Buxbaum JD. 2014. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature. 515(7526):209-215. DOI:10.1038/nature13772 The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones. Article and data available via http://europepmc.org/abstract/MED/25363760Nature Publishing Group -
Hyman S. 2014. Mental health: depression needs large human-genetics studies. Nature. 515(7526):189-91. Pubmed: 25391945 DOI:10.1038/515189a Hyman S. 2014. Mental health: depression needs large human-genetics studies. Nature. 515(7526):189-91. Pubmed: 25391945 DOI:10.1038/515189a -
Hyman SE. 2014. How far can mice carry autism research?. Cell. 158(1):13-4. Pubmed: 24995974 DOI:S0092-8674(14)00824-1 Hyman SE. 2014. How far can mice carry autism research?. Cell. 158(1):13-4. Pubmed: 24995974 DOI:S0092-8674(14)00824-1 In the face of growing controversy about the utility of genetic mouse models of human disease, Rothwell et al. report on a shared mechanism by which two different neuroligin-3 mutations, associated with autism spectrum disorders in humans, produce an enhancement in motor learning. The open question is how much we can learn about human ills from such models.Copyright © 2014 Elsevier Inc. All rights reserved. -
McCarroll SA, Feng G, Hyman SE. 2014. Genome-scale neurogenetics: methodology and meaning. Nature neuroscience. 17(6):756-63. Pubmed: 24866041 DOI:10.1038/nn.3716 McCarroll SA, Feng G, Hyman SE. 2014. Genome-scale neurogenetics: methodology and meaning. Nature neuroscience. 17(6):756-63. Pubmed: 24866041 DOI:10.1038/nn.3716 Genetic analysis is currently offering glimpses into molecular mechanisms underlying such neuropsychiatric disorders as schizophrenia, bipolar disorder and autism. After years of frustration, success in identifying disease-associated DNA sequence variation has followed from new genomic technologies, new genome data resources, and global collaborations that could achieve the scale necessary to find the genes underlying highly polygenic disorders. Here we describe early results from genome-scale studies of large numbers of subjects and the emerging significance of these results for neurobiology. -
Hyman SE. 2014. Time for new schizophrenia Rx. Science (New York, N.Y.). 343(6176):1177. Pubmed: 24626901 DOI:10.1126/science.1252603 Hyman SE. 2014. Time for new schizophrenia Rx. Science (New York, N.Y.). 343(6176):1177. Pubmed: 24626901 DOI:10.1126/science.1252603 -
Hyman SE. 2014. Revitalizing psychiatric therapeutics. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 39(1):220-9. Pubmed: 24317307 DOI:10.1038/npp.2013.181 Hyman SE. 2014. Revitalizing psychiatric therapeutics. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 39(1):220-9. Pubmed: 24317307 DOI:10.1038/npp.2013.181 Despite high prevalence and enormous unmet medical need, the pharmaceutical industry has recently de-emphasized neuropsychiatric disorders as 'too difficult' a challenge to warrant major investment. Here I describe major obstacles to drug discovery and development including a lack of new molecular targets, shortcomings of current animal models, and the lack of biomarkers for clinical trials. My major focus, however, is on new technologies and scientific approaches to neuropsychiatric disorders that give promise for revitalizing therapeutics and may thus answer industry's concerns. 2013
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Casey BJ, Craddock N, Cuthbert BN, Hyman SE, Lee FS, Ressler KJ. 2013. DSM-5 and RDoC: progress in psychiatry research?. Nature reviews. Neuroscience. 14(11):810-4. Pubmed: 24135697 DOI:10.1038/nrn3621 Casey BJ, Craddock N, Cuthbert BN, Hyman SE, Lee FS, Ressler KJ. 2013. DSM-5 and RDoC: progress in psychiatry research?. Nature reviews. Neuroscience. 14(11):810-4. Pubmed: 24135697 DOI:10.1038/nrn3621 Neuroscience studies into psychiatric disorders generally rely on disease definitions that are based on the influential Diagnostic and Statistical Manual of Mental Disorders (DSM), the fifth edition of which (DSM-5) was released earlier this year. Designed as a purely diagnostic tool, the DSM considers different disorders as distinct entities. However, boundaries between disorders are often not as strict as the DSM suggests. To provide an alternative framework for research into psychiatric disorders, the US National Institute of Mental Health (NIMH) has recently introduced its Research Domain Criteria (RDoC) project. In the RDoC, five 'domains' each reflect a brain system in which functioning is impaired, to different degrees, in different psychiatric conditions. Nature Reviews Neuroscience asked six leading investigators for their thoughts on how DSM-5 and the RDoC will influence neuroscience research into psychiatric disorders. -
McCarroll SA, Hyman SE. 2013. Progress in the genetics of polygenic brain disorders: significant new challenges for neurobiology. Neuron. 80(3):578-87. Pubmed: 24183011 DOI:S0896-6273(13)00998-7 McCarroll SA, Hyman SE. 2013. Progress in the genetics of polygenic brain disorders: significant new challenges for neurobiology. Neuron. 80(3):578-87. Pubmed: 24183011 DOI:S0896-6273(13)00998-7 Advances in genome analysis, accompanied by the assembly of large patient cohorts, are making possible successful genetic analyses of polygenic brain disorders. If the resulting molecular clues, previously hidden in the genomes of affected individuals, are to yield useful information about pathogenesis and inform the discovery of new treatments, neurobiology will have to rise to many difficult challenges. Here we review the underlying logic of the genetic investigations, describe in more detail progress in schizophrenia and autism, and outline the challenges for neurobiology that lie ahead. We argue that technologies at the disposal of neuroscience are adequately advanced to begin to study the biology of common and devastating polygenic disorders.Copyright © 2013 Elsevier Inc. All rights reserved. -
Hyman SE. 2013. Might stimulant drugs support moral agency in ADHD children?. Journal of medical ethics. 39(6):369-70; discussion 372-3. Pubmed: 23001921 DOI:10.1136/medethics-2012-100846 Hyman SE. 2013. Might stimulant drugs support moral agency in ADHD children?. Journal of medical ethics. 39(6):369-70; discussion 372-3. Pubmed: 23001921 DOI:10.1136/medethics-2012-100846 Stimulants have been shown to be safe and effective for reduction of the symptoms of attention deficit hyperactivity disorder. Despite much debate, however, there has been little empirical evidence as to whether stimulants affect authenticity and moral agency in children. Singh presents evidence that stimulants do not undercut children's' sense of self and increase their experience of agency. These findings are consistent with laboratory evidence that stimulant drugs in therapeutic doses improve cognitive control over thought and behavior. 2012
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Hyman SE. 2012. Target practice: HDAC inhibitors for schizophrenia. Nature neuroscience. 15(9):1180-1. Pubmed: 22929911 DOI:10.1038/nn.3200 Hyman SE. 2012. Target practice: HDAC inhibitors for schizophrenia. Nature neuroscience. 15(9):1180-1. Pubmed: 22929911 DOI:10.1038/nn.3200 -
Hyman SE. 2012. Revolution stalled. Science translational medicine. 4(155):155cm11. Pubmed: 23052291 DOI:10.1126/scitranslmed.3003142 Hyman SE. 2012. Revolution stalled. Science translational medicine. 4(155):155cm11. Pubmed: 23052291 DOI:10.1126/scitranslmed.3003142 Drug discovery is at a near standstill for treating psychiatric disorders such as schizophrenia, bipolar disorder, depression, and common forms of autism. Despite high prevalence and unmet medical need, major pharmaceutical companies are deemphasizing or exiting psychiatry, thus removing significant capacity from efforts to discover new medicines. In this Commentary, I develop a view of what has gone wrong scientifically and ask what can be done to address this parlous situation. 2011
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Hyman SE. 2011. Commentary: Repairing a plane while it is flying--reflections on Rutter (2011). Journal of child psychology and psychiatry, and allied disciplines. 52(6):661-2; discussion 673-5. Pubmed: 21434920 DOI:10.1111/j.1469-7610.2011.02386.x Hyman SE. 2011. Commentary: Repairing a plane while it is flying--reflections on Rutter (2011). Journal of child psychology and psychiatry, and allied disciplines. 52(6):661-2; discussion 673-5. Pubmed: 21434920 DOI:10.1111/j.1469-7610.2011.02386.x -
Collins PY, Patel V, Joestl SS, March D, Insel TR, Daar AS, Anderson W, Dhansay MA, Phillips A, Shurin S, Walport M, Ewart W, Savill SJ, Bordin IA, Costello EJ, Durkin M, Fairburn C, Glass RI, Hall W, Huang Y, Hyman SE, Jamison K, Kaaya S, Kapur S, Kleinman A, Ogunniyi A, Otero-Ojeda A, Poo MM, Ravindranath V, Sahakian BJ, Saxena S, Singer PA, Stein DJ. 2011. Grand challenges in global mental health. Nature. 475(7354):27-30. Pubmed: 21734685 DOI:10.1038/475027a Collins PY, Patel V, Joestl SS, March D, Insel TR, Daar AS, Anderson W, Dhansay MA, Phillips A, Shurin S, Walport M, Ewart W, Savill SJ, Bordin IA, Costello EJ, Durkin M, Fairburn C, Glass RI, Hall W, Huang Y, Hyman SE, Jamison K, Kaaya S, Kapur S, Kleinman A, Ogunniyi A, Otero-Ojeda A, Poo MM, Ravindranath V, Sahakian BJ, Saxena S, Singer PA, Stein DJ. 2011. Grand challenges in global mental health. Nature. 475(7354):27-30. Pubmed: 21734685 DOI:10.1038/475027a -
Hyman SE. 2011. Genome-sequencing anniversary. The meaning of the Human Genome Project for neuropsychiatric disorders. Science (New York, N.Y.). 331(6020):1026. Pubmed: 21350167 DOI:10.1126/science.1203544 Hyman SE. 2011. Genome-sequencing anniversary. The meaning of the Human Genome Project for neuropsychiatric disorders. Science (New York, N.Y.). 331(6020):1026. Pubmed: 21350167 DOI:10.1126/science.1203544 -
Hyman SE. 2011. Cognitive enhancement: promises and perils. Neuron. 69(4):595-8. Pubmed: 21338872 DOI:10.1016/j.neuron.2011.02.012 Hyman SE. 2011. Cognitive enhancement: promises and perils. Neuron. 69(4):595-8. Pubmed: 21338872 DOI:10.1016/j.neuron.2011.02.012 The potential use of drugs to enhance cognition, emotion, and executive function has engendered controversy despite the fact that few such agents exist today. Here, I provide a context for discussions based on medical, regulatory, and ethical concerns that have been raised by the possibility that enhancers will emerge from current efforts to discover drugs for neuropsychiatric disorders.Copyright © 2011 Elsevier Inc. All rights reserved. -
Hyman SE. 2011. Grouping diagnoses of mental disorders by their common risk factors. The American journal of psychiatry. 168(1):1-3. Pubmed: 21205810 DOI:10.1176/appi.ajp.2010.10111655 Hyman SE. 2011. Grouping diagnoses of mental disorders by their common risk factors. The American journal of psychiatry. 168(1):1-3. Pubmed: 21205810 DOI:10.1176/appi.ajp.2010.10111655 2010
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Hyman SE. 2010. Emerging neurotechnologies for lie-detection: where are we now? An appraisal of Wolpe, Foster and Langleben's "Emerging neurotechnologies for lie-detection: promise and perils" five years later. The American journal of bioethics : AJOB. 10(10):49-50. Pubmed: 20945267 DOI:10.1080/15265161.2010.527263 Hyman SE. 2010. Emerging neurotechnologies for lie-detection: where are we now? An appraisal of Wolpe, Foster and Langleben's "Emerging neurotechnologies for lie-detection: promise and perils" five years later. The American journal of bioethics : AJOB. 10(10):49-50. Pubmed: 20945267 DOI:10.1080/15265161.2010.527263 -
Nestler EJ, Hyman SE. 2010. Animal models of neuropsychiatric disorders. Nature neuroscience. 13(10):1161-9. Pubmed: 20877280 DOI:10.1038/nn.2647 Nestler EJ, Hyman SE. 2010. Animal models of neuropsychiatric disorders. Nature neuroscience. 13(10):1161-9. Pubmed: 20877280 DOI:10.1038/nn.2647 Modeling of human neuropsychiatric disorders in animals is extremely challenging given the subjective nature of many symptoms, the lack of biomarkers and objective diagnostic tests, and the early state of the relevant neurobiology and genetics. Nonetheless, progress in understanding pathophysiology and in treatment development would benefit greatly from improved animal models. Here we review the current state of animal models of mental illness, with a focus on schizophrenia, depression and bipolar disorder. We argue for areas of focus that might increase the likelihood of creating more useful models, at least for some disorders, and for explicit guidelines when animal models are reported. -
Hyman SE. 2010. A bone to pick with compulsive behavior. Cell. 141(5):752-4. Pubmed: 20510922 DOI:10.1016/j.cell.2010.05.010 Hyman SE. 2010. A bone to pick with compulsive behavior. Cell. 141(5):752-4. Pubmed: 20510922 DOI:10.1016/j.cell.2010.05.010 Mice with mutations in the Hoxb8 gene exhibit compulsive grooming behavior. Chen et al. (2010) now report that this behavior stems from Hoxb8 deficiency in microglia, a type of immune cell in the brain derived from bone marrow. These findings provide intriguing connections between immune dysfunction and neuropsychiatric disorders.Copyright 2010 Elsevier Inc. All rights reserved. -
Hyman SE. 2010. The diagnosis of mental disorders: the problem of reification. Annual review of clinical psychology. 6:155-79. Pubmed: 17716032 Hyman SE. 2010. The diagnosis of mental disorders: the problem of reification. Annual review of clinical psychology. 6:155-79. Pubmed: 17716032 A pressing need for interrater reliability in the diagnosis of mental disorders emerged during the mid-twentieth century, prompted in part by the development of diverse new treatments. The Diagnostic and Statistical Manual of Mental Disorders (DSM), third edition answered this need by introducing operationalized diagnostic criteria that were field-tested for interrater reliability. Unfortunately, the focus on reliability came at a time when the scientific understanding of mental disorders was embryonic and could not yield valid disease definitions. Based on accreting problems with the current DSM-fourth edition (DSM-IV) classification, it is apparent that validity will not be achieved simply by refining criteria for existing disorders or by the addition of new disorders. Yet DSM-IV diagnostic criteria dominate thinking about mental disorders in clinical practice, research, treatment development, and law. As a result, the modern DSM system, intended to create a shared language, also creates epistemic blinders that impede progress toward valid diagnoses. Insights that are beginning to emerge from psychology, neuroscience, and genetics suggest possible strategies for moving forward. 2009
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Andrews G, Goldberg DP, Krueger RF, Carpenter WT, Hyman SE, Sachdev P, Pine DS. 2009. Exploring the feasibility of a meta-structure for DSM-V and ICD-11: could it improve utility and validity?. Psychological medicine. 39(12):1993-2000. Pubmed: 19796425 DOI:10.1017/S0033291709990250 Andrews G, Goldberg DP, Krueger RF, Carpenter WT, Hyman SE, Sachdev P, Pine DS. 2009. Exploring the feasibility of a meta-structure for DSM-V and ICD-11: could it improve utility and validity?. Psychological medicine. 39(12):1993-2000. Pubmed: 19796425 DOI:10.1017/S0033291709990250 Array -
Hyman SE. 2009. How adversity gets under the skin. Nature neuroscience. 12(3):241-3. Pubmed: 19238182 DOI:10.1038/nn0309-241 Hyman SE. 2009. How adversity gets under the skin. Nature neuroscience. 12(3):241-3. Pubmed: 19238182 DOI:10.1038/nn0309-241 2008
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Hyman SE. 2008. How might cocaine interfere with brain development?. PLoS medicine. 5(6):e130. Pubmed: 18547140 DOI:10.1371/journal.pmed.0050130 Hyman SE. 2008. How might cocaine interfere with brain development?. PLoS medicine. 5(6):e130. Pubmed: 18547140 DOI:10.1371/journal.pmed.0050130 Steven Hyman discusses a new study using cell culture and fetal rat models to investigate mechanisms by which cocaine might decrease the number of neurons in the brain. -
Hyman SE, Ivleva E. 2008. Cognition in schizophrenia. The American journal of psychiatry. 165(3):312. Pubmed: 18316429 DOI:10.1176/appi.ajp.2008.08010114 Hyman SE, Ivleva E. 2008. Cognition in schizophrenia. The American journal of psychiatry. 165(3):312. Pubmed: 18316429 DOI:10.1176/appi.ajp.2008.08010114 -
Hyman SE. 2008. A glimmer of light for neuropsychiatric disorders. Nature. 455(7215):890-3. Pubmed: 18923510 DOI:10.1038/nature07454 Hyman SE. 2008. A glimmer of light for neuropsychiatric disorders. Nature. 455(7215):890-3. Pubmed: 18923510 DOI:10.1038/nature07454 Understanding the pathogenesis of neuropsychiatric disorders is a substantial challenge for neurobiologists. It has long been hoped that identifying alleles that confer increased risk of such disorders would provide clues for neurobiological investigation. But this quest has been stymied by a lack of validated biological markers for characterizing and distinguishing the different disorders and by the genetic complexity underpinning these diseases. Now, modern genomic technologies have begun to facilitate the discovery of relevant genes. -
Paletzki RF, Myakishev MV, Polesskaya O, Orosz A, Hyman SE, Vinson C. 2008. Inhibiting activator protein-1 activity alters cocaine-induced gene expression and potentiates sensitization. Neuroscience. 152(4):1040-53. Pubmed: 18355967 DOI:10.1016/j.neuroscience.2008.01.045 Paletzki RF, Myakishev MV, Polesskaya O, Orosz A, Hyman SE, Vinson C. 2008. Inhibiting activator protein-1 activity alters cocaine-induced gene expression and potentiates sensitization. Neuroscience. 152(4):1040-53. Pubmed: 18355967 DOI:10.1016/j.neuroscience.2008.01.045 We have expressed A-FOS, an inhibitor of activator protein-1 (AP-1) DNA binding, in adult mouse striatal neurons. We observed normal behavior including locomotion and exploratory activities. Following a single injection of cocaine, locomotion increased similarly in both the A-FOS expressing and littermate controls. However, following repeated injections of cocaine, the A-FOS expressing mice showed increased locomotion relative to littermate controls, an increase that persisted following a week of withdrawal and subsequent cocaine administration. These results indicate that AP-1 suppresses this behavioral response to cocaine. We analyzed mRNA from the striatum before and 4 and 24 h after a single cocaine injection in both A-FOS and control striata using Affymetrix microarrays (430 2.0 Array) to identify genes mis-regulated by A-FOS that may mediate the increased locomotor sensitization to cocaine. A-FOS expression did not change gene expression in the basal state or 4 h following cocaine treatment relative to controls. However, 24 h after an acute cocaine treatment, 84 genes were identified that were differentially expressed between the A-FOS and control mice. Fifty-six genes are down-regulated while 28 genes are up-regulated including previously identified candidates for addiction including brain-derived neurotrophic factor and period homolog 1. Using a random sample of identified genes, quantitative PCR was used to verify the microarray studies. The chromosomal location of these 84 genes was compared with human genome scans of addiction to identify potential genes in humans that are involved in addiction. 2007
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Hyman SE, Insel TR. 2007. Public health contributions. Schizophrenia bulletin. 33(5):1151-2. Pubmed: 17631617 Hyman SE, Insel TR. 2007. Public health contributions. Schizophrenia bulletin. 33(5):1151-2. Pubmed: 17631617 -
Hyman SE. 2007. How mice cope with stressful social situations. Cell. 131(2):232-4. Pubmed: 17956724 Hyman SE. 2007. How mice cope with stressful social situations. Cell. 131(2):232-4. Pubmed: 17956724 Individuals differ greatly in their psychological responses to chronic stress. As a step toward understanding the neural basis for these individual differences, Krishnan et al. (2007) reveal molecular changes in the brain's reward circuits that make some mice resistant to the effects of social defeat. -
Hyman SE. 2007. The neurobiology of addiction: implications for voluntary control of behavior. The American journal of bioethics : AJOB. 7(1):8-11. Pubmed: 17366151 Hyman SE. 2007. The neurobiology of addiction: implications for voluntary control of behavior. The American journal of bioethics : AJOB. 7(1):8-11. Pubmed: 17366151 There continues to be a debate on whether addiction is best understood as a brain disease or a moral condition. This debate, which may influence both the stigma attached to addiction and access to treatment, is often motivated by the question of whether and to what extent we can justly hold addicted individuals responsible for their actions. In fact, there is substantial evidence for a disease model, but the disease model per se does not resolve the question of voluntary control. Recent research at the intersection of neuroscience and psychology suggests that addicted individuals have substantial impairments in cognitive control of behavior, but this "loss of control" is not complete or simple. Possible mechanisms and implications are briefly reviewed. -
Hyman SE. 2007. Neuroscience: obsessed with grooming. Nature. 448(7156):871-2. Pubmed: 17713517 Hyman SE. 2007. Neuroscience: obsessed with grooming. Nature. 448(7156):871-2. Pubmed: 17713517 -
Hyman SE. 2007. Can neuroscience be integrated into the DSM-V?. Nature reviews. Neuroscience. 8(9):725-32. Pubmed: 17704814 Hyman SE. 2007. Can neuroscience be integrated into the DSM-V?. Nature reviews. Neuroscience. 8(9):725-32. Pubmed: 17704814 To date, the diagnosis of mental disorders has been based on clinical observation, specifically: the identification of symptoms that tend to cluster together, the timing of the symptoms' appearance, and their tendency to resolve, recur or become chronic. The Diagnostic and Statistical Manual of Mental Disorders and the International Classification of Disease, the manuals that specify these diagnoses and the criteria for making them, are currently undergoing revision. It is thus timely to ask whether neuroscience has progressed to the point that the next editions of these manuals can usefully incorporate information about brain structure and function. 2006
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Hyman SE, Malenka RC, Nestler EJ. 2006. Neural mechanisms of addiction: the role of reward-related learning and memory. Annual review of neuroscience. 29:565-98. Pubmed: 16776597 Hyman SE, Malenka RC, Nestler EJ. 2006. Neural mechanisms of addiction: the role of reward-related learning and memory. Annual review of neuroscience. 29:565-98. Pubmed: 16776597 Addiction is a state of compulsive drug use; despite treatment and other attempts to control drug taking, addiction tends to persist. Clinical and laboratory observations have converged on the hypothesis that addiction represents the pathological usurpation of neural processes that normally serve reward-related learning. The major substrates of persistent compulsive drug use are hypothesized to be molecular and cellular mechanisms that underlie long-term associative memories in several forebrain circuits (involving the ventral and dorsal striatum and prefrontal cortex) that receive input from midbrain dopamine neurons. Here we review progress in identifying candidate mechanisms of addiction. -
Sgambato-Faure V, Xiong Y, Berke JD, Hyman SE, Strehler EE. 2006. The Homer-1 protein Ania-3 interacts with the plasma membrane calcium pump. Biochemical and biophysical research communications. 343(2):630-7. Pubmed: 16554037 DOI:10.1016/j.bbrc.2006.03.020 Sgambato-Faure V, Xiong Y, Berke JD, Hyman SE, Strehler EE. 2006. The Homer-1 protein Ania-3 interacts with the plasma membrane calcium pump. Biochemical and biophysical research communications. 343(2):630-7. Pubmed: 16554037 DOI:10.1016/j.bbrc.2006.03.020 The Homer family of scaffold proteins couples NMDA receptors to metabotropic glutamate receptors and links extracellular signals to calcium release from intracellular stores. Ania-3 is a member of the Homer family and is rapidly inducible in brain in response to diverse stimuli. Here, we report the identification of the plasma membrane Ca2+ ATPase (PMCA) as a novel Ania-3/Homer-associated protein. Ania-3/Homer interacts with the b-splice forms of all PMCAs (PMCA1b, 2b, 3b, and 4b) via their PDZ domain-binding COOH-terminal tail. Ectopically expressed Ania-3 colocalized with the PMCA at the plasma membrane of polarized MDCK epithelial cells, and endogenous Ania-3/Homer and PMCA2 are co-expressed in the soma and dendrites of primary rat hippocampal neurons. The interaction between Ania-3/Homer and PMCAs may represent a novel mechanism by which local calcium signaling and hence synaptic function can be modulated in neurons. -
Moldin SO, Rubenstein JL, Hyman SE. 2006. Can autism speak to neuroscience?. The Journal of neuroscience : the official journal of the Society for Neuroscience. 26(26):6893-6. Pubmed: 16807319 Moldin SO, Rubenstein JL, Hyman SE. 2006. Can autism speak to neuroscience?. The Journal of neuroscience : the official journal of the Society for Neuroscience. 26(26):6893-6. Pubmed: 16807319 -
Hyman SE. 2006. Even chromatin gets the blues. Nature neuroscience. 9(4):465-6. Pubmed: 16568101 Hyman SE. 2006. Even chromatin gets the blues. Nature neuroscience. 9(4):465-6. Pubmed: 16568101 2005
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Voulalas PJ, Holtzclaw L, Wolstenholme J, Russell JT, Hyman SE. 2005. Metabotropic glutamate receptors and dopamine receptors cooperate to enhance extracellular signal-regulated kinase phosphorylation in striatal neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience. 25(15):3763-73. Pubmed: 15829628 Voulalas PJ, Holtzclaw L, Wolstenholme J, Russell JT, Hyman SE. 2005. Metabotropic glutamate receptors and dopamine receptors cooperate to enhance extracellular signal-regulated kinase phosphorylation in striatal neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience. 25(15):3763-73. Pubmed: 15829628 Striatal medium spiny neurons are an important site of convergence for signaling mediated by the neurotransmitters dopamine and glutamate. We report that in striatal neurons in primary culture, signaling through group I metabotropic glutamate receptors (mGluRs) 1/5 and the D1 class of dopamine receptors (DRs) 1/5 converges to increase phosphorylation of the mitogen-activated protein kinase ERK2 (extracellular signal-regulated kinase 2). Induction of mitogen-activated protein kinase kinase-dependent signaling cascades by either mGluR1/5 or DR1/5 gave rise to increases in phosphorylation of ERK2. Coactivation of mGluR1/5 and DR1/5 with (S)-3,5-dihydroxyphenylglycine and (+)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride enhanced the phosphorylation of ERK2. This interaction between mGluR1/5 and DR1/5 required protein kinase C (PKC), because the PKC inhibitors calphostin C, bisindolylmaleimide I, and Gö6976 blocked DR1/5-enhanced phosphorylation of ERK2. Use of the phosphatase inhibitors calyculin and okadaic acid indicated that inhibition of protein phosphatases 1 and 2A dramatically enhanced ERK2 phosphorylation by mGluR1/5. Coactivation of mGluR1/5 and DR1/5 also enhanced cAMP-response element binding protein (CREB) phosphorylation (compared with each receptor agonist alone) but did not enhance CREB-mediated transcriptional activity. Thus, signal transduction pathways activated by DR1/5 and mGluR5 interact to modify downstream events in striatal neurons while retaining numerous regulatory checkpoints. -
Hyman SE. 2005. Neurotransmitters. Current biology : CB. 15(5):R154-8. Pubmed: 15753022 Hyman SE. 2005. Neurotransmitters. Current biology : CB. 15(5):R154-8. Pubmed: 15753022 -
Yehuda R, Hyman SE. 2005. The impact of terrorism on brain, and behavior: what we know and what we need to know. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 30(10):1773-80. Pubmed: 16012534 Yehuda R, Hyman SE. 2005. The impact of terrorism on brain, and behavior: what we know and what we need to know. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 30(10):1773-80. Pubmed: 16012534 Following the recent US experience with terrorism, including bioterrorism, significant biomedical research resources have been appropriately focused on bioterror weapons. Far less research attention has been focused on the behavioral and psychobiological effects of terrorism. Yet, the psychological responses to terrorism exert significant effects on mental and physical health and on society. We present a research agenda, based on a comprehensive review of the literature, to address the troubling gaps in our knowledge about the long-term effects of terrorism on brain, behavior, and physical health, the risk factors for predicting who will be most affected by terrorism, and interventions that might promote resilience at an individual and population level. -
Hyman SE. 2005. Addiction: a disease of learning and memory. The American journal of psychiatry. 162(8):1414-22. Pubmed: 16055762 Hyman SE. 2005. Addiction: a disease of learning and memory. The American journal of psychiatry. 162(8):1414-22. Pubmed: 16055762 If neurobiology is ultimately to contribute to the development of successful treatments for drug addiction, researchers must discover the molecular mechanisms by which drug-seeking behaviors are consolidated into compulsive use, the mechanisms that underlie the long persistence of relapse risk, and the mechanisms by which drug-associated cues come to control behavior. Evidence at the molecular, cellular, systems, behavioral, and computational levels of analysis is converging to suggest the view that addiction represents a pathological usurpation of the neural mechanisms of learning and memory that under normal circumstances serve to shape survival behaviors related to the pursuit of rewards and the cues that predict them. The author summarizes the converging evidence in this area and highlights key questions that remain. 2004
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Makris N, Gasic GP, Seidman LJ, Goldstein JM, Gastfriend DR, Elman I, Albaugh MD, Hodge SM, Ziegler DA, Sheahan FS, Caviness VS, Tsuang MT, Kennedy DN, Hyman SE, Rosen BR, Breiter HC. 2004. Decreased absolute amygdala volume in cocaine addicts. Neuron. 44(4):729-40. Pubmed: 15541319 Makris N, Gasic GP, Seidman LJ, Goldstein JM, Gastfriend DR, Elman I, Albaugh MD, Hodge SM, Ziegler DA, Sheahan FS, Caviness VS, Tsuang MT, Kennedy DN, Hyman SE, Rosen BR, Breiter HC. 2004. Decreased absolute amygdala volume in cocaine addicts. Neuron. 44(4):729-40. Pubmed: 15541319 The amygdala is instrumental to a set of brain processes that lead to cocaine consumption, including those that mediate reward and drug craving. This study examined the volumes of the amygdala and hippocampus in cocaine-addicted subjects and matched healthy controls and determined that the amygdala but not the hippocampus was significantly reduced in volume. The right-left amygdala asymmetry in control subjects was absent in the cocaine addicts. Topological analysis of amygdala isosurfaces (population averages) revealed that the isosurface of the cocaine-dependent group undercut the anterior and superior surfaces of the control group, implicating a difference in the corticomedial and basolateral nuclei. In cocaine addicts, amygdala volume did not correlate with any measure of cocaine use. The amygdala symmetry coefficient did correlate with baseline but not cocaine-primed craving. These findings argue for a condition that predisposes the individual to cocaine dependence by affecting the amygdala, or a primary event early in the course of cocaine use. -
Montague PR, Hyman SE, Cohen JD. 2004. Computational roles for dopamine in behavioural control. Nature. 431(7010):760-7. Pubmed: 15483596 Montague PR, Hyman SE, Cohen JD. 2004. Computational roles for dopamine in behavioural control. Nature. 431(7010):760-7. Pubmed: 15483596 Neuromodulators such as dopamine have a central role in cognitive disorders. In the past decade, biological findings on dopamine function have been infused with concepts taken from computational theories of reinforcement learning. These more abstract approaches have now been applied to describe the biological algorithms at play in our brains when we form value judgements and make choices. The application of such quantitative models has opened up new fields, ripe for attack by young synthesizers and theoreticians. -
Hyman SE. 2004. Introduction: the brain's special status. Cerebrum : the Dana forum on brain science. 6(4):9-12. Pubmed: 15986528 Hyman SE. 2004. Introduction: the brain's special status. Cerebrum : the Dana forum on brain science. 6(4):9-12. Pubmed: 15986528 2003
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Hyman SE, Fenton WS. 2003. Medicine. What are the right targets for psychopharmacology?. Science (New York, N.Y.). 299(5605):350-1. Pubmed: 12532001 Hyman SE, Fenton WS. 2003. Medicine. What are the right targets for psychopharmacology?. Science (New York, N.Y.). 299(5605):350-1. Pubmed: 12532001 -
Hyman SE. 2003. Methylphenidate-induced plasticity: what should we be looking for?. Biological psychiatry. 54(12):1310-1. Pubmed: 14675793 Hyman SE. 2003. Methylphenidate-induced plasticity: what should we be looking for?. Biological psychiatry. 54(12):1310-1. Pubmed: 14675793 -
Hyman SE. 2003. Diagnosing disorders. Scientific American. 289(3):96-103. Pubmed: 12951833 Hyman SE. 2003. Diagnosing disorders. Scientific American. 289(3):96-103. Pubmed: 12951833 -
Sgambato V, Minassian R, Nairn AC, Hyman SE. 2003. Regulation of ania-6 splice variants by distinct signaling pathways in striatal neurons. Journal of neurochemistry. 86(1):153-64. Pubmed: 12807435 Sgambato V, Minassian R, Nairn AC, Hyman SE. 2003. Regulation of ania-6 splice variants by distinct signaling pathways in striatal neurons. Journal of neurochemistry. 86(1):153-64. Pubmed: 12807435 The striatum is a brain region involved in motor control and in diverse forms of implicit memory. It is also involved in the pathogenesis of many significant human disorders, including drug addiction, that are thought to involve adaptive changes in gene expression. We have previously shown that the cyclin L, ania-6, is expressed as at least two splice forms, which are differentially regulated in striatal neurons by different neurotransmitters. Here, we report that ania-6 transcription is mostly regulated via cAMP response element binding protein (CREB), but that signaling pathways that converge on CREB at the transcriptional level produce different effects on splicing and neuronal gene expression. Glutamate induced a long ania-6 mRNA that encodes a truncated form of the cyclin. This effect depended on the activation of NMDA receptors but was independent of both calcium/calmodulin-dependent protein kinases (CaMK) and extracellular regulated kinase (ERK). Forskolin or brain-derived neurotropic factor (BDNF) induced a short ania-6 mRNA, that encodes the full-length cyclin, and this induction depended on ERK. However, KCl-mediated induction of ania-6 short mRNA, which required activation of L-type calcium channels, was independent of ERK but depended on CaMK. These data suggest that different neuronal signals can differentially regulate splicing and that different intracellular pathways can be recruited to yield a given splice variant. 2002
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Lo B, Albert MS, Hyman S, Parens E, Wolpe PR, Mobley W. 2002. Ethics and the practice of brain science. Cerebrum : the Dana forum on brain science. 4(3):64-6. Pubmed: 16619416 Lo B, Albert MS, Hyman S, Parens E, Wolpe PR, Mobley W. 2002. Ethics and the practice of brain science. Cerebrum : the Dana forum on brain science. 4(3):64-6. Pubmed: 16619416 -
Hyman SE. 2002. Neuroscience, genetics, and the future of psychiatric diagnosis. Psychopathology. 35(2-3):139-44. Pubmed: 12145499 Hyman SE. 2002. Neuroscience, genetics, and the future of psychiatric diagnosis. Psychopathology. 35(2-3):139-44. Pubmed: 12145499 Nearly three decades after Robins and Guze's seminal delineation of the steps required to validate a psychiatric diagnosis, a pathophysiologically based classification of psychiatric disorders remains elusive. Contrary to optimistic expectations, approaches to diagnostic validity based on clinical description, laboratory studies, natural history of illness, and familial aggregation have not converged to yield a nosology based on valid disease entities. Defining a rational nosology for disorders of the brain, the body's most complex organ, is clearly one of the great challenges for modern medical science. Nonetheless, fundamental advances in our understanding of the genetic and environmental determinants of disease risk, and of the neural circuitry supporting normal and pathological mental processes promises to form the basis of improved classification in the coming decades.Copyright 2002 S. Karger AG, Basel -
Hyman SE. 2002. A new beginning for research on borderline personality disorder. Biological psychiatry. 51(12):933-5. Pubmed: 12062876 Hyman SE. 2002. A new beginning for research on borderline personality disorder. Biological psychiatry. 51(12):933-5. Pubmed: 12062876 -
Kupfer DJ, Hyman SE, Schatzberg AF, Pincus HA, Reynolds CF. 2002. Recruiting and retaining future generations of physician scientists in mental health. Archives of general psychiatry. 59(7):657-60. Pubmed: 12090819 Kupfer DJ, Hyman SE, Schatzberg AF, Pincus HA, Reynolds CF. 2002. Recruiting and retaining future generations of physician scientists in mental health. Archives of general psychiatry. 59(7):657-60. Pubmed: 12090819 The authors discuss 6 challenges facing the recruitment and retention of physician scientists as career mental health researchers. These challenges include (1) early identification and recruitment at the undergraduate and medical student level; (2) recruitment of a more diverse group of trainees; (3) safety nets for reducing attrition; (4) strategies to promote successful competition for K awards; (5) definition of appropriate roles and career development opportunities in multisite clinical trials; and (6) strategies for the mentoring "cost." A coalition of stakeholders--federal, academic, foundational, and in the pharmaceutical industry--is needed to meet these challenges. -
Kopnisky KL, Cowan WM, Hyman SE. 2002. Levels of analysis in psychiatric research. Development and psychopathology. 14(3):437-61. Pubmed: 12349868 Kopnisky KL, Cowan WM, Hyman SE. 2002. Levels of analysis in psychiatric research. Development and psychopathology. 14(3):437-61. Pubmed: 12349868 Most of the major psychiatric disorders have been analyzed at each of several different levels. For example, at the broadest level, epidemiological studies have served to establish the incidence of disorders like schizophrenia and major depression in a number of different populations. Family and twin studies have been important in determining the heritability of certain mental illnesses, and chromosomal and linkage analyses have identified a number of discrete loci that appear to be implicated in disease susceptibility or, even directly, in the pathogenesis of some disorders. In a few cases, specific genes have been found to be mutated or polymorphic and proteins they encode are currently being analyzed. This article reviews how these different levels contribute to our understanding of a number of psychiatric disorders, including drug addiction, which has been the focus of much of our own work. -
Cowan WM, Kopnisky KL, Hyman SE. 2002. The human genome project and its impact on psychiatry. Annual review of neuroscience. 25:1-50. Pubmed: 12052903 Cowan WM, Kopnisky KL, Hyman SE. 2002. The human genome project and its impact on psychiatry. Annual review of neuroscience. 25:1-50. Pubmed: 12052903 There has been substantial evidence for more than three decades that the major psychiatric illnesses such as schizophrenia, bipolar disorder, autism, and alcoholism have a strong genetic basis. During the past 15 years considerable effort has been expended in trying to establish the genetic loci associated with susceptibility to these and other mental disorders using principally linkage analysis. Despite this, only a handful of specific genes have been identified, and it is now generally recognized that further advances along these lines will require the analysis of literally hundreds of affected individuals and their families. Fortunately, the emergence in the past three years of a number of new approaches and more effective tools has given new hope to those engaged in the search for the underlying genetic and environmental factors involved in causing these illnesses, which collectively are among the most serious in all societies. Chief among these new tools is the availability of the entire human genome sequence and the prospect that within the next several years the entire complement of human genes will be known and the functions of most of their protein products elucidated. In the meantime the search for susceptibility loci is being facilitated by the availability of single nucleotide polymorphisms (SNPs) and by the beginning of haplotype mapping, which tracks the distribution of clusters of SNPs that segregate as a group. Together with high throughput DNA sequencing, microarrays for whole genome scanning, advances in proteomics, and the development of more sophisticated computer programs for analyzing sequence and association data, these advances hold promise of greatly accelerating the search for the genetic basis of most mental illnesses while, at the same time, providing molecular targets for the development of new and more effective therapies. -
Hyman SE. 2002. Managing emotional fallout. Parting remarks from America's top psychiatrist. Interview by Diane Coutu. Harvard business review. 80(2):55-60, 127. Pubmed: 11894678 Hyman SE. 2002. Managing emotional fallout. Parting remarks from America's top psychiatrist. Interview by Diane Coutu. Harvard business review. 80(2):55-60, 127. Pubmed: 11894678 Last fall, the United States was brutally thrust into a new and dangerous world. As the twin towers of the World Trade Center collapsed and the Pentagon burned, the horrible reality of terrorism seared the American consciousness. It touched more than the victims and their families; everyone who sat transfixed before the horrific images on TV lived through the trauma. In a sense, we were all eyewitnesses, and we must all cope with feelings of anger, stress, and anxiety. That poses a huge immediate challenge for business, because it is largely in the workplace--where we spend so many of our waking hours--that we will confront these emotions. And many companies have risen to the challenge, establishing new guidelines for processing mail in light of anthrax fears and organizing stress reduction programs for employees. While the logic of taking such action is incontestable, it raises a much larger question: What responsibility does a company bear for the mental well-being of its work-force? If companies help employees deal with depression and anxiety in the wake of terrorist acts, doesn't that put mental health care on the business agenda? To answer these questions, HBR senior editor Diane Coutu talked with Dr. Steven Hyman, the former director of the National Institute for Mental Health. In this interview, he discusses the implications of coping with tragedy, the resilience of individuals, and the treatment of mental illness. And he suggests that September 11, 2001, may come to be seen as a tipping point--the moment when managers started to think about dealing with mental health issues on a regular basis. 2001
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Hyman SE. 2001. Mental health in an aging population: the NIMH perspective. The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry. 9(4):330-9. Pubmed: 11739060 Hyman SE. 2001. Mental health in an aging population: the NIMH perspective. The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry. 9(4):330-9. Pubmed: 11739060 -
Berke JD, Sgambato V, Zhu PP, Lavoie B, Vincent M, Krause M, Hyman SE. 2001. Dopamine and glutamate induce distinct striatal splice forms of Ania-6, an RNA polymerase II-associated cyclin. Neuron. 32(2):277-87. Pubmed: 11683997 Berke JD, Sgambato V, Zhu PP, Lavoie B, Vincent M, Krause M, Hyman SE. 2001. Dopamine and glutamate induce distinct striatal splice forms of Ania-6, an RNA polymerase II-associated cyclin. Neuron. 32(2):277-87. Pubmed: 11683997 Control of neuronal gene expression by drugs or neurotransmitters is a critical step in long-term neural plasticity. Here, we show that a gene induced in the striatum by cocaine or direct dopamine stimulation, ania-6, is a member of a novel family of cyclins with homology to cyclins K/T/H/C. Further, different types of neurotransmitter stimulation cause selective induction of distinct ania-6 isoforms, through alternative splicing. The longer Ania-6 protein colocalizes with nuclear speckles and is associated with key elements of the RNA elongation/processing complex, including the hyperphosphorylated form of RNA polymerase II, the splicing factor SC-35, and the p110 PITSLRE cyclin-dependent kinase. Distinct types of neuronal stimulation may therefore differentially modulate nuclear RNA processing, through altered transcription and splicing of ania-6. -
Hyman SE. 2001. A 28-year-old man addicted to cocaine. JAMA. 286(20):2586-94. Pubmed: 11722273 Hyman SE. 2001. A 28-year-old man addicted to cocaine. JAMA. 286(20):2586-94. Pubmed: 11722273 -
Hyman SE, Malenka RC. 2001. Addiction and the brain: the neurobiology of compulsion and its persistence. Nature reviews. Neuroscience. 2(10):695-703. Pubmed: 11584307 Hyman SE, Malenka RC. 2001. Addiction and the brain: the neurobiology of compulsion and its persistence. Nature reviews. Neuroscience. 2(10):695-703. Pubmed: 11584307 People take addictive drugs to elevate mood, but with repeated use these drugs produce serious unwanted effects, which can include tolerance to some drug effects, sensitization to others, and an adapted state - dependence - which sets the stage for withdrawal symptoms when drug use stops. The most serious consequence of repetitive drug taking, however, is addiction: a persistent state in which compulsive drug use escapes control, even when serious negative consequences ensue. Addiction is characterized by a long-lasting risk of relapse, which is often initiated by exposure to drug-related cues. Substantial progress has been made in understanding the molecular and cellular mechanisms of tolerance, dependence and withdrawal, but as yet we understand little of the neural substrates of compulsive drug use and its remarkable persistence. Here we review evidence for the possibility that compulsion and its persistence are based on a pathological usurpation of molecular mechanisms that are normally involved in memory. -
Kosofsky BE, Hyman SE. 2001. No time for complacency: the fetal brain on drugs. The Journal of comparative neurology. 435(3):259-62. Pubmed: 11406809 Kosofsky BE, Hyman SE. 2001. No time for complacency: the fetal brain on drugs. The Journal of comparative neurology. 435(3):259-62. Pubmed: 11406809 -
Hyman SE. 2001. Mood disorders in children and adolescents: an NIMH perspective. Biological psychiatry. 49(12):962-9. Pubmed: 11430838 Hyman SE. 2001. Mood disorders in children and adolescents: an NIMH perspective. Biological psychiatry. 49(12):962-9. Pubmed: 11430838 2000
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Hyman S. 2000. Mental illness: genetically complex disorders of neural circuitry and neural communication. Neuron. 28(2):321-3. Pubmed: 11144341 Hyman S. 2000. Mental illness: genetically complex disorders of neural circuitry and neural communication. Neuron. 28(2):321-3. Pubmed: 11144341 -
Hyman SE. 2000. Genes, gene expression, and behavior. Neurobiology of disease. 7(5):528-32. Pubmed: 11042069 Hyman SE. 2000. Genes, gene expression, and behavior. Neurobiology of disease. 7(5):528-32. Pubmed: 11042069 -
Hyman SE, Shore D. 2000. An NIMH perspective on the use of placebos. National Institute of Mental Health. Biological psychiatry. 47(8):689-91. Pubmed: 10773173 Hyman SE, Shore D. 2000. An NIMH perspective on the use of placebos. National Institute of Mental Health. Biological psychiatry. 47(8):689-91. Pubmed: 10773173 -
Berke JD, Hyman SE. 2000. Addiction, dopamine, and the molecular mechanisms of memory. Neuron. 25(3):515-32. Pubmed: 10774721 Berke JD, Hyman SE. 2000. Addiction, dopamine, and the molecular mechanisms of memory. Neuron. 25(3):515-32. Pubmed: 10774721 -
Hyman SE. 2000. The NIMH perspective: next steps in schizophrenia research. Biological psychiatry. 47(1):1-7. Pubmed: 10650443 Hyman SE. 2000. The NIMH perspective: next steps in schizophrenia research. Biological psychiatry. 47(1):1-7. Pubmed: 10650443 -
Hyman SE. 2000. The genetics of mental illness: implications for practice. Bulletin of the World Health Organization. 78(4):455-63. Pubmed: 10885164 Hyman SE. 2000. The genetics of mental illness: implications for practice. Bulletin of the World Health Organization. 78(4):455-63. Pubmed: 10885164 Many of the comfortable and relatively simple models of the nature of mental disorders, their causes and their neural substrates now appear quite frayed. Gone is the idea that symptom clusters, course of illness, family history and treatment response would coalesce in a simple way to yield valid diagnoses. Also too simple was the concept, born of early pharmacological successes, that abnormal levels of one or more neurotransmitters would satisfactorily explain the pathogenesis of depression or schizophrenia. Gone is the notion that there is a single gene that causes any mental disorder or determines any behavioural variant. The concept of the causative gene has been replaced by that of genetic complexity, in which multiple genes act in concert with non-genetic factors to produce a risk of mental disorder. Discoveries in genetics and neuroscience can be expected to lead to better models that provide improved representation of the complexity of the brain and behaviour and the development of both. There are likely to be profound implications for clinical practice. The complex genetics of risk should reinvigorate research on the epidemiology and classification of mental disorders and explain the complex patterns of disease transmission within families. Knowledge of the timing of the expression of risk genes during brain development and of their function should not only contribute to an understanding of gene action and the pathophysiology of disease but should also help to direct the search for modifiable environmental risk factors that convert risk into illness. The function of risk genes can only become comprehensible in the context of advances at the molecular, cellular and systems levels in neuroscience and the behavioural sciences. Genetics should yield new therapies aimed not just at symptoms but also at pathogenic processes, thus permitting the targeting of specific therapies to individual patients. -
Hyman SE. 2000. The millennium of mind, brain, and behavior. Archives of general psychiatry. 57(1):88-9. Pubmed: 10632239 Hyman SE. 2000. The millennium of mind, brain, and behavior. Archives of general psychiatry. 57(1):88-9. Pubmed: 10632239 Psychiatry enters the new millennium poised to answer many of its central questions. Given the complexity of the human brain and its interactions with our world, these questions are among the most difficult ever addressed by human science. How is the human brain built? How does it change over the life span? What are the precise genetic and environmental risk factors for mental illnesses? What are the pathophysiologic processes that produce the symptoms and disabilities? How do our treatments, including psychotherapy, work? What objective markers can we discover to monitor the progression of the pathogenic processes and the effects of treatment? How will we discover preventive measures and cures that will be effective in diverse populations and settings? Parallel to the pursuit of its public health agenda, psychiatry will grow closer to neuroscience, behavioral science, and neurology. In so doing, those who practice these disciplines will be better positioned to ask meaningful questions about the relationship among mind, brain, and behavior, and to finally overcome the pervasive Cartesianism that continues to incubate stigma and ignorance about mental illness. -
Hyman SE. 2000. National Institute of Mental Health goals for behavioral science. Experimental and clinical psychopharmacology. 8(3):271-2. Pubmed: 10975615 Hyman SE. 2000. National Institute of Mental Health goals for behavioral science. Experimental and clinical psychopharmacology. 8(3):271-2. Pubmed: 10975615 Because all health conditions for which the National Institute of Mental Health (NIMH) is responsible manifest at the level of behavior, and all interventions must have an impact at the behavioral level, NIMH is firmly committed to the support of behavioral science. In an era in which research in areas that some view as reductionist--for example, genomics, genetics, functional genomics and proteomics, and molecular science--is especially promising, NIMH is striving to maintain a balance in its portfolio with studies that explore integrative aspects of biology, including behavior. Without this perspective, new information about fundamental processes will prove ultimately to be shallow. This commentary discusses how understanding of brain and behavior in mental illness and health calls for integrating bottom-up research that studies brain and behavior through genes and molecules, with top-down research that examines the impact of environment. -
Hyman SE. 2000. Goals for research on bipolar disorder: the view from NIMH. Biological psychiatry. 48(6):436-41. Pubmed: 11018216 Hyman SE. 2000. Goals for research on bipolar disorder: the view from NIMH. Biological psychiatry. 48(6):436-41. Pubmed: 11018216 We have much yet to accomplish in research on bipolar disorder. We must find vulnerability genes. We must identify the circuits that regulate mood, emotion, energy, and other relevant functions that are affected in bipolar disorder, and we must determine what goes wrong in those circuits during mania, depression, and other aspects of this illness. We will need to translate findings in basic neuroscience, genetics, and basic behavioral science into diverse clinical applications: novel treatments, diagnostic tools, epidemiologic approaches that could lead to preventive interventions, and surrogate markers for clinical trials. We must develop improved psychosocial interventions and test both pharmacologic and psychosocial treatments in trials that, simultaneously, improve the quality of care available and convince insurers and employers that these treatments are of substantial benefit and cost effective. The agenda is ambitious, but entirely feasible, given the scientific tools and technologies that are currently available or on the horizon. The National Institute of Mental Health is newly recommitted to harnessing these tools and technologies for the benefit of people with bipolar disorder. -
Hyman SE. 2000. The needs for database research and for privacy collide. The American journal of psychiatry. 157(11):1723-4. Pubmed: 11058462 Hyman SE. 2000. The needs for database research and for privacy collide. The American journal of psychiatry. 157(11):1723-4. Pubmed: 11058462 -
Kogai T, Curcio F, Hyman S, Cornford EM, Brent GA, Hershman JM. 2000. Induction of follicle formation in long-term cultured normal human thyroid cells treated with thyrotropin stimulates iodide uptake but not sodium/iodide symporter messenger RNA and protein expression. The Journal of endocrinology. 167(1):125-35. Pubmed: 11018760 Kogai T, Curcio F, Hyman S, Cornford EM, Brent GA, Hershman JM. 2000. Induction of follicle formation in long-term cultured normal human thyroid cells treated with thyrotropin stimulates iodide uptake but not sodium/iodide symporter messenger RNA and protein expression. The Journal of endocrinology. 167(1):125-35. Pubmed: 11018760 Iodide uptake by the sodium/iodide symporter (NIS) in thyrocytes is essential for thyroid hormone production. Reduced NIS activity has been reported in thyroid diseases, including thyroid cancer and congenital hypothyroidism. The study of iodide uptake in thyrocytes has been limited by the availability of appropriate in vitro models. A new culture technique was recently developed that allows normal human thyroid primary culture cells to grow as monolayer cells and express differentiated functions for more than 3 months. We used this technique to study the effect of follicle formation and TSH on iodide uptake in these cells. Iodide uptake by the cells grown in monolayer was very low. Follicle formation was induced from monolayer cells, and electron micrographs demonstrated cell polarity in the follicles. No significant increase in iodide uptake was observed after TSH treatment of cells in monolayer or when follicle formation was induced without TSH. TSH stimulation of follicles, however, significantly increased iodide uptake ( approximately 4. 4-fold; P<0.001). Compared with iodide uptake in monolayers, the combination of follicle formation and TSH treatment stimulated iodide uptake synergistically to 12.0-fold (P<0.001). NIS messenger RNA (mRNA) and protein levels were almost the same in both monolayer cells and follicles. TSH treatment of monolayers and follicles produced significant (P<0.05) stimulation of mRNA ( approximately 4. 8- and approximately 4.3-fold respectively) and protein ( approximately 6.8- and 4.9-fold respectively). TSH stimulated NIS protein levels in both monolayer and follicles, however, stimulation of functional iodide uptake was only seen with TSH stimulation of follicles. The function of NIS may involve post-transcriptional events, such as intracellular sorting, membrane localization of NIS or another NIS regulatory factor. Polarized functions, such as iodide efflux into follicular lumina, may also contribute to the increased iodide concentration after follicle formation. 1999
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Norquist G, Hyman SE. 1999. Advances in understanding and treating mental illness: implications for policy. Health affairs (Project Hope). 18(5):32-47. Pubmed: 10495590 Norquist G, Hyman SE. 1999. Advances in understanding and treating mental illness: implications for policy. Health affairs (Project Hope). 18(5):32-47. Pubmed: 10495590 Mental illnesses have a significant impact on public health and contribute to a substantial part of the disability of the general population. Recent research on understanding and treating such illnesses has produced data that can inform policymakers about how to improve the condition of persons who suffer from these illnesses. This paper discusses how this research can be used to inform policy decisions regarding the allocation of community treatment resources and what research is still needed. -
Morwood DT, Nichter LS, Hyman S, Bindiger A, Miller JH, McComb JG. 1999. Omental transfer to the brain: an experimental study in hydrocephalic rabbits. Annals of plastic surgery. 42(2):174-9. Pubmed: 10029483 Morwood DT, Nichter LS, Hyman S, Bindiger A, Miller JH, McComb JG. 1999. Omental transfer to the brain: an experimental study in hydrocephalic rabbits. Annals of plastic surgery. 42(2):174-9. Pubmed: 10029483 Hydrocephalus is a common and potentially lethal condition in children that results from an imbalance between absorption and production of cerebral spinal fluid (CSF). Silastic shunts are inserted to drain excess CSF, but they are prone to a number of problems, and at times may be unreliable and ineffective. This study examines the physiological basis of a pedicled omental transfer to the brain as a functional conduit for CSF in an experimentally induced hydrocephalic rabbit model. The ability of the omentum to transport CSF from the subarachnoid space was tested using radioactive tracer substances: radio-iodinated serum albumin (125I-RISA), chromium 51-ethylenediaminetetraacetate (51Cr-EDTA), and technetium 99m (99mTc) glucoheptonate. Immediate ability of exteriorized omentum to transport artificial CSF, as well as transposed omental transport of subarachnoid CSF at 1 month, were examined. Nuclear scan measurements were correlated with clinical observation and a double-blind histological analysis with trichrome and hematoxylin-eosin stain. Exteriorized omentum rapidly absorbed 99mTc glucoheptonate-labeled artificial CSF, with a rapid appearance in the systemic circulatory and urinary systems. Transposed omentum to the brain in animals with artificially created hydrocephalus showed evidence of CSF-labeled 125I-RISA and 51Cr-EDTA absorption in those animals demonstrating histologically viable omentum. -
Kobierski LA, Wong AE, Srivastava S, Borsook D, Hyman SE. 1999. Cyclic AMP-dependent activation of the proenkephalin gene requires phosphorylation of CREB at serine-133 and a Src-related kinase. Journal of neurochemistry. 73(1):129-38. Pubmed: 10386963 Kobierski LA, Wong AE, Srivastava S, Borsook D, Hyman SE. 1999. Cyclic AMP-dependent activation of the proenkephalin gene requires phosphorylation of CREB at serine-133 and a Src-related kinase. Journal of neurochemistry. 73(1):129-38. Pubmed: 10386963 The transcription factor CREB [cyclic AMP response element (CRE)-binding protein] is activated by several kinase pathways on phosphorylation of serine-133. Phosphorylation of CREB at serine-133 is required for the induction of target gene expression. The proenkephalin gene is a target of cyclic AMP-dependent agonists like forskolin, and its expression is driven by the enhancer element CRE-2. It has been shown that CREB binds CRE-2 in extracts from striatum and hypothalamus. However, these studies did not show a functional requirement for CREB serine-133 phosphorylation in CRE-2 function. We demonstrate that CREB binds CRE-2 in primary astrocyte cultures and that transcriptional activation of CRE-2 requires CREB phosphorylation at serine-133. In addition, it has recently been shown that, at least in some contexts, CREB phosphorylation is not sufficient to activate target gene expression and that another intracellular signal seems to be required. Therefore, we also sought to determine if another signaling event, in addition to CREB phosphorylation, might be involved in cyclic AMP-mediated induction of the proenkephalin gene. We have found that the inhibition of src-related nonreceptor tyrosine kinases blocks forskolin-induced proenkephalin gene expression without having any effect on serine-133-phosphorylated CREB levels and that constitutively activated src kinase can activate the proenkephalin promoter. -
Schwarzschild MA, Cole RL, Meyers MA, Hyman SE. 1999. Contrasting calcium dependencies of SAPK and ERK activations by glutamate in cultured striatal neurons. Journal of neurochemistry. 72(6):2248-55. Pubmed: 10349832 Schwarzschild MA, Cole RL, Meyers MA, Hyman SE. 1999. Contrasting calcium dependencies of SAPK and ERK activations by glutamate in cultured striatal neurons. Journal of neurochemistry. 72(6):2248-55. Pubmed: 10349832 Stress-activated protein kinase (SAPK) and extracellular signal-regulated kinase (ERK), both members of the mitogen-activated protein kinase (MAPK) family, may in some circumstances serve opposing functions with respect to cell survival. However, SAPK and ERK can also be coordinately activated in neurons in response to glutamate stimulation of NMDA receptors. To explore the mechanisms of these MAPK activations, we compared the ionic mechanisms mediating SAPK and ERK activations by glutamate. In primary cultures of striatal neurons, glutamatergic activation of ERK and one of its transcription factor targets, CREB, showed a calcium dependence typical of NMDA receptor-mediated responses. In contrast, extracellular calcium was not required for glutamatergic, NMDA receptor-mediated activation of SAPK and phosphorylation of its substrate, c-Jun. Increasing extracellular calcium enhanced ERK activation but reversed SAPK activation, further distinguishing the calcium dependencies of these two NMDA receptor-mediated effects. Finally, reducing extracellular sodium prevented the glutamatergic activation of SAPK but only partially blocked that of ERK. These contrasting ionic dependencies suggest a mechanism by which NMDA receptor activation may, under distinct conditions, differentially regulate neuronal MAPKs and their divergent functions. -
Van Koughnet K, Smirnova O, Hyman SE, Borsook D. 1999. Proenkephalin transgene regulation in the paraventricular nucleus of the hypothalamus by lipopolysaccharide and interleukin-1beta. The Journal of comparative neurology. 405(2):199-215. Pubmed: 10023810 Van Koughnet K, Smirnova O, Hyman SE, Borsook D. 1999. Proenkephalin transgene regulation in the paraventricular nucleus of the hypothalamus by lipopolysaccharide and interleukin-1beta. The Journal of comparative neurology. 405(2):199-215. Pubmed: 10023810 Immunologic challenge with lipopolysaccharide (LPS) or interleukin-1beta (IL-1beta) produces a functional response within the paraventricular nucleus of the hypothalamus (PVN) and leads to changes in gene expression within PVN neurons. Regulated expression of neuropeptide genes within neurons of the PVN is a potential mechanism by which an organism can adapt to stressful challenges. Here, the authors used a transgenic mouse model in which expression of a readily measurable beta-galactosidase reporter was driven in PVN neurons by human proenkephalin regulatory sequences. This proenkephalin-beta-galactosidase transgene has been demonstrated previously to respond appropriately to a variety of stressors. It is demonstrated that expression of the proenkephalin transgene product was up-regulated significantly in a subset of PVN neurons 6 hours following intraperitoneal LPS (16-400 microg/kg) administration, remained elevated at 12 hours, and fell below basal levels by 24 hours. A more rapid and transient pattern of transgene up-regulation in the PVN followed administration of intraperitoneal IL-1beta (10 microg/kg) with significant induction by 2 hours, peak levels reached by 4 hours, and a return toward basal levels by 6 hours. IL-1beta (10-50 ng/mouse) administered intracerebroventricularly also led to up-regulation of the transgene 6 hours following infusion. Transgene expression was not up-regulated in hypothalamic slice cultures treated directly with IL-1beta (5-10 ng/ml media). Up-regulation of transgene expression does not appear to result from local action of IL-1beta at the level of the PVN but, rather, through as yet unidentified intermediates. The authors demonstrate phosphorylation of the cyclic amino-3-hydroxy-5-methyl-4-isoxazolepropionate response element binding protein, a transcription factor known to interact with proenkephalin regulatory sequences within the transgene, in the PVN following LPS administration. LPS induced up-regulation of the transgene was blocked by pretreatment with naltrexone, indicating an additional role for endogenous opioid systems in regulation of the PVN response to immune challenge. -
Hyman SE. 1999. Introduction to the complex genetics of mental disorders. Biological psychiatry. 45(5):518-21. Pubmed: 10088041 Hyman SE. 1999. Introduction to the complex genetics of mental disorders. Biological psychiatry. 45(5):518-21. Pubmed: 10088041 -
Hyman SE. 1999. Protecting patients, preserving progress: ethics in mental health illness research. Academic medicine : journal of the Association of American Medical Colleges. 74(3):258-9. Pubmed: 10099647 Hyman SE. 1999. Protecting patients, preserving progress: ethics in mental health illness research. Academic medicine : journal of the Association of American Medical Colleges. 74(3):258-9. Pubmed: 10099647 -
Shore D, Hyman SE. 1999. NIMH symptom challenge and medication discontinuation workshop. Biological psychiatry. 46(8):1009-10. Pubmed: 10536734 Shore D, Hyman SE. 1999. NIMH symptom challenge and medication discontinuation workshop. Biological psychiatry. 46(8):1009-10. Pubmed: 10536734 -
Hyman SE. 1999. Selective gene expression increases behavioral sensitivity to cocaine. Nature neuroscience. 2(10):855-6. Pubmed: 10491599 Hyman SE. 1999. Selective gene expression increases behavioral sensitivity to cocaine. Nature neuroscience. 2(10):855-6. Pubmed: 10491599 Addictive drugs induce a truncated form of fosB in the striatum. A new study shows that mice engineered to mimic this expression pattern are abnormally sensitive to cocaine. -
Mosher LR, Goodwin FK, Thompson J, Hyman SE, Emmet W. 1999. Are psychiatrists betraying their patients?. Psychology today. 32(5):40-42, 80, 82. Pubmed: 11660751 Mosher LR, Goodwin FK, Thompson J, Hyman SE, Emmet W. 1999. Are psychiatrists betraying their patients?. Psychology today. 32(5):40-42, 80, 82. Pubmed: 11660751 -
Shore D, Hyman SE. 1999. An NIMH commentary on the NBAC report. Biological psychiatry. 46(8):1013-6. Pubmed: 10536736 Shore D, Hyman SE. 1999. An NIMH commentary on the NBAC report. Biological psychiatry. 46(8):1013-6. Pubmed: 10536736 1998
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Cornford EM, Hyman S, Cornford ME, Damian RT. 1998. Glut1 glucose transporter in the primate choroid plexus endothelium. Journal of neuropathology and experimental neurology. 57(5):404-14. Pubmed: 9596411 Cornford EM, Hyman S, Cornford ME, Damian RT. 1998. Glut1 glucose transporter in the primate choroid plexus endothelium. Journal of neuropathology and experimental neurology. 57(5):404-14. Pubmed: 9596411 The objective of the present study was to define the cellular location of the Glut1 glucose transporter in the primate choroid plexus. Immunogold electron microscopy indicated that Glut1 epitopes were associated primarily with choroid plexus endothelial cells. Digitized analyses of electron microscopic images provided quantitative estimates of the relative number of Glut1 glucose transporter epitopes on luminal and abluminal endothelial cell membranes within the choroid plexuses. We recorded a high density of Glut1 in the microvascular endothelium of primate choroid plexus, which was consistent in vervet monkeys (5-10 Glut1 gold particles per micrometer of endothelial cell plasma membrane), as well as in baboons (5-20 Glut1 gold particles per micrometer of capillary plasma membrane). In the baboon choroid plexus, we observed that perivascular cells (presumed to be pericytes) were also Glut1-positive, but with substantially reduced activity compared with endothelial cells. Occasional Glut1-immunogold particles were also seen in the basolateral membranes of the choroid plexus cuboidal cells. Light microscopic immunocytochemistry confirmed the abundance of Glut1 immunoreactivity in choroid plexus endothelial cells of vervet monkeys and baboons. A similar pattern was observed in surgically resected human choroid plexus, suggesting differences between primates, including humans and laboratory animals. The only difference was that erythrocytes within the human choroid plexus exhibited a florid Glut1-positive response, but were weakly immunoreactive in nonhuman primates. The observation of high glucose transporter densities in choroid plexus endothelial cells is consistent with the suggestion that choroidal epithelia and capillaries provide a metabolic work capability for maintaining ionic gradients and secretory functions across the blood-CSF barriers. -
Hyman SE. 1998. The K-05 award controversy. Archives of general psychiatry. 55(1):21-2. Pubmed: 9435755 Hyman SE. 1998. The K-05 award controversy. Archives of general psychiatry. 55(1):21-2. Pubmed: 9435755 -
Hyman SE. 1998. Brain neurocircuitry of anxiety and fear: implications for clinical research and practice. Biological psychiatry. 44(12):1201-3. Pubmed: 9861461 Hyman SE. 1998. Brain neurocircuitry of anxiety and fear: implications for clinical research and practice. Biological psychiatry. 44(12):1201-3. Pubmed: 9861461 -
Genova LM, Hyman SE. 1998. 5-HT3 receptor activation is required for induction of striatal c-Fos and phosphorylation of ATF-1 by amphetamine. Synapse (New York, N.Y.). 30(1):71-8. Pubmed: 9704883 Genova LM, Hyman SE. 1998. 5-HT3 receptor activation is required for induction of striatal c-Fos and phosphorylation of ATF-1 by amphetamine. Synapse (New York, N.Y.). 30(1):71-8. Pubmed: 9704883 Dopamine (DA) has been shown to be required for the induction of striatal gene expression by psychostimulants. However, direct DA agonists or selective inhibitors of DA reuptake are relatively weak inducers of striatal gene expression compared with cocaine or amphetamine. So although necessary, DA alone is not sufficient to mediate the full gene induction response to psychostimulants. In addition to its actions on the DA transporter, amphetamine also enhances serotonin (5-HT) release in the striatum. In this study, we investigated the mechanism by which 5-HT contributes to the regulation of striatal gene expression by amphetamine. We found that selective lesions of serotonergic terminals in the rat forebrain using 5,7-dihydroxytryptamine prevented the full induction of striatal c-Fos by 4 mg/kg amphetamine. Furthermore, amphetamine-induced striatal c-Fos was completely inhibited by administration of the 5-HT3 receptor antagonist, MDL-72222, but not by the 5-HT2A/2C receptor antagonist, ritanserin. Consistent with this finding, the induction of c-Fos by 5-HT in primary cultures of E18 striatal neurons devoid of DA input was blocked by the 5-HT3 receptor antagonists, MDL-72222 and ICS 205-930, but not by 5-HT2A/2C antagonism. Additionally, blockade of 5-HT3 receptors by MDL-72222 inhibited the phosphorylation of activating transcription factor-1 (ATF-1) at Ser63 by amphetamine, but not the phosphorylation of cAMP response element binding protein (CREB) at Ser133. These results suggest that 5-HT3 receptor activation may be required for amphetamine-induced expression of ATF-1-regulated target genes in the striatum, which may include c-Fos. -
Cornford EM, Hyman S, Cornford ME, Landaw EM, Delgado-Escueta AV. 1998. Interictal seizure resections show two configurations of endothelial Glut1 glucose transporter in the human blood-brain barrier. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 18(1):26-42. Pubmed: 9428303 Cornford EM, Hyman S, Cornford ME, Landaw EM, Delgado-Escueta AV. 1998. Interictal seizure resections show two configurations of endothelial Glut1 glucose transporter in the human blood-brain barrier. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 18(1):26-42. Pubmed: 9428303 Immunogold electron microscopy was used to analyze and quantify the Glut1 glucose transporter in brain tissue from five patients undergoing surgery for treatment of seizures. Samples were prepared from two different regions of each resection: (1) the most actively spiking epileptogenic site, and (2) the least actively spiking region, as indicated by intraoperative EEG monitoring. Two configurations of endothelial cell Glut1 were observed. About one half of the capillary profiles examined displayed abundant Glut1 immunoreactivity on both luminal and abluminal endothelial membranes. In the remainder of the profiles, reduced Glut1 labeling was seen, but adjacent erythrocyte membranes remained highly Glut1 immunoreactive, suggesting that reduced endothelial Glut1 reactivity was not attributable to method artifacts. Immunogold studies using antisera to human glial fibrillary acidic protein and human serum albumin demonstrated increased quantities of these two epitopes in the extravascular regions in which more EEG spiking activity had been demonstrated. These observations were consistent with the hypotheses that capillary integrity was more compromised, and gliosis was quantitatively increased, in the more actively spiking region of the resection. Altered glucose transporter activity in the blood-brain barrier was characterized by a bimodal Glut1 distribution in which the smaller (type B) endothelial cells displayed low Glut1 immunoreactivity, whereas adjacent (and even contiguous) larger (type A) endothelial cells showed 5- to 10-fold greater expression of membrane Glut1 transporter protein. Because this transporter facilitates glucose entry to the brain, small pericapillary volumes of brain tissue may have quite different concentrations of glucose. We hypothesize that in complex partial seizures and other forms of brain insult, an alteration of blood-brain barrier Glut1 glucose transporter activity is indicated by the appearance of these two subpopulations of endothelial cells. In comparison with previous studies of human brain capillaries in hemangioblastoma and brain injury, endothelial Glut1 density was apparently reduced (interictally) in affected temporal lobes of patients with complex partial seizures. -
Hyman SE, Zuckerman B. 1998. Drug interactions in cocaine abuse: methodologic concerns in human and animal studies. Annals of the New York Academy of Sciences. 846:69-75. Pubmed: 9668398 Hyman SE, Zuckerman B. 1998. Drug interactions in cocaine abuse: methodologic concerns in human and animal studies. Annals of the New York Academy of Sciences. 846:69-75. Pubmed: 9668398 -
Gollub RL, Breiter HC, Kantor H, Kennedy D, Gastfriend D, Mathew RT, Makris N, Guimaraes A, Riorden J, Campbell T, Foley M, Hyman SE, Rosen B, Weisskoff R. 1998. Cocaine decreases cortical cerebral blood flow but does not obscure regional activation in functional magnetic resonance imaging in human subjects. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 18(7):724-34. Pubmed: 9663502 Gollub RL, Breiter HC, Kantor H, Kennedy D, Gastfriend D, Mathew RT, Makris N, Guimaraes A, Riorden J, Campbell T, Foley M, Hyman SE, Rosen B, Weisskoff R. 1998. Cocaine decreases cortical cerebral blood flow but does not obscure regional activation in functional magnetic resonance imaging in human subjects. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 18(7):724-34. Pubmed: 9663502 The authors used functional magnetic resonance imaging (fMRI) to determine whether acute intravenous (i.v.) cocaine use would change global cerebral blood flow (CBF) or visual stimulation-induced functional activation. They used flow-sensitive alternating inversion recovery (FAIR) scan sequences to measure CBF and blood oxygen level-dependent (BOLD) sensitive T2* scan sequences during visual stimulation to measure neuronal activation before and after cocaine and saline infusions. Cocaine (0.6 mg/kg i.v. over 30 seconds) increased heart rate and mean blood pressure and decreased end tidal carbon dioxide (CO2). All measures returned to baseline by 2 hours, the interinfusion interval, and were unchanged by saline. Flow-sensitive alternating inversion recovery imaging demonstrated that cortical gray matter CBF was unchanged after saline infusion (-2.4 +/- 6.5%) but decreased (-14.1 +/- 8.5%) after cocaine infusion (n = 8, P < 0.01). No decreases were detected in white matter, nor were changes found comparing BOLD signal intensity in cortical gray matter immediately before cocaine infusion with that measured 10 minutes after infusion. Visual stimulation resulted in comparable BOLD signal increases in visual cortex in all conditions (before and after cocaine and saline infusion). Despite a small (14%) but significant decrease in global cortical gray matter CBF after acute cocaine infusion, specific regional increases in BOLD imaging, mediated by neurons, can be measured reliably. -
Berke JD, Paletzki RF, Aronson GJ, Hyman SE, Gerfen CR. 1998. A complex program of striatal gene expression induced by dopaminergic stimulation. The Journal of neuroscience : the official journal of the Society for Neuroscience. 18(14):5301-10. Pubmed: 9651213 Berke JD, Paletzki RF, Aronson GJ, Hyman SE, Gerfen CR. 1998. A complex program of striatal gene expression induced by dopaminergic stimulation. The Journal of neuroscience : the official journal of the Society for Neuroscience. 18(14):5301-10. Pubmed: 9651213 Dopamine acting in the striatum is necessary for normal movement and motivation. Drugs that change striatal dopamine neurotransmission can have long-term effects on striatal physiology and behavior; these effects are thought to involve alterations in gene expression. Using the 6-hydroxydopamine lesion model of Parkinson's disease and differential display PCR, we have identified a set of more than 30 genes whose expression rapidly increases in response to stimulation of striatal dopamine D1 receptors. The induced mRNAs include both novel and previously described genes, with diverse time courses of expression. Some genes are expressed at near-maximal levels within 30 min, whereas others show no substantial induction until 2 hr or more after stimulation. Some of the induced genes, such as CREM, CHOP, and MAP kinase phosphatase-1, may be components of a homeostatic response to excessive stimulation. Others may be part of a genetic program involved in cellular and synaptic plasticity. A very similar set of genes is induced in unlesioned animals by administration of the psychostimulant cocaine or the antipsychotic eticlopride, although in distinct striatal cell populations. In contrast to some previously described early genes, most of the novel genes are not induced in cortex by apomorphine, indicating specificity of induction. Thus we have identified novel components of a complex, coordinated genetic program that is induced in striatal cells in response to various dopaminergic manipulations. -
Fienberg AA, Hiroi N, Mermelstein PG, Song W, Snyder GL, Nishi A, Cheramy A, O'Callaghan JP, Miller DB, Cole DG, Corbett R, Haile CN, Cooper DC, Onn SP, Grace AA, Ouimet CC, White FJ, Hyman SE, Surmeier DJ, Girault J, Nestler EJ, Greengard P. 1998. DARPP-32: regulator of the efficacy of dopaminergic neurotransmission. Science (New York, N.Y.). 281(5378):838-42. Pubmed: 9694658 Fienberg AA, Hiroi N, Mermelstein PG, Song W, Snyder GL, Nishi A, Cheramy A, O'Callaghan JP, Miller DB, Cole DG, Corbett R, Haile CN, Cooper DC, Onn SP, Grace AA, Ouimet CC, White FJ, Hyman SE, Surmeier DJ, Girault J, Nestler EJ, Greengard P. 1998. DARPP-32: regulator of the efficacy of dopaminergic neurotransmission. Science (New York, N.Y.). 281(5378):838-42. Pubmed: 9694658 Dopaminergic neurons exert a major modulatory effect on the forebrain. Dopamine and adenosine 3',5'-monophosphate-regulated phosphoprotein (32 kilodaltons) (DARPP-32), which is enriched in all neurons that receive a dopaminergic input, is converted in response to dopamine into a potent protein phosphatase inhibitor. Mice generated to contain a targeted disruption of the DARPP-32 gene showed profound deficits in their molecular, electrophysiological, and behavioral responses to dopamine, drugs of abuse, and antipsychotic medication. The results show that DARPP-32 plays a central role in regulating the efficacy of dopaminergic neurotransmission. -
Hyman SE. 1998. NIMH during the tenure of Director Steven E. Hyman, M.D. (1996-present): the now and future of NIMH. The American journal of psychiatry. 155(9 Suppl):36-40. Pubmed: 9736863 Hyman SE. 1998. NIMH during the tenure of Director Steven E. Hyman, M.D. (1996-present): the now and future of NIMH. The American journal of psychiatry. 155(9 Suppl):36-40. Pubmed: 9736863 -
Hyman SE. 1998. A new image for fear and emotion. Nature. 393(6684):417-8. Pubmed: 9623995 Hyman SE. 1998. A new image for fear and emotion. Nature. 393(6684):417-8. Pubmed: 9623995 1997
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Genova L, Berke J, Hyman SE. 1997. Molecular adaptations to psychostimulants in striatal neurons: toward a pathophysiology of addiction. Neurobiology of disease. 4(3-4):239-46. Pubmed: 9361300 Genova L, Berke J, Hyman SE. 1997. Molecular adaptations to psychostimulants in striatal neurons: toward a pathophysiology of addiction. Neurobiology of disease. 4(3-4):239-46. Pubmed: 9361300 -
Breiter HC, Gollub RL, Weisskoff RM, Kennedy DN, Makris N, Berke JD, Goodman JM, Kantor HL, Gastfriend DR, Riorden JP, Mathew RT, Rosen BR, Hyman SE. 1997. Acute effects of cocaine on human brain activity and emotion. Neuron. 19(3):591-611. Pubmed: 9331351 Breiter HC, Gollub RL, Weisskoff RM, Kennedy DN, Makris N, Berke JD, Goodman JM, Kantor HL, Gastfriend DR, Riorden JP, Mathew RT, Rosen BR, Hyman SE. 1997. Acute effects of cocaine on human brain activity and emotion. Neuron. 19(3):591-611. Pubmed: 9331351 We investigated brain circuitry mediating cocaine-induced euphoria and craving using functional MRI (fMRI). During double-blind cocaine (0.6 mg/kg) and saline infusions in cocaine-dependent subjects, the entire brain was imaged for 5 min before and 13 min after infusion while subjects rated scales for rush, high, low, and craving. Cocaine induced focal signal increases in nucleus accumbens/subcallosal cortex (NAc/SCC), caudate, putamen, basal forebrain, thalamus, insula, hippocampus, parahippocampal gyrus, cingulate, lateral prefrontal and temporal cortices, parietal cortex, striate/extrastriate cortices, ventral tegmentum, and pons and produced signal decreases in amygdala, temporal pole, and medial frontal cortex. Saline produced few positive or negative activations, which were localized to lateral prefrontal cortex and temporo-occipital cortex. Subjects who underwent repeat studies showed good replication of the regional fMRI activation pattern following cocaine and saline infusions, with activations on saline retest that might reflect expectancy. Brain regions that exhibited early and short duration signal maxima showed a higher correlation with rush ratings. These included the ventral tegmentum, pons, basal forebrain, caudate, cingulate, and most regions of lateral prefrontal cortex. In contrast, regions that demonstrated early but sustained signal maxima were more correlated with craving than with rush ratings; such regions included the NAc/SCC, right parahippocampal gyrus, and some regions of lateral prefrontal cortex. Sustained negative signal change was noted in the amygdala, which correlated with craving ratings. Our data demonstrate the ability of fMRI to map dynamic patterns of brain activation following cocaine infusion in cocaine-dependent subjects and provide evidence of dynamically changing brain networks associated with cocaine-induced euphoria and cocaine-induced craving. -
Schwarzschild MA, Cole RL, Hyman SE. 1997. Glutamate, but not dopamine, stimulates stress-activated protein kinase and AP-1-mediated transcription in striatal neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience. 17(10):3455-66. Pubmed: 9133371 Schwarzschild MA, Cole RL, Hyman SE. 1997. Glutamate, but not dopamine, stimulates stress-activated protein kinase and AP-1-mediated transcription in striatal neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience. 17(10):3455-66. Pubmed: 9133371 Drugs that stimulate dopamine and glutamate receptors have been shown to induce the expression of AP-1 proteins (such as c-Fos and c-Jun) in the striatum and to induce binding of these proteins to AP-1 sites on DNA, leading to the hypothesis that AP-1-mediated transcription contributes to the long-term effects of these drugs. To examine this hypothesis, we compared the regulation of AP-1-mediated transcription to the inductions of AP-1-binding activity and genes encoding AP-1 proteins in primary cultures of striatal neurons. Although glutamate, dopamine, and forskolin (an activator of adenylate cyclase) all induce c-fos mRNA and AP-1 binding, we found, surprisingly, that only glutamate induces transcription of a transfected AP-1-driven fusion gene. To explore the basis for this discrepancy, we investigated the possibility that the phosphorylation of c-Jun may also be required for AP-1-mediated transcription in striatal neurons. Glutamate, but neither dopamine nor forskolin, raises the levels of phosphorylated c-Jun as well as the activity of a Jun kinase (SAPK/JNK) in striatal cultures. Both the glutamatergic induction of AP-1-mediated transcription and activation of SAPK/JNK appear to be mediated, at least in part, via NMDA receptors. In striatal neurons, the phosphorylation of AP-1 proteins produced by glutamate may be required to convert AP-1 protein expression and binding to transcriptional activation. -
Glick TH, Armstrong EG, Hyman SE, Hundert EM, Furshpan EJ. 1997. Neurologic education for the future: a decade of curricular reform at Harvard Medical School. European journal of neurology. 4(2):102-6. Pubmed: 24283899 DOI:10.1111/j.1468-1331.1997.tb00312.x Glick TH, Armstrong EG, Hyman SE, Hundert EM, Furshpan EJ. 1997. Neurologic education for the future: a decade of curricular reform at Harvard Medical School. European journal of neurology. 4(2):102-6. Pubmed: 24283899 DOI:10.1111/j.1468-1331.1997.tb00312.x The field of neurology is undergoing significant changes to which curricular reform is both responding and contributing. We reflect on a decade of experience at Harvard Medical School with integration of neuroscience, behaviour, pathophysiology and introductory clinical skills. As part of Harvard's "New Pathway" curriculum, this coordinated, pre-clerkship program embraces a "hybrid" form of problem-based learning. A variety of methods are employed synergistically to meet the two broad goals of preparing for competency in neurologic clerkships and for career-long learning in clinically relevant neuroscience. We articulate specific ways of elevating the level of intellectual inquiry, involving multi-disciplinary faculty more productively, and vertically integrating the learning experience through the years of medical school.1997 Lippincott Williams & Wilkins. -
Glick TH, Armstrong EG, Waterman MA, Hundert EM, Hyman SE. 1997. An integrated preclerkship curriculum in neuroscience, psychiatry, and neurology. Academic psychiatry : the journal of the American Association of Directors of Psychiatric Residency Training and the Association for Academic Psychiatry. 21(4):212-8. Pubmed: 24435648 DOI:10.1007/BF03341434 Glick TH, Armstrong EG, Waterman MA, Hundert EM, Hyman SE. 1997. An integrated preclerkship curriculum in neuroscience, psychiatry, and neurology. Academic psychiatry : the journal of the American Association of Directors of Psychiatric Residency Training and the Association for Academic Psychiatry. 21(4):212-8. Pubmed: 24435648 DOI:10.1007/BF03341434 The study's objective was to promote understanding of the integration of preclerkship learning in neuroscience, psychiatry, and neurology and to share the authors' experience with such a program. A dualism, which may have survived in the past for lack of robust evidence of mind-brain relationships, is now increasingly outmoded. Medical school education should reflect the increasing coherence to be found in these fields. The authors describe curricular and course innovations and revisions at Harvard Medical School that have been implemented in successive iterations over the past decade. These changes have depended upon multidisciplinary leadership, planning, and faculty participation, as well as faculty development and closer coordination between classroom- and hospital-based activity. A hybrid, problem-based block course in the second year integrates basic science with neurologic and psychiatric topics that are aligned with practice of relevant clinical skills. The authors have achieved a high level of integration and coordination of these subjects at preclerkship levels in the domains of both knowledge and skills. The students, as well as the faculty, strongly endorse an intellectually coherent and clinically relevant program of integrated preclerkship learning in neuroscience, psychiatry, and neurology. 1996
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Berhow MT, Hiroi N, Kobierski LA, Hyman SE, Nestler EJ. 1996. Influence of cocaine on the JAK-STAT pathway in the mesolimbic dopamine system. The Journal of neuroscience : the official journal of the Society for Neuroscience. 16(24):8019-26. Pubmed: 8987828 Berhow MT, Hiroi N, Kobierski LA, Hyman SE, Nestler EJ. 1996. Influence of cocaine on the JAK-STAT pathway in the mesolimbic dopamine system. The Journal of neuroscience : the official journal of the Society for Neuroscience. 16(24):8019-26. Pubmed: 8987828 Chronic exposure to cocaine produces characteristic biochemical adaptations within the rat ventral tegmental area (VTA), a brain region rich in dopaminergic neurons implicated in the reinforcing and locomotor-activating properties of cocaine. Some of these changes are mimicked by chronic ciliary neurotrophic factor (CNTF) infusions into the same brain area. We show in this study that chronic cocaine treatment regulates the signal transduction pathway used by CNTF specifically in the VTA. There is an increase in immunoreactivity of Janus kinase (JAK2), a CNTF-regulated protein tyrosine kinase, in the VTA after chronic but not acute cocaine administration. This increase is not seen in the nearby substantia nigra or several other brain regions studied. Furthermore, this increase in JAK2 is not seen after chronic administration of other psychotropic drugs and was not observed for JAK1. The increase in JAK2 levels is associated with an increased responsiveness of the system to acute CNTF infusion into the VTA, as measured by induction in this brain region of signal transducers and activators of transcription (STAT) DNA binding activity and of Fos-like proteins, two known functional endpoints of JAK activation. Double-labeling immunohistochemical studies show that JAK2 immunoreactivity in the VTA is enriched in dopaminergic and nondopaminergic cells, both of which exhibit increased JAK2 immunoreactivity after chronic cocaine treatment. These findings suggest a scheme whereby some of the effects of chronic cocaine on VTA dopaminergic neurons are mediated directly by regulation of the JAK-STAT pathway in these cells, as well as perhaps indirectly by regulation of this pathway in nondopaminergic cells. -
Hyman SE, Borsook D. 1996. Mechanisms regulating proenkephalin gene expression: contributions of transgenic models. NIDA research monograph. 161:59-71. Pubmed: 8784844 Hyman SE, Borsook D. 1996. Mechanisms regulating proenkephalin gene expression: contributions of transgenic models. NIDA research monograph. 161:59-71. Pubmed: 8784844 This chapter gives an overview of the utility of one type of transgenic mouse model for substance abuse research, the use of transgenes in which genomic regulatory sequences of interest are coupled to a reporter gene. Using this mouse model, exploration of the mechanisms regulating expression of the proenkephalin gene in the mouse hypothalamus have begun. The resulting information supplements experiments on gene regulation performed in cell lines with information about regulation by pharmacologic and physiologic stimuli of interest within the brain. With special reference to mechanisms of opioid dependence, the particular model that has been examined appears to be a useful tool to investigate mechanistic aspects of the regulation of endogenous opioid genes by exogenous opioids. -
Hyman SE, Nestler EJ. 1996. Initiation and adaptation: a paradigm for understanding psychotropic drug action. The American journal of psychiatry. 153(2):151-62. Pubmed: 8561194 Hyman SE, Nestler EJ. 1996. Initiation and adaptation: a paradigm for understanding psychotropic drug action. The American journal of psychiatry. 153(2):151-62. Pubmed: 8561194 Array -
Breiter HC, Etcoff NL, Whalen PJ, Kennedy WA, Rauch SL, Buckner RL, Strauss MM, Hyman SE, Rosen BR. 1996. Response and habituation of the human amygdala during visual processing of facial expression. Neuron. 17(5):875-87. Pubmed: 8938120 Breiter HC, Etcoff NL, Whalen PJ, Kennedy WA, Rauch SL, Buckner RL, Strauss MM, Hyman SE, Rosen BR. 1996. Response and habituation of the human amygdala during visual processing of facial expression. Neuron. 17(5):875-87. Pubmed: 8938120 We measured amygdala activity in human volunteers during rapid visual presentations of fearful, happy, and neutral faces using functional magnetic resonance imaging (fMRI). The first experiment involved a fixed order of conditions both within and across runs, while the second one used a fully counterbalanced order in addition to a low level baseline of simple visual stimuli. In both experiments, the amygdala was preferentially activated in response to fearful versus neutral faces. In the counterbalanced experiment, the amygdala also responded preferentially to happy versus neutral faces, suggesting a possible generalized response to emotionally valenced stimuli. Rapid habituation effects were prominent in both experiments. Thus, the human amygdala responds preferentially to emotionally valenced faces and rapidly habituates to them. -
Hyman SE. 1996. Shaking out the cause of addiction. Science (New York, N.Y.). 273(5275):611-2. Pubmed: 8701316 Hyman SE. 1996. Shaking out the cause of addiction. Science (New York, N.Y.). 273(5275):611-2. Pubmed: 8701316 -
Konradi C, Leveque JC, Hyman SE. 1996. Amphetamine and dopamine-induced immediate early gene expression in striatal neurons depends on postsynaptic NMDA receptors and calcium. The Journal of neuroscience : the official journal of the Society for Neuroscience. 16(13):4231-9. Pubmed: 8753884 Konradi C, Leveque JC, Hyman SE. 1996. Amphetamine and dopamine-induced immediate early gene expression in striatal neurons depends on postsynaptic NMDA receptors and calcium. The Journal of neuroscience : the official journal of the Society for Neuroscience. 16(13):4231-9. Pubmed: 8753884 Amphetamine and cocaine induce the expression of both immediate early genes (IEGs) and neuropeptide genes in rat striatum. Despite the demonstrated dependence of these effects on D1 dopamine receptors, which activate the cyclic AMP pathway, there are several reports that amphetamine and cocaine-induced IEG expression can be inhibited in striatum in vivo by NMDA receptor antagonists. We find that in vivo, the NMDA receptor antagonist MK-801 inhibits amphetamine induction of c-fos acutely and also prevents downregulation of IEG expression with chronic amphetamine administration. Such observations raise the question of whether dopamine/glutamate interactions occur at the level of corticostriatal and mesostriatal circuitry or within striatal neurons. Therefore, we studied dissociated striatal cultures in which midbrain and cortical presynaptic inputs are removed. In these cultures, we find that dopamine- or forskolin-mediated IEG induction requires Ca2+ entry via NMDA receptors but not via L-type Ca2+ channels. Moreover, blockade of NMDA receptors diminishes the ability of dopamine to induce phosphorylation of the cyclic AMP responsive element binding protein CREB. Although these results do not rule out a role for circuit-level dopamine/glutamate interactions, they demonstrate a requirement at the cellular level for interactions between the cyclic AMP and NMDA receptor pathways in dopamine-regulated gene expression in striatal neurons. -
Hyman SE. 1996. Addiction to cocaine and amphetamine. Neuron. 16(5):901-4. Pubmed: 8630246 Hyman SE. 1996. Addiction to cocaine and amphetamine. Neuron. 16(5):901-4. Pubmed: 8630246 1995
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Gollub RL, Hyman SE. 1995. G proteins and second messengers in psychiatry. Harvard review of psychiatry. 3(1):41-4. Pubmed: 9410573 Gollub RL, Hyman SE. 1995. G proteins and second messengers in psychiatry. Harvard review of psychiatry. 3(1):41-4. Pubmed: 9410573 -
Borsook D, Hyman SE. 1995. Proenkephalin gene regulation in the neuroendocrine hypothalamus: a model of gene regulation in the CNS. The American journal of physiology. 269(3 Pt 1):E393-408. Pubmed: 7573416 Borsook D, Hyman SE. 1995. Proenkephalin gene regulation in the neuroendocrine hypothalamus: a model of gene regulation in the CNS. The American journal of physiology. 269(3 Pt 1):E393-408. Pubmed: 7573416 During the past decade, a great deal of progress has been made in studying the mechanisms by which transcription of neuropeptides is regulated by second messengers and neural activity. Such investigations, which have depended to a great extent on the use of transformed cell lines, are far from complete. Yet a major challenge for the coming decade is to understand the regulation of neuropeptide genes by physiologically and pharmacologically relevant stimuli in appropriate cell types in vivo. The proenkephalin gene, a member of the opioid gene family, has served as a model to study regulated transcription, not only in cell lines, but also in central (e.g., hypothalamic) and peripheral (e.g., adrenal) neuroendocrine tissues. Here we review regulation of proenkephalin gene expression in the hypothalamus. Several approaches, including in situ hybridization, use of transgenic mice, and the adaptation of electrophoretic mobility shift assays to complex tissues, have played critical roles in recent advances. A summary of possible future developments in this field of research is also presented. -
Konradi C, Cole RL, Green D, Senatus P, Leveque JC, Pollack AE, Grossbard SJ, Hyman SE. 1995. Analysis of the proenkephalin second messenger-inducible enhancer in rat striatal cultures. Journal of neurochemistry. 65(3):1007-15. Pubmed: 7643080 Konradi C, Cole RL, Green D, Senatus P, Leveque JC, Pollack AE, Grossbard SJ, Hyman SE. 1995. Analysis of the proenkephalin second messenger-inducible enhancer in rat striatal cultures. Journal of neurochemistry. 65(3):1007-15. Pubmed: 7643080 We have previously shown that in cell extracts from rat striatum, cyclic AMP response element (CRE) binding protein (CREB), rather than AP-1 proteins, preferentially interacts with the CRE-2 element of the proenkephalin second messenger-inducible enhancer, even under conditions in which AP-1 proteins are highly induced. Here we use primary striatal cultures to permit a more detailed analysis of CRE-2 function and protein binding in relevant neural cell types. By transfection we find that in primary striatal cultures, as in transformed cell lines, the CRE-1 and CRE-2 elements are required for significant induction by cyclic AMP. We report that cyclic AMP induction of the proenkephalin gene in striatal cultures is protein synthesis independent, excluding a role for newly synthesized proteins like c-Fos. We also show that cyclic AMP induces CREB phosphorylation and that phosphorylated CREB interacts strongly with CRE-2 and weakly with CRE-1. The predominant protein bound to CRE-1 is not CREB, however, and remains to be identified. Despite some prior predictions, we do not find a role for c-Fos in cyclic AMP regulation of proenkephalin gene expression in neurons. -
Cole RL, Konradi C, Douglass J, Hyman SE. 1995. Neuronal adaptation to amphetamine and dopamine: molecular mechanisms of prodynorphin gene regulation in rat striatum. Neuron. 14(4):813-23. Pubmed: 7718243 Cole RL, Konradi C, Douglass J, Hyman SE. 1995. Neuronal adaptation to amphetamine and dopamine: molecular mechanisms of prodynorphin gene regulation in rat striatum. Neuron. 14(4):813-23. Pubmed: 7718243 Induction of prodynorphin gene expression by psychostimulant drugs may represent a compensatory adaptation to excessive dopamine stimulation and may contribute to the aversive aspects of withdrawal. We therefore investigated the molecular mechanisms by which dopamine psychostimulant drugs induce prodynorphin gene expression in vivo and in rat primary striatal cultures. We demonstrate that three recently described cAMP response elements (CREs), rather than a previously reported noncanonical AP-1 site, are critical for dopamine induction of the prodynorphin gene in striatal neurons. CRE-binding protein (CREB) binds to these CREs in striatal cell extracts and is phosphorylated on Ser-133 after dopamine stimulation in a D1 dopamine receptor-dependent manner. Surprisingly, following chronic administration of amphetamine, levels of phosphorylated CREB are increased above basal in rat striatum in vivo, whereas c-fos mRNA is suppressed below basal levels. D1 receptor-mediated CREB phosphorylation appears to mediate adaptations to psychostimulant drugs in the striatum. -
Kosofsky BE, Genova LM, Hyman SE. 1995. Substance P phenotype defines specificity of c-fos induction by cocaine in developing rat striatum. The Journal of comparative neurology. 351(1):41-50. Pubmed: 7534774 Kosofsky BE, Genova LM, Hyman SE. 1995. Substance P phenotype defines specificity of c-fos induction by cocaine in developing rat striatum. The Journal of comparative neurology. 351(1):41-50. Pubmed: 7534774 Activation of c-fos, a member of the class of immediate early genes that act as transcription factors, may be one of the initial molecular mechanisms underlying plastic changes in gene expression in response to drugs of abuse. By combining c-fos (radioactive) in situ hybridization histochemistry with nonradioactive in situ hybridization histochemistry for mRNAs encoding other striatal markers [preprotachykinin (substance P), proenkephalin, and D1 and D2 receptors], we have identified the cellular phenotype of striatal neurons activated by acute administration of cocaine to P8, P15, P28, and adult rats. At each age examined, substance P+, enkephalin- striatal neurons were the predominant class of cells in which cocaine induced c-fos gene expression. In addition, the topography of cellular activation at each age examined was distinct and reflected the topography of distribution of cells expressing high levels of substance P mRNA. We conclude that there is a marked specificity of cellular activation in striatum following acute cocaine administration restricted predominantly to subsets of substance P-expressing cells, with age-specific patterns in their topographic distribution. -
Kosofsky BE, Genova LM, Hyman SE. 1995. Postnatal age defines specificity of immediate early gene induction by cocaine in developing rat brain. The Journal of comparative neurology. 351(1):27-40. Pubmed: 7896938 Kosofsky BE, Genova LM, Hyman SE. 1995. Postnatal age defines specificity of immediate early gene induction by cocaine in developing rat brain. The Journal of comparative neurology. 351(1):27-40. Pubmed: 7896938 Clinical and animal data suggest that exposure of developing brain to cocaine has adverse consequences. One candidate mechanism for such effects is drug regulation of gene expression. In adult rats, cocaine induces expression of nuclear immediate early genes with specific spatial and temporal patterns. The products of such genes (e.g., c-Fos, c-Jun, and Zif/268) subserve the coupling of cell surface receptor stimulation to transcriptional regulation. Thus, activation of immediate early gene expression in developing brain by cocaine could alter programs of neural gene expression and, thereby, neuronal phenotype and function. We report that, during rat brain development, cocaine produced brain region-specific and developmental age-specific induction of c-fos, c-jun, and zif/268 mRNAs. At each age studied (P8, P15, P28, and adults), we found that acute cocaine administration resulted in a unique cell-specific pattern of c-fos mRNA induction and c-Fos protein expression in striatum. We also observed cocaine-induced activation of AP-1 DNA binding activity in striatal extracts prepared at these different ages, suggesting that the observed induction of c-fos and c-jun may have biological consequences for the developing brain. These findings suggest a mechanism by which cocaine could alter patterns of gene expression during critical developmental periods with differential regional, temporal, and cellular vulnerabilities and, therefore, consequences for developing brain. -
Naidu S, Hyman S, Harris EL, Narayanan V, Johns D, Castora F. 1995. Rett syndrome studies of natural history and search for a genetic marker. Neuropediatrics. 26(2):63-6. Pubmed: 7566454 Naidu S, Hyman S, Harris EL, Narayanan V, Johns D, Castora F. 1995. Rett syndrome studies of natural history and search for a genetic marker. Neuropediatrics. 26(2):63-6. Pubmed: 7566454 The commonly held notion that Rett syndrome (RS) is a neurodegenerative disorder with normal early development was examined by an epidemiological survey and review of medical records and serial neurological and development evaluations. In some subjects, deviance from normal development was evident from the perinatal period, and gradually became more prominent with age. These findings are convincing when seen in conjunction with a reduction in velocity of brain growth, as early as 2-4 months of life, well before the recognition of gross neurological deficits. Neurodevelopmental evaluations provide no indication that there is progressive loss of adaptive behaviors, or communication skills to indicate a neurodegenerative process. Taken together with the known neuropathological and neurochemical changes in RS brain we hypothesize that RS is a neurodevelopmental disorder, which has a genetic basis, and affects subsets of neurons and their connections during a period of vigorous brain growth, when synapse formation and pruning are at a peak. Studies of mitochondrial (mt) DNA in brain to understand the genetic mechanisms underlying matrilineal inheritance in the few familial cases, and mt structural and enzyme deficiencies have been unrevealing to date. -
Hyman SE, Cole RL, Konradi C, Kosofsky BE. 1995. Dopamine regulation of transcription factor-target interactions in rat striatum. Chemical senses. 20(2):257-60. Pubmed: 7583020 Hyman SE, Cole RL, Konradi C, Kosofsky BE. 1995. Dopamine regulation of transcription factor-target interactions in rat striatum. Chemical senses. 20(2):257-60. Pubmed: 7583020 Transcriptional regulation is an important mechanism by which neurons adapt to environmental stimuli. The indirect dopamine agonists, amphetamine and cocaine have been shown to induce expression of immediate early genes, such as c-fos, and neuropeptide genes, such as prodynorphin in the rat striatum. Here we show that phosphorylation of transcription factor CREB is a critical early event coupling dopamine stimulation to gene regulation. CREB interacts with functional regulatory elements in both the c-fos and prodynorphin genes, and is phosphorylated in response to dopamine in a D1 dopamine receptor-dependent manner. In addition, we show by intra-striatal injection of antisense oligonucleotides directed against CREB mRNA, that CREB protein is required for c-fos induction by amphetamine. -
Hyman SE. 1995. A man with alcoholism and HIV infection. JAMA. 274(10):837-43. Pubmed: 7650809 Hyman SE. 1995. A man with alcoholism and HIV infection. JAMA. 274(10):837-43. Pubmed: 7650809 -
Hyman SE. 1995. Current treatment for alcohol withdrawal. Journal of general internal medicine. 10(9):523-4. Pubmed: 8523158 Hyman SE. 1995. Current treatment for alcohol withdrawal. Journal of general internal medicine. 10(9):523-4. Pubmed: 8523158 1994
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Borsook D, Falkowski O, Rosen H, Comb M, Hyman SE. 1994. Opioids modulate stress-induced proenkephalin gene expression in the hypothalamus of transgenic mice: a model of endogenous opioid gene regulation by exogenous opioids. The Journal of neuroscience : the official journal of the Society for Neuroscience. 14(12):7261-71. Pubmed: 7996174 Borsook D, Falkowski O, Rosen H, Comb M, Hyman SE. 1994. Opioids modulate stress-induced proenkephalin gene expression in the hypothalamus of transgenic mice: a model of endogenous opioid gene regulation by exogenous opioids. The Journal of neuroscience : the official journal of the Society for Neuroscience. 14(12):7261-71. Pubmed: 7996174 Stressful stimuli strongly induce proenkephalin gene expression within the paraventricular nucleus (PVN) of the hypothalamus. A human proenkephalin-beta-galactosidase fusion gene has previously been shown to give correct phenotypic expression and appropriate stress regulation within the hypothalamus of transgenic mice; this model provides high sensitivity, cellular resolution, and ready quantification of levels of proenkephalin gene expression. Here we describe use of this transgenic model to study modulation of stress-regulated gene expression in the PVN by opiates. Acute or subacute morphine administration prior to a hypertonic saline stress produced marked superinduction of transgene expression compared with hypertonic saline stress alone. In contrast, chronic morphine administration decreased basal expression of the transgene, and inhibited stress-induced expression of the transgene. The endogenous proenkephalin mRNA was induced in parallel with the transgene as demonstrated by in situ hybridization; the immediate-early gene c-fos was also regulated in parallel with the transgene. These data suggest that acute or subacute morphine administration sensitizes proenkephalin neurons within the PVN and other regions of the hypothalamus to stress and that chronic morphine administration desensitizes this response. Because the molecular mechanisms regulating the expression of the transgene are well understood, this model provides a useful tool for investigating cellular and molecular effects of opioids on the hypothalamus. -
Symes A, Lewis S, Corpus L, Rajan P, Hyman SE, Fink JS. 1994. STAT proteins participate in the regulation of the vasoactive intestinal peptide gene by the ciliary neurotrophic factor family of cytokines. Molecular endocrinology (Baltimore, Md.). 8(12):1750-63. Pubmed: 7708062 Symes A, Lewis S, Corpus L, Rajan P, Hyman SE, Fink JS. 1994. STAT proteins participate in the regulation of the vasoactive intestinal peptide gene by the ciliary neurotrophic factor family of cytokines. Molecular endocrinology (Baltimore, Md.). 8(12):1750-63. Pubmed: 7708062 Ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF) are members of a family of neuropoietic cytokines that have a broad range of actions on many different neuronal populations. In cultured sympathetic neurons, CNTF and LIF induce transcription of the VIP and other neuropeptide genes as part of a program of differentiation. To gain insight into the nuclear events involved in cytokine-mediated activation of the neuropeptide genes involved in neuronal differentiation, we have investigated the mechanisms of transcriptional activation of the vasoactive intestinal peptide (VIP) gene by the CNTF family of cytokines. In the neuroblastoma cell line NBFL, CNTF, LIF, and a related cytokine, oncostatin-M, activate VIP gene transcription through a 180-base pair cytokine response element (CyRE). Deletion analysis of the VIP CyRE showed that multiple regions within the 180 base-pairs are important for cytokine-mediated transcriptional activation of the VIP gene. To one of these regions within the CyRE, cytokine treatment induces binding of a protein complex composed of members of the signal transducers and activators of transcription (STAT) transcription factor family. Mutation of this STAT-binding site attenuates cytokine-mediated transcriptional activation. LIF treatment of primary sympathetic neurons also induced binding of a STAT-containing protein complex to the VIP CyRE. Thus, activation of STAT transcription factors contributes to the induction of the VIp gene by the CNTF family of cytokines and may be involved in cytokine-mediated differentiation of sympathetic neurons. -
Cole DG, Kobierski LA, Konradi C, Hyman SE. 1994. 6-Hydroxydopamine lesions of rat substantia nigra up-regulate dopamine-induced phosphorylation of the cAMP-response element-binding protein in striatal neurons. Proceedings of the National Academy of Sciences of the United States of America. 91(20):9631-5. Pubmed: 7937819 Cole DG, Kobierski LA, Konradi C, Hyman SE. 1994. 6-Hydroxydopamine lesions of rat substantia nigra up-regulate dopamine-induced phosphorylation of the cAMP-response element-binding protein in striatal neurons. Proceedings of the National Academy of Sciences of the United States of America. 91(20):9631-5. Pubmed: 7937819 Destruction of the substantia nigra produces striatal D1 dopamine receptor supersensitivity without increasing receptor number or affinity, thus implicating postreceptor mechanisms. The nature of these mechanisms is unknown. Increased striatal c-fos expression ipsilateral to a unilateral lesion of the substantia nigra in rats treated with appropriate dopamine agonists provides a cellular marker of D1 receptor supersensitivity. D1 receptors are positively linked to adenylate cyclase and therefore to cAMP-dependent protein kinase. Because expression of the c-fos gene in response to cAMP- and Ca2+/calmodulin-regulated protein kinases depends on phosphorylation of cAMP-response element-binding protein (CREB) at Ser-133, we examined CREB phosphorylation after dopaminergic stimulation in cultured striatal neurons and in the striatum of rats after unilateral 6-hydroxydopamine ablation of the substantia nigra. Using an antiserum specific for CREB phosphorylated at Ser-133, we found that dopamine increases CREB phosphorylation in cultured striatal neurons. This effect was blocked by a D1 antagonist. L-Dopa produced marked CREB phosphorylation in striatal neurons in rats ipsilateral, but not contralateral, to a 6-hydroxydopamine lesion. This response was blocked by a D1 antagonist, but not a D2 antagonist, and was reproduced by a D1 agonist, but not a D2 agonist. These findings are consistent with the hypothesis that D1 receptor supersensitivity is associated with upregulated activity of cAMP-dependent or Ca2+/calmodulin-dependent protein kinases, or both, following dopamine denervation of striatal neurons. -
Hyman SE, Gollub RL. 1994. More serotonin: not as simple as it seems. Harvard review of psychiatry. 2(4):222-4. Pubmed: 9384905 Hyman SE, Gollub RL. 1994. More serotonin: not as simple as it seems. Harvard review of psychiatry. 2(4):222-4. Pubmed: 9384905 -
Borsook D, Falkowski O, Burstein R, Strassman A, Konradi C, Dauber A, Comb M, Hyman SE. 1994. Stress-induced regulation of a human proenkephalin-beta-galactosidase fusion gene in the hypothalamus of transgenic mice. Molecular endocrinology (Baltimore, Md.). 8(1):116-25. Pubmed: 8152426 Borsook D, Falkowski O, Burstein R, Strassman A, Konradi C, Dauber A, Comb M, Hyman SE. 1994. Stress-induced regulation of a human proenkephalin-beta-galactosidase fusion gene in the hypothalamus of transgenic mice. Molecular endocrinology (Baltimore, Md.). 8(1):116-25. Pubmed: 8152426 Transgenic mice expressing an Escherichia coli beta-galactosidase reporter gene under the control of 3 kilobases of human proenkephalin gene 5'-flanking sequence and 1.2 kilobases of 3'-flanking sequence exhibited an anatomically correct pattern of basal and stress-regulated transgene expression within the hypothalamus. Acute osmotic stress and hypovolemia induced transgene expression in neurons within both the paraventricular and supraoptic nuclei. Chronic osmotic stress resulted in dramatic induction of transgene expression in both nuclei. These results demonstrate that the information required for correct hypothalamic expression and stress regulation of the proenkephalin gene is contained within our fusion construct. -
Lewis SE, Rao MS, Symes AJ, Dauer WT, Fink JS, Landis SC, Hyman SE. 1994. Coordinate regulation of choline acetyltransferase, tyrosine hydroxylase, and neuropeptide mRNAs by ciliary neurotrophic factor and leukemia inhibitory factor in cultured sympathetic neurons. Journal of neurochemistry. 63(2):429-38. Pubmed: 7518494 Lewis SE, Rao MS, Symes AJ, Dauer WT, Fink JS, Landis SC, Hyman SE. 1994. Coordinate regulation of choline acetyltransferase, tyrosine hydroxylase, and neuropeptide mRNAs by ciliary neurotrophic factor and leukemia inhibitory factor in cultured sympathetic neurons. Journal of neurochemistry. 63(2):429-38. Pubmed: 7518494 The neurotransmitter phenotype switch that occurs in cultures of rat superior cervical ganglion neurons after treatment with leukemia inhibitory factor or ciliary neurotrophic factor is a useful model permitting investigation of the mechanisms of cytokine-mediated differentiation. Recently the actions of leukemia inhibitory factor and ciliary neurotrophic factor have been linked through their interactions with related receptor complexes. Here we compare the effects of these two cytokines on gene expression in sympathetic neuronal cultures and begin to investigate their mechanisms. We report that, as has been shown for leukemia inhibitory factor, ciliary neurotrophic factor regulates peptides and classical transmitters in these cultures at the mRNA level. In addition, we find that the induction of substance P mRNA by these cytokines is rapid, dependent on protein synthesis, and occurs in 40-50% of superior cervical ganglion neurons in dissociated culture. -
Hyman SE. 1994. Why does the brain prefer opium to broccoli?. Harvard review of psychiatry. 2(1):43-6. Pubmed: 9384879 Hyman SE. 1994. Why does the brain prefer opium to broccoli?. Harvard review of psychiatry. 2(1):43-6. Pubmed: 9384879 -
Borsook D, Konradi C, Falkowski O, Comb M, Hyman SE. 1994. Molecular mechanisms of stress-induced proenkephalin gene regulation: CREB interacts with the proenkephalin gene in the mouse hypothalamus and is phosphorylated in response to hyperosmolar stress. Molecular endocrinology (Baltimore, Md.). 8(2):240-8. Pubmed: 8170480 Borsook D, Konradi C, Falkowski O, Comb M, Hyman SE. 1994. Molecular mechanisms of stress-induced proenkephalin gene regulation: CREB interacts with the proenkephalin gene in the mouse hypothalamus and is phosphorylated in response to hyperosmolar stress. Molecular endocrinology (Baltimore, Md.). 8(2):240-8. Pubmed: 8170480 We have established a transgenic model to facilitate the study of stress-induced gene regulation in the hypothalamus. This model, which uses a human proenkephalin-beta-galactosidase fusion gene, readily permits anatomic and cellular colocalization of stress-regulated immediate early gene products (e.g. Fos) and other transcription factors [e.g. cAMP response element-binding protein (CREB)] with the product of a potential target gene. Moreover, Fos provides a marker of cellular activation that is independent of the transgene. Hypertonic saline stress induced Fos in almost all cells in the PVN that exhibited basal expression of the proenkephalin transgene; however, all cells in which the transgene was activated by stress also expressed Fos. CREB was found in essentially all neurons. Gel shift analysis with and without antisera to Fos and CREB showed that AP-1 binding activity, containing Fos protein, was induced by hyperosmotic stress. However, Fos was not detected binding to the proenkephalin second messenger-inducible enhancer even in hypothalamic cell extracts from stressed animals. In contrast, CREB formed specific complexes with both the proenkephalin enhancer and a cAMP- and calcium-regulated element (CaRE) within the c-fos gene. Moreover, we found that hypertonic saline induced CREB phosphorylation in cells that express the transgene within the paraventricular nucleus and supraoptic nucleus. These results suggest a model in which proenkephalin gene expression in the paraventricular nucleus is regulated by CREB in response to hypertonic stress. -
Cornford EM, Hyman S, Swartz BE. 1994. The human brain GLUT1 glucose transporter: ultrastructural localization to the blood-brain barrier endothelia. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 14(1):106-12. Pubmed: 8263045 Cornford EM, Hyman S, Swartz BE. 1994. The human brain GLUT1 glucose transporter: ultrastructural localization to the blood-brain barrier endothelia. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 14(1):106-12. Pubmed: 8263045 Immunogold electron microscopy was used to examine human brain resections to localize the GLUT1 glucose transporter. The tissue examined was obtained from a patient undergoing surgery for treatment of seizures, and the capillary profiles examined had characteristics identical to those described previously for active, epileptogenic sites (confirmed by EEG analyses). A rabbit polyclonal antiserum to the full-length human erythrocyte glucose transporter (GLUT1) was labeled with 10-nm gold particle-secondary antibody conjugates and localized immunoreactive GLUT1 molecules in human brain capillary endothelia, with < 0.25% of the particles beyond the capillary profile. Erythrocyte membranes were also highly immunoreactive, whereas macrophage membranes were GLUT1-negative. The number of immunoreactive sites per capillary profile was observed to be 10-fold greater in humans than in previous studies of rat and rabbit brain capillaries. In addition, half of the total number of immunoreactive gold particles were localized to the luminal capillary membrane. We suggest that the blood-brain barrier GLUT1 glucose transporter is up-regulated in seizures, and this elevated transporter activity is characterized by increased GLUT1 transporters, particularly on the luminal capillary membranes. In addition, acute modulation of glucose transporter activity is presumed to involve translocation of GLUT1 from cytoplasmic to luminal membrane sites, demonstrable with quantitative immunogold electron microscopy. -
Hyman SE. 1994. Another one bites the dust: an infectious origin for peptic ulcers. Harvard review of psychiatry. 1(5):294-5. Pubmed: 9384861 Hyman SE. 1994. Another one bites the dust: an infectious origin for peptic ulcers. Harvard review of psychiatry. 1(5):294-5. Pubmed: 9384861 -
Hyman SE, Konradi C, Kobierski L, Cole R, Senatus P, Green D. 1994. Pharmacologic regulation of striatal proenkephalin gene expression via transcription factor CREB. Progress in clinical and biological research. 390:155-71. Pubmed: 7724644 Hyman SE, Konradi C, Kobierski L, Cole R, Senatus P, Green D. 1994. Pharmacologic regulation of striatal proenkephalin gene expression via transcription factor CREB. Progress in clinical and biological research. 390:155-71. Pubmed: 7724644 -
Cornford EM, Hyman S, Landaw EM. 1994. Developmental modulation of blood-brain-barrier glucose transport in the rabbit. Brain research. 663(1):7-18. Pubmed: 7850472 Cornford EM, Hyman S, Landaw EM. 1994. Developmental modulation of blood-brain-barrier glucose transport in the rabbit. Brain research. 663(1):7-18. Pubmed: 7850472 Blood-brain barrier (BBB) glucose transport rates were measured using the intracarotid injection method in newborn, 14-day-old suckling, 28-day-old weanling and adult rabbits, and compared with membrane transporter density. Light microscope immunochemistry confirmed the presence of the GLUT1 glucose transporter isoform in these rabbits. Quantitative electron microscopic immunogold analyses of GLUT1-immunoreactive sites per micrometer of capillary membrane indicated GLUT1 density increased with age, and correlated with in vivo measurements of Vmax. Maximal transport velocities (Vmax) of glucose transfer (an indicator of the activity and relative number of transporter proteins) increased significantly (P = 0.05) with age: in neonates Vmax = 0.61 mumol.min-1.g-1, in sucklings Vmax = 0.68 mumol.min-1.g-1, in weanlings Vmax = 0.88 mumol.min-1.g-1, and in adults Vmax = 1.01 mumol.min-1 g-1. Cerebral blood flow (CBF) rates, increased with age from 0.19 and 0.26 ml.min-1.g-1 in neonates and sucklings to 0.51 (weanlings) and 0.70 (adults) ml.min-1.g-1. Non-linear regression analyses indicated the half-saturation constant (Km) for glucose transport ranged from 13 mM in adult rabbits to 19 mM in 14-day-old sucklings: differences in Km were not significant. Age-related changes in the Permeability-Surface Area product (PS +/- S.E.) of both water and glucose were also seen. At all ages studied, the diffusion component (Kd) of glucose uptake was not distinguishable from zero. We conclude developmental up-regulation of the rabbit BBB glucose transporter is characterized by no changes in transporter affinity, and provide the first demonstration of increased membrane transporter proteins correlating with an age-related increase (65%) in glucose transporter maximal velocity. -
Konradi C, Cole RL, Heckers S, Hyman SE. 1994. Amphetamine regulates gene expression in rat striatum via transcription factor CREB. The Journal of neuroscience : the official journal of the Society for Neuroscience. 14(9):5623-34. Pubmed: 8083758 Konradi C, Cole RL, Heckers S, Hyman SE. 1994. Amphetamine regulates gene expression in rat striatum via transcription factor CREB. The Journal of neuroscience : the official journal of the Society for Neuroscience. 14(9):5623-34. Pubmed: 8083758 Amphetamine is a psychostimulant drug of abuse that can produce long-lived changes in behavior including sensitization and dependence. The neural substrates of these drug effects remain unknown, but based on their prolonged time course, we hypothesize that they involve drug-induced alterations in gene expression. It has recently been demonstrated that amphetamine regulates the expression of several genes, including c-fos, via dopamine D1 receptors in rat striatum. Here we report that amphetamine induces phosphorylation of transcription factor cAMP response element binding protein (CREB) in rat striatum in vivo and that dopamine D1 receptor stimulation induces phosphorylation of CREB within specific complexes bound to cAMP regulatory elements. In addition, we show by antisense injection that CREB is necessary for c-fos induction by amphetamine in vivo. Since CREB has been implicated in the activation of a number of immediate-early genes as well as several neuropeptide genes, CREB phosphorylation may be an important early nuclear event mediating long-term consequences of amphetamine administration. -
Schwarzschild MA, Dauer WT, Lewis SE, Hamill LK, Fink JS, Hyman SE. 1994. Leukemia inhibitory factor and ciliary neurotrophic factor increase activated Ras in a neuroblastoma cell line and in sympathetic neuron cultures. Journal of neurochemistry. 63(4):1246-54. Pubmed: 7523587 Schwarzschild MA, Dauer WT, Lewis SE, Hamill LK, Fink JS, Hyman SE. 1994. Leukemia inhibitory factor and ciliary neurotrophic factor increase activated Ras in a neuroblastoma cell line and in sympathetic neuron cultures. Journal of neurochemistry. 63(4):1246-54. Pubmed: 7523587 The cytokines leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF) have been implicated in determination of neuronal phenotype as well as promotion of neuronal survival. However, the intracellular mechanisms by which their signals are transduced remain poorly understood. We have previously studied the regulation of vasoactive intestinal polypeptide gene expression by LIF and CNTF in the NBFL neuroblastoma cell line. Because these cytokines induce tyrosine phosphorylation that may lead to Ras activation, we explored a possible role for Ras in LIF- and CNTF-induced signal transduction. In NBFL cells LIF increases activated Ras in a rapid, transient, and concentration-dependent manner. CNTF and a related cytokine, oncostatin M, produce similar increases. CNTF and LIF also increase activated Ras in neuron-enriched dissociated cultures of sympathetic ganglia. Moreover, these cytokines rapidly and transiently induce specific tyrosine-phosphorylated proteins, p165 and p195. The protein kinase inhibitors K252a and staurosporine block LIF-induced increases in tyrosine phosphorylation, activated Ras, and vasoactive intestinal polypeptide mRNA in NBFL cells. These data support a possible role for Ras in the cell differentiation effects of LIF and CNTF. 1993
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Hyman SE, Kosofsky BE, Nguyen TV, Cohen BM, Comb MJ. 1993. Everything activates c-fos--how can it matter?. NIDA research monograph. 125:25-38. Pubmed: 8341366 Hyman SE, Kosofsky BE, Nguyen TV, Cohen BM, Comb MJ. 1993. Everything activates c-fos--how can it matter?. NIDA research monograph. 125:25-38. Pubmed: 8341366 It is probably safe to say that the regulation of c-fos expression by drug treatment and other stimulus paradigms has biological specificity and mechanistic significance. However, as this brief essay makes clear, the immunohistochemical detection of c-fos is only the tip of the biological iceberg. IEGs deserve to be studied as critical components of the intracellular signaling machinery that may transduce intercellular signals, including those produced by drugs of abuse, into longer term changes in cellular function. However, the study of IEG expression must be related to biologically significant target genes and must be complemented by the study of phosphorylation of constitutively expressed transcription factors. Moreover, as illustrated by the proenkephalin gene, the regulation of genes that play important roles in differentiated cell function may differ depending on which cell types and stimulus conditions are investigated. Finally, attention must be paid to the complexities of gene regulation under conditions of repetitive and chronic stimulation if phenomena such as the neural substrates of drug dependence are to be understood. -
Tang G, Hyman S, Schneider JH, Giannotta SL. 1993. Application of photodynamic therapy to the treatment of atherosclerotic plaques. Neurosurgery. 32(3):438-43; discussion 443. Pubmed: 8455769 Tang G, Hyman S, Schneider JH, Giannotta SL. 1993. Application of photodynamic therapy to the treatment of atherosclerotic plaques. Neurosurgery. 32(3):438-43; discussion 443. Pubmed: 8455769 Photodynamic therapy is a therapeutic modality long studies for its application to the treatment of malignant neoplasms. Recently, studies have suggested its potential use in the treatment of atherosclerosis. In this study, two atherosclerotic plaques were induced in the abdominal aortas of 35 rabbits. The animals then received Photofrin II (Quadralogic Technologies Inc., Pearl River, NY), a photosensitizer, at doses of 5 mg/kg and 2.5 mg/kg. After 48 hours, the plaques were irradiated by a fiberoptic connected to an argon ion laser. Fluency rates from 32 mW to 256 mW and energy doses from 1.6 to 60 joules were applied. Only one of the paired plaques was irradiated, the other remaining as a control. Four weeks after treatment, the vessels were assessed. Of 26 plaques treated with photodynamic therapy, 22 were no longer grossly visible, while the nine animals that received light irradiation but no Photofrin II all had visible plaque (P < 0.001). Studies of the vessel sections confirmed a reduction in intimal thickness from 0.74 +/- 0.15 mm in matched controls as compared with 0.51 +/- 0.13 mm in animals with treated plaques. There was a concomitant enlargement of the luminal diameter from 1.13 +/- 0.51 to 1.41 +/- 0.72. On the microscopic level, plaque reduction was most complete in the groups treated with 40 and 60 joules. Different fluency rates and drug dosages did not lead to differing outcomes. Our findings indicate that photodynamic therapy with dihematoporphyrin ether met our goal of reducing plaque size and may represent a means of treating atherosclerotic plaques. -
Hyman SE. 1993. New insights into how antipsychotic drugs might work. Harvard review of psychiatry. 1(1):68-9. Pubmed: 9384831 Hyman SE. 1993. New insights into how antipsychotic drugs might work. Harvard review of psychiatry. 1(1):68-9. Pubmed: 9384831 -
Symes AJ, Rao MS, Lewis SE, Landis SC, Hyman SE, Fink JS. 1993. Ciliary neurotrophic factor coordinately activates transcription of neuropeptide genes in a neuroblastoma cell line. Proceedings of the National Academy of Sciences of the United States of America. 90(2):572-6. Pubmed: 8093644 Symes AJ, Rao MS, Lewis SE, Landis SC, Hyman SE, Fink JS. 1993. Ciliary neurotrophic factor coordinately activates transcription of neuropeptide genes in a neuroblastoma cell line. Proceedings of the National Academy of Sciences of the United States of America. 90(2):572-6. Pubmed: 8093644 Differentiation factors have been identified that influence the phenotype of sympathetic neurons by altering expression of classical neurotransmitters and neuropeptides. Investigation of the molecular mechanisms through which such factors act would be facilitated by the availability of a neuronal cell line that responds to these factors in a fashion similar to sympathetic neurons. We have identified a human neuroblastoma cell line, NBFL, that responds to the differentiation factor ciliary neurotrophic factor (CNTF) by coordinately inducing multiple neuropeptide genes as do sympathetic neurons. Treatment of NBFL cells with CNTF increases vasoactive intestinal polypeptide (VIP), somatostatin, and calcitonin gene-related peptide (CGRP) mRNAs but does not change other neurotransmitter properties. The induction of VIP mRNA by CNTF in NBFL cells is dose dependent, rapid, sustained, and independent of new protein synthesis. Genomic 5' flanking sequences located within a 1.59-kilobase region of the human VIP gene and distinct from the previously defined cAMP-responsive element subserve transcriptional activation by CNTF. Further examination of NBFL cells should permit the elucidation of the molecular mechanisms by which CNTF and other differentiation factors coordinately activate neuropeptide gene transcription to influence neuronal differentiation. Similar mechanisms may mediate the effect of CNTF on neuronal survival. -
Hyman SE. 1993. Molecular and cell biology of addiction. Current opinion in neurology and neurosurgery. 6(4):609-13. Pubmed: 8400475 Hyman SE. 1993. Molecular and cell biology of addiction. Current opinion in neurology and neurosurgery. 6(4):609-13. Pubmed: 8400475 Progress was made during the past year in several important areas relevant to cellular and molecular research on addiction. This includes a better understanding of the functioning of neural circuitry involved in the reinforcing properties of drugs of abuse, the cloning of complementary DNA's encoding important molecular targets of addictive drugs, including the first opiate receptors to be cloned, and progress in understanding the molecular basis of adaptive processes underlying dependence and withdrawal. -
Konradi C, Kobierski LA, Nguyen TV, Heckers S, Hyman SE. 1993. The cAMP-response-element-binding protein interacts, but Fos protein does not interact, with the proenkephalin enhancer in rat striatum. Proceedings of the National Academy of Sciences of the United States of America. 90(15):7005-9. Pubmed: 8346209 Konradi C, Kobierski LA, Nguyen TV, Heckers S, Hyman SE. 1993. The cAMP-response-element-binding protein interacts, but Fos protein does not interact, with the proenkephalin enhancer in rat striatum. Proceedings of the National Academy of Sciences of the United States of America. 90(15):7005-9. Pubmed: 8346209 The proenkephalin gene is a well-studied model of transcription factor-target gene interaction in the nervous system and has been proposed as a regulatory target of the protein product of the immediate-early gene c-fos. This regulatory mechanism has been proposed, in part, because the cAMP response element 2 (CRE-2) site, the key DNA regulatory element within the proenkephalin second-messenger-inducible enhancer, avidly binds AP-1 proteins, including Fos, in vitro. However, we observe a dissociation in the time course of activation of c-fos and proenkephalin mRNA in rat striatum after administration of the dopamine D2 receptor antagonist haloperidol. This result prompted us to investigate the composition of protein complexes in striatal nuclear extracts that bind to the CRE-2 site. Even though our striatal nuclear extracts had substantial basal and haloperidol-inducible AP-1-binding activities that contained Fos, we could not detect Fos in complexes bound to the CRE-2 element. Instead, as determined by antibody supershift analysis, we detect CRE-binding protein (CREB)-like proteins binding to CRE-2 in both basal and haloperidol-stimulated conditions. Finally, we show that haloperidol induces CREB protein phosphorylation in striatum. -
Cornford EM, Hyman S, Pardridge WM. 1993. An electron microscopic immunogold analysis of developmental up-regulation of the blood-brain barrier GLUT1 glucose transporter. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 13(5):841-54. Pubmed: 8360290 Cornford EM, Hyman S, Pardridge WM. 1993. An electron microscopic immunogold analysis of developmental up-regulation of the blood-brain barrier GLUT1 glucose transporter. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 13(5):841-54. Pubmed: 8360290 Electron microscopy was used to quantitate blood-brain barrier (BBB) glucose transporters in newborn, 14-day-old suckling, 28-day-old weanling, and adult rabbits. A rabbit polyclonal antiserum to a synthetic peptide encoding the 13 C-terminal amino acids of the human erythrocyte glucose transporter (GLUT1) was labeled with 10-nm gold particle-secondary antibody conjugates and localized immunoreactive GLUT1 molecules in rabbit brain capillary endothelia. Three distinct populations of brain capillary profiles were identified in newborn rabbits: prepatent capillary buds, partially patent capillaries with highly amplified luminal membranes, and patent capillaries. Immunogold analyses indicated that the GLUT1 transporter abundance positively correlated with capillary developmental status. The mean number of gold particles per capillary profile increased at each developmental age examined, suggesting that developmental up-regulation of the BBB glucose transporter occurred in rabbits. GLUT1 immunoreactivity was three- to fourfold greater on the abluminal than luminal capillary membranes among all ages examined. Changes in the proportions of GLUT1 transporter were also seen, and possible reasons for the postnatal decrease in the percentage of cytoplasmic GLUT1 transporter are discussed. The numbers of cytoplasmic and membrane-associated immunogold particles increased with age. We conclude that regulatory modulations of BB glucose transport may be characterized by increases in BBB glucose transporter density with age and state of development. In addition, modulation of glucose transporter activity may be reflected by minor postnatal shifts of GLUT1 from cytoplasmic to membrane compartments, which can be demonstrated with quantitative immunogold electron microscopy. -
Kosofsky BE, Hyman SE. 1993. The ontogeny of immediate early gene response to cocaine: a molecular analysis of the effects of cocaine on developing rat brain. NIDA research monograph. 125:161-71. Pubmed: 8341363 Kosofsky BE, Hyman SE. 1993. The ontogeny of immediate early gene response to cocaine: a molecular analysis of the effects of cocaine on developing rat brain. NIDA research monograph. 125:161-71. Pubmed: 8341363 1992
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Hope B, Kosofsky B, Hyman SE, Nestler EJ. 1992. Regulation of immediate early gene expression and AP-1 binding in the rat nucleus accumbens by chronic cocaine. Proceedings of the National Academy of Sciences of the United States of America. 89(13):5764-8. Pubmed: 1631058 Hope B, Kosofsky B, Hyman SE, Nestler EJ. 1992. Regulation of immediate early gene expression and AP-1 binding in the rat nucleus accumbens by chronic cocaine. Proceedings of the National Academy of Sciences of the United States of America. 89(13):5764-8. Pubmed: 1631058 Chronic treatment of rats with cocaine leads to long-term biochemical changes in the nucleus accumbens (NAc), a brain region implicated in mediating the reinforcing effects of cocaine and other drugs of abuse. Immediate early genes (IEGs) and their protein products appear to play an important role in transducing extracellular stimuli into altered patterns of cellular gene expression and, therefore, into long-term changes in cellular functioning. We therefore examined changes in the mRNA levels for the IEGs c-fos, c-jun, fosB, junB, and zif268 in the NAc of rats treated acutely and chronically with cocaine. A single cocaine injection increased the mRNA levels of all of the IEGs examined. Following chronic cocaine treatment, however, IEG expression had returned to control levels and was not significantly increased following a further acute challenge with cocaine, suggesting desensitization in the ability of cocaine to induce these IEGs. Similarly, levels of Fos-like immunoreactivity, which are increased in the NAc by acute cocaine, were reduced to control levels in chronic cocaine-treated rats. Fos, Jun, and a number of related proteins activate or repress transcription of genes by binding to DNA response elements called AP-1 sites. As would be expected from the RNA data and immunohistochemistry, acute cocaine administration increased AP-1 binding activity in the NAc, an effect that reverted completely to control levels within 8-12 hr. In contrast, AP-1 binding activity in the NAc of animals treated chronically with cocaine remained elevated at acute levels 18 hr after the last chronic injection, a time at which c-fos and c-jun mRNA levels and Fos-like immunoreactivity had returned to control values. An additional acute cocaine challenge did not further increase AP-1 binding. The data suggest that chronic cocaine treatment leads to a persistent increase in AP-1 binding activity, which may be involved in some of the physiological and behavioral aspects of cocaine addiction. -
Comb MJ, Kobierski L, Chu HM, Tan Y, Borsook D, Herrup K, Hyman SE. 1992. Regulation of opioid gene expression: a model to understand neural plasticity. NIDA research monograph. 126:98-112. Pubmed: 1491720 Comb MJ, Kobierski L, Chu HM, Tan Y, Borsook D, Herrup K, Hyman SE. 1992. Regulation of opioid gene expression: a model to understand neural plasticity. NIDA research monograph. 126:98-112. Pubmed: 1491720 The recent finding that neurotransmitters and drugs that affect neurotransmission have important influences on gene expression suggests that drug-induced alterations in gene expression may underlie many long-term effects of addictive drugs, for example, dependence and drug-seeking behaviors. These long-term adaptive responses to opiate drugs have been particularly difficult to understand at a mechanistic level. Data presented here indicate that the gene encoding the opioid precursor proenkephalin is highly regulated by neural activity, second-messenger pathways, and PKA. These observations raise the possibility that drugs of abuse (e.g., opiates acting through opiate receptors) may act at the genetic level to modulate the expression of endogenous opiates and that these effects may underlie one component of the brain's long-term adaptive response to exogenous opiates. The transgenic animals described above can be used to investigate opiate drug-induced changes in proenkephalin gene expression, allowing rapid analysis of changes in proenkephalin gene expression in highly restricted populations of neurons in a fashion previously impossible. In addition, by analyzing the effects of specific enhancer mutations on tissue-specific and transsynaptic regulation of proenkephalin expression, transgenic models will permit mechanistic investigations within the intact nervous system that cannot otherwise be undertaken. Investigation of mechanisms underlying this process requires the analysis of intracellular signaling pathways, responsive DNA regulatory elements, and the transcription factors transducing synaptic signals into gene regulation. In the studies described herein, we demonstrate that AP-1 complexes consisting of different Jun proteins differentially regulate proenkephalin transcription at the CRE-2 element. c-Jun constitutively activates proenkephalin transcription, whereas JunD activates in a fashion completely dependent on the activation of second-messenger pathways and the cAMP-dependent PKA. JunB alone has no effect on proenkephalin gene expression, yet this molecule effectively blocks activation mediated by JunD and, hence, may act as a repressor. These data are consistent with a model (figure 4) in which preexisting JunD mediates the rapid cAMP-dependent activation of the proenkephalin enhancer, whereas IEGs such as JunB or c-Fos mediate the protein synthesis-dependent inactivation. Because c-Jun activates proenkephalin transcription constitutively, induction of c-Jun may lead to a further and prolonged activation of proenkephalin gene expression. Hence, the ratio of c-Jun to JunB induction may determine whether proenkephalin is repressed or further activated. -
Nguyen TV, Kosofsky BE, Birnbaum R, Cohen BM, Hyman SE. 1992. Differential expression of c-fos and zif268 in rat striatum after haloperidol, clozapine, and amphetamine. Proceedings of the National Academy of Sciences of the United States of America. 89(10):4270-4. Pubmed: 1374894 Nguyen TV, Kosofsky BE, Birnbaum R, Cohen BM, Hyman SE. 1992. Differential expression of c-fos and zif268 in rat striatum after haloperidol, clozapine, and amphetamine. Proceedings of the National Academy of Sciences of the United States of America. 89(10):4270-4. Pubmed: 1374894 Antipsychotic drugs are monoamine receptor antagonists. However, the mechanisms by which these direct actions are translated into therapeutic effects are unknown. Candidate mechanisms include receptor-mediated regulation of gene expression in target neurons. Inducible transcription factors, including certain immediate early genes (IEGs), may mediate between receptor-activated second messenger systems and expression of genes involved in the differentiated functions of neurons. We examined the specificity of induction of the IEGs c-fos and zif268 after acute administration of several antipsychotic drugs and, for comparison, the stimulant amphetamine, which has pharmacologic effects relatively opposite to those of antipsychotics. Antipsychotic drugs with potent dopamine D2 receptor antagonist properties, such as haloperidol, induced both c-fos and zif268 mRNA in the caudate-putamen; however, the atypical antipsychotic drug clozapine induced zif268 but not c-fos mRNA in that region. Similarly, haloperidol, but not clozapine, induced c-Fos-like immunoreactivity in the caudate-putamen. In contrast, both drugs induced c-Fos-like immunoreactivity in the nucleus accumbens. Like haloperidol, amphetamine induced both c-fos and zif268 mRNA in the caudate-putamen, but the anatomic patterns of induction of c-Fos-like immunoreactivity by the two drugs were dramatically different. Haloperidol and amphetamine induced AP-1 binding activity in cell extracts from the caudate-putamen, indicating that drug-induced IEG expression results in protein products that may function in the regulation of target gene expression. Thus these data demonstrate that inductions of IEG expression by haloperidol, clozapine, and amphetamine are specific, may be biologically relevant, and suggest avenues for further investigation. -
Borsook D, Rosen H, Collard M, Dressler H, Herrup K, Comb MJ, Hyman SE. 1992. Expression and regulation of a proenkephalin beta-galactosidase fusion gene in the reproductive system of transgenic mice. Molecular endocrinology (Baltimore, Md.). 6(9):1502-12. Pubmed: 1435791 Borsook D, Rosen H, Collard M, Dressler H, Herrup K, Comb MJ, Hyman SE. 1992. Expression and regulation of a proenkephalin beta-galactosidase fusion gene in the reproductive system of transgenic mice. Molecular endocrinology (Baltimore, Md.). 6(9):1502-12. Pubmed: 1435791 A fusion gene containing 3 kilobases of human proenkephalin 5'-flanking sequences and 1 kilobase of human proenkephalin 3'-flanking sequence and the easily visualized histochemical marker, Escherichia coli beta-galactosidase, was used to study the function of cis-regulatory elements within the human proenkephalin gene in transgenic mice. Here data are presented on expression and regulation of this fusion gene in the reproductive system of three independent lines of transgenic mice. Within the male reproductive system, the fusion gene is expressed in the proximal epididymis and in developing germinal cells but not in mature or elongating spermatids. In the female reproductive system, the transgene was expressed at low basal levels, but expression was dramatically stimulated in the ovary and oviduct by hormonal stimulation and pregnancy; additionally, expression was induced at the uteroplacental junction in pregnant mice. Taken together these observations suggest that critical sequences for expression and regulation of the proenkephalin gene within the reproductive system are contained within sequences of the construct. 1991
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Zlokovic BV, Segal MB, McComb JG, Hyman S, Weiss MH, Davson H. 1991. Kinetics of circulating vasopressin uptake by choroid plexus. The American journal of physiology. 260(2 Pt 2):F216-24. Pubmed: 1899978 Zlokovic BV, Segal MB, McComb JG, Hyman S, Weiss MH, Davson H. 1991. Kinetics of circulating vasopressin uptake by choroid plexus. The American journal of physiology. 260(2 Pt 2):F216-24. Pubmed: 1899978 Uptake of circulating arginine vasopressin (AVP) by choroid plexus was studied by means of the in situ brain perfusion technique in anesthetized guinea pig and by means of single-circulation paired-tracer dilution technique in isolated perfused sheep choroid plexus. Kinetic analysis revealed saturable AVP uptake with Michaelis constant (Km) values of 32 +/- 4 and 31 +/- 5 nM and maximal saturable influx rate (Vmax) of 0.45 +/- 0.06 and 12.1 +/- 0.67 pmol.min-1.g-1 in guinea pig and sheep choroid plexus, respectively. The peptide fragments AVP-(1-8) and [pGlu4,Cyt6]AVP-(4-9), the amino acids L-phenylalanine, L-tyrosine, and 2-aminobicyclo(2,2,1)heptane-2-carboxylic acid, and the aminopeptidase inhibitors Bestatin and bacitracin did not influence hormone kinetics. However, the V1 antagonist [(1-beta-mercapto-beta,beta-cyclo-pentamethylenepropionic acid)-O-methyl-Tyr2]AVP significantly inhibited AVP uptake with inhibitor constant (Ki) values of 0.19 +/- 0.03 (guinea pig) and 0.07 +/- 0.01 microM (sheep). The V2 agonist 1-desamino-8-D-AVP and pressinoic acid produced weak inhibitions only in guinea pig choroid plexus, and Ki/Km ratios indicated 220 and 310 times lower affinities than for AVP, respectively. It is suggested that the membrane mechanism responsible for AVP uptake in choroid plexus has a binding site with properties similar to those of V1 receptor. -
Zlokovic BV, Hyman S, McComb JG, Tang G, Rezai AR, Weiss MH. 1991. Vasopressin uptake by hypothalamopituitary axis and pineal gland in guinea pigs. The American journal of physiology. 260(4 Pt 1):E633-40. Pubmed: 1902062 Zlokovic BV, Hyman S, McComb JG, Tang G, Rezai AR, Weiss MH. 1991. Vasopressin uptake by hypothalamopituitary axis and pineal gland in guinea pigs. The American journal of physiology. 260(4 Pt 1):E633-40. Pubmed: 1902062 The uptake of circulating arginine vasopressin (AVP) by the pituitary gland (anterior lobe), pineal gland, and hypothalamus (ventromedial part) was investigated in an isolated in situ perused brain of anesthetized guinea pig. Kinetic experiments revealed saturable AVP uptake in all studied regions with Km values of 0.79, 0.19, and 0.76 microM and maximum velocity values of 22, 2.1, and 1.6 pmol.min-1.g-1 for the pituitary gland, pineal gland, and hypothalamus, respectively. The nonsaturable components (diffusion constants) were not significantly different from zero. Peptide fragments, L-phenylalanine, and Bestatin (an aminopeptidase inhibitor) did not interfere with AVP uptake. However, uptake of AVP was strongly inhibited in the presence of the V1 antagonist [1-(beta-mercapto-beta-beta-cyclopentamethylenepropionic acid), 2-(O-methyl)tyrosine]AVP at 2.7 microM, and regional Ki values, assuming that the observed inhibitions were purely competitive, ranged between 0.32 and 2.23 microM. The V2 agonist 1-desamino-8-D-AVP at 2.7 microM produced only a weak inhibition of AVP uptake, and regional Ki values ranged between 9.56 and 21.3 microM. It is concluded that specific uptake mechanisms in the hypothalamopituitary axis and pineal gland are sensitive enough to detect blood-borne AVP under the physiological hormonal state. It is suggested that AVP binding in situ is primarily related to V1 receptors, which may be involved in mediating the central effects of this circulating peptide. -
Comb M, Hyman SE, Kobierski L, Chu HM, Van Nguyen T. 1991. Mechanisms underlying synaptic regulation of proenkephalin transcription. NIDA research monograph. 111:149-70. Pubmed: 1663581 Comb M, Hyman SE, Kobierski L, Chu HM, Van Nguyen T. 1991. Mechanisms underlying synaptic regulation of proenkephalin transcription. NIDA research monograph. 111:149-70. Pubmed: 1663581 1990
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Cohen BM, Nguyen TV, Hyman SE. 1990. Cocaine-induced changes in gene expression in rat brain. NIDA research monograph. 105:175-81. Pubmed: 1831539 Cohen BM, Nguyen TV, Hyman SE. 1990. Cocaine-induced changes in gene expression in rat brain. NIDA research monograph. 105:175-81. Pubmed: 1831539 -
Ross ME, Evinger MJ, Hyman SE, Carroll JM, Mucke L, Comb M, Reis DJ, Joh TH, Goodman HM. 1990. Identification of a functional glucocorticoid response element in the phenylethanolamine N-methyltransferase promoter using fusion genes introduced into chromaffin cells in primary culture. The Journal of neuroscience : the official journal of the Society for Neuroscience. 10(2):520-30. Pubmed: 2303857 Ross ME, Evinger MJ, Hyman SE, Carroll JM, Mucke L, Comb M, Reis DJ, Joh TH, Goodman HM. 1990. Identification of a functional glucocorticoid response element in the phenylethanolamine N-methyltransferase promoter using fusion genes introduced into chromaffin cells in primary culture. The Journal of neuroscience : the official journal of the Society for Neuroscience. 10(2):520-30. Pubmed: 2303857 The rat gene encoding phenylethanolamine N-methyltransferase (PNMT) was cloned and a consensus sequence for a glucocorticoid response element (GRE) was found at -513 bp, 5' to the transcriptional start site. In order to define the function of this element, fusion genes containing the PNMT promoter and a chloramphenicol acetyltransferase (CAT) reporter gene were constructed. These constructs did not express after transfection into any of 7 continuous cell lines, none of which endogenously produce PNMT. A system for transfecting chromaffin cells in primary culture was therefore devised using constructs containing 200 bp of the proenkephalin (ENK) promoter, whose expression characteristics are well known. pENK beta GAL-1, containing the ENK promoter with a lac Z reporter, was introduced into these cells and beta-galactosidase activity was visualized in situ. Approximately 90% of cells transfected were chromaffin; transfection efficiency was 5%. High levels of CAT activity were measured in chromaffin cells transfected with pENKAT12, possessing a CAT reporter. In contrast to tumor cell lines, pENKAT12 induction in these cells by forskolin and phorbol esters did not require a phosphodiesterase inhibitor. In this chromaffin system, both basal and regulated expression of the PNMT fusion genes were detected. Dexamethasone (dex) induced expression of pPNMT3000 and pPNMT900, containing the putative GRE and 3000 bp or 863 bp of PNMT promoter sequence, 4- to 10-fold. Expression of pPNMT300 and pPNMT100, which lack the GRE and contain 273 bp or 99 bp of PNMT promoter sequence, was unaffected by dex. Addition of the PNMT region spanning -490 to -863 bp conferred full dex responsiveness to a thymidine kinase promoter. Deletion of the putative GRE sequence by site-directed mutagenesis abolished the dex response. These data identify the sequence at -513 bp in the rat PNMT gene as a functional, positively acting GRE. Primary cultures of bovine chromaffin cells provide a biologically relevant expression system for transcriptional studies of catecholamine genes and their related neuropeptides. -
Van Nguyen T, Kobierski L, Comb M, Hyman SE. 1990. The effect of depolarization on expression of the human proenkephalin gene is synergistic with cAMP and dependent upon a cAMP-inducible enhancer. The Journal of neuroscience : the official journal of the Society for Neuroscience. 10(8):2825-33. Pubmed: 2167356 Van Nguyen T, Kobierski L, Comb M, Hyman SE. 1990. The effect of depolarization on expression of the human proenkephalin gene is synergistic with cAMP and dependent upon a cAMP-inducible enhancer. The Journal of neuroscience : the official journal of the Society for Neuroscience. 10(8):2825-33. Pubmed: 2167356 Membrane depolarization is a critical component of neural signaling; in recent years there also has been a great deal of evidence that membrane depolarization can regulate neural gene expression. Therefore, excitatory neurotransmission may be an important mechanism of neural plasticity. We have investigated the intracellular pathways and DNA regulatory elements through which membrane depolarization activates expression of the neural gene encoding human proenkephalin. In PC12 and C6-glioma cells, depolarization-induced expression of a transfected proenkephalin fusion gene was proportional to extracellular calcium concentration and was inhibited by verapamil. Activation of the gene by KCl-induced depolarization or the calcium ionophore A23187 was dependent upon and synergistic with cAMP in PC12 and C6-glioma cells, but neither depolarization nor treatment with A23187 affected cAMP levels. Trifluoperazine and W7 inhibited depolarization-induced gene expression but did not affect expression induced by the adenylyl cyclase activator forskolin. At the level of the DNA, depolarization-induced activation is conferred on the proenkephalin gene by a previously characterized cAMP-inducible enhancer. Multiple copies of a single component element of that enhancer, containing the CGTCA sequence motif characteristic of cAMP regulatory elements, can reconstitute the entire repertoire of responses to both cAMP and depolarization. These data suggest a model in which membrane depolarization activates gene expression through a calcium-dependent pathway, potentially involving calmodulin, and in which the transcriptional responses to both cAMP and calcium are transduced by the same DNA element. -
Jenike MA, Hyman S, Baer L, Holland A, Minichiello WE, Buttolph L, Summergrad P, Seymour R, Ricciardi J. 1990. A controlled trial of fluvoxamine in obsessive-compulsive disorder: implications for a serotonergic theory. The American journal of psychiatry. 147(9):1209-15. Pubmed: 2143637 Jenike MA, Hyman S, Baer L, Holland A, Minichiello WE, Buttolph L, Summergrad P, Seymour R, Ricciardi J. 1990. A controlled trial of fluvoxamine in obsessive-compulsive disorder: implications for a serotonergic theory. The American journal of psychiatry. 147(9):1209-15. Pubmed: 2143637 Thirty-eight patients with primary obsessive-compulsive disorder participated in a 10-week, double-blind, placebo-controlled trial of the potent, selective serotonin reuptake inhibitor fluvoxamine. Fluvoxamine was significantly better than placebo on two of three measures of improvement in obsessive-compulsive symptoms. The authors also compared studies of the serotonergic agents fluvoxamine, sertraline, fluoxetine, and clomipramine and found that a greater effect size was associated with less serotonergic specificity and that some ability to affect other neurotransmitter systems may be a necessary but not sufficient requirement for antiobsessional activity. These data lend only partial support to a serotonin hypothesis of obsessive-compulsive disorder. 1989
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Erlich SS, McComb JG, Hyman S, Weiss MH. 1989. Ultrastructure of the orbital pathway for cerebrospinal fluid drainage in rabbits. Journal of neurosurgery. 70(6):926-31. Pubmed: 2715821 Erlich SS, McComb JG, Hyman S, Weiss MH. 1989. Ultrastructure of the orbital pathway for cerebrospinal fluid drainage in rabbits. Journal of neurosurgery. 70(6):926-31. Pubmed: 2715821 An increasing number of physiological and morphological studies indicate that cerebrospinal fluid (CSF) drains via nonarachnoidal pathways in several mammalian species. Ultrastructural tracer studies were undertaken to examine the orbital route for CSF absorption in the rabbit. At the termination of the optic nerve subarachnoid space, an area of connective tissue containing numerous small tortuous channels is present. Ferritin (molecular weight 400,000) infused into the ventricles at normal and increased intraventricular pressure was present in these channels by 15 minutes postinfusion, and subsequently reached the intraorbital connective tissue. Elevating the intraventricular pressure did not noticeably alter the morphological appearance of this region or change the gross distribution pattern of the ferritin. Ferritin did not penetrate the scleral barrier to reach the choriocapillaris, nor did it breach the arachnoid barrier layer proximal to the transitional zone at the optic subarachnoid space to reach the dura mater. These results are very similar to those described for the hamster orbital region and the rabbit cribriform region. These experiments support the concept that macromolecules exit the subarachnoid space at the termination of the optic nerve via open channels, and that no significant barrier to drainage of macromolecules in CSF is present at this location. -
Breeze RE, McComb JG, Hyman S, Gilles FH. 1989. CSF production in acute ventriculitis. Journal of neurosurgery. 70(4):619-22. Pubmed: 2647919 Breeze RE, McComb JG, Hyman S, Gilles FH. 1989. CSF production in acute ventriculitis. Journal of neurosurgery. 70(4):619-22. Pubmed: 2647919 Clinically, there appears to be a significant reduction in cerebrospinal fluid (CSF) formation during acute ventriculitis--an observation that has not been well documented by experimental studies. To examine this phenomenon, an inoculum of Escherichia coli was injected into the lateral ventricles of New Zealand White rabbits. Approximately 18 hours later, the survivors (64%) underwent a 3-hour ventriculocisternal perfusion of carbon-14-dextran (MW 7 X 10(4)) as a reference marker for CSF formation. On the average, CSF formation in this experimental group was reduced by one-half to two-thirds of normal, confirming the clinical observation. Histologically, the stroma of the choroid plexus was the site of an extensive inflammatory infiltrate. Meningitis, ependymitis, and focal encephalitis completed the picture. Vasculitis was not present in the choroid plexus. The epithelium of the choroid plexus underwent patchy cellular swelling or frank necrosis and destruction. It is postulated that the changes in the choroid plexus caused by the inflammatory process were responsible for the diminished CSF formation in this acute setting. Reduced choroidal blood flow and/or enterotoxin may play a role in these alterations. -
Hyman SE, Comb M, Pearlberg J, Goodman HM. 1989. An AP-2 element acts synergistically with the cyclic AMP- and phorbol ester-inducible enhancer of the human proenkephalin gene. Molecular and cellular biology. 9(1):321-4. Pubmed: 2538722 Hyman SE, Comb M, Pearlberg J, Goodman HM. 1989. An AP-2 element acts synergistically with the cyclic AMP- and phorbol ester-inducible enhancer of the human proenkephalin gene. Molecular and cellular biology. 9(1):321-4. Pubmed: 2538722 An enhancer with two DNA elements, one containing the sequence CGTCA, is required for cyclic AMP- and phorbol ester-inducible transcription of the human proenkephalin gene. We report that an AP-2 element located adjacent to the enhancer acts synergistically with it to confer maximal response to cyclic AMP and phorbol esters. 1988
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Neave V, Giannotta S, Hyman S, Schneider J. 1988. Hematoporphyrin uptake in atherosclerotic plaques: therapeutic potentials. Neurosurgery. 23(3):307-12. Pubmed: 2976125 Neave V, Giannotta S, Hyman S, Schneider J. 1988. Hematoporphyrin uptake in atherosclerotic plaques: therapeutic potentials. Neurosurgery. 23(3):307-12. Pubmed: 2976125 Atherosclerotic plaques were induced in abdominal aortas of rabbits. At 8 weeks, 5 mg of dihematoporphyrin ether (Photofrin II) per kg was injected intravenously followed by sacrifice of the animal, fluorescence microscopy, and quantitative assay of porphyrin in the plaque-containing aortas at 1, 12, 24, 48, and 72 hours. Photofrin II was taken up preferentially by the plaque, with the highest plaque to normal wall ratio occurring at 48 hours. Phototherapy was carried out in 13 animals in each of which two plaques had been induced. With a 630-nm light source 48 hours after the infusion of Photofrin, one of the pair of plaques was treated while the other served as a control. Animals were killed at 2, 4, and 6 weeks. The 6-week specimens showed the most dramatic reduction in plaque in comparison to controls. Photodynamic therapy may provide an alternate strategy in dealing with focal atherosclerosis. -
Hyman SE. 1988. Recent developments in neurobiology: Part I. Synaptic transmission. Psychosomatics. 29(2):157-65. Pubmed: 2453072 Hyman SE. 1988. Recent developments in neurobiology: Part I. Synaptic transmission. Psychosomatics. 29(2):157-65. Pubmed: 2453072 -
Hyman SE. 1988. Recent developments in neurobiology: Part III. Effectors of transmitter action. Psychosomatics. 29(4):373-8. Pubmed: 2906447 Hyman SE. 1988. Recent developments in neurobiology: Part III. Effectors of transmitter action. Psychosomatics. 29(4):373-8. Pubmed: 2906447 -
Hyman SE. 1988. The role of molecular biology in psychiatry. Psychosomatics. 29(3):328-32. Pubmed: 2900535 Hyman SE. 1988. The role of molecular biology in psychiatry. Psychosomatics. 29(3):328-32. Pubmed: 2900535 -
Hyman SE, Comb M, Lin YS, Pearlberg J, Green MR, Goodman HM. 1988. A common trans-acting factor is involved in transcriptional regulation of neurotransmitter genes by cyclic AMP. Molecular and cellular biology. 8(10):4225-33. Pubmed: 2903436 Hyman SE, Comb M, Lin YS, Pearlberg J, Green MR, Goodman HM. 1988. A common trans-acting factor is involved in transcriptional regulation of neurotransmitter genes by cyclic AMP. Molecular and cellular biology. 8(10):4225-33. Pubmed: 2903436 Activation of neurotransmitter receptors can regulate transcription in postsynaptic cells through the actions of second messengers. Trans-synaptic regulation of transcription appears to be an important mechanism controlling the synthesis of molecules involved in neuronal signaling, especially neuropeptides. Proenkephalin, vasoactive intestinal polypeptide, and somatostatin have been shown to be transcriptionally regulated by the second messenger, cyclic AMP (cAMP), as has the catecholamine synthesizing enzyme tryosine hydroxylase. cAMP-inducible elements have been mapped within these genes, and trans-acting factors which bind to several such elements have been identified. With the discovery that individual neurons generally contain multiple transmitters within their synaptic terminals, it has become important to understand in detail the mechanisms by which the synthesis of transmitters can be coregulated. Here we compare the structure and function of the proenkephalin cAMP-inducible enhancer with the mapped cAMP-inducible elements of the vasoactive intestinal polypeptide, somatostatin, and tyrosine hydroxylase genes and a putative cAMP-inducible element in the proto-oncogene c-fos. We have previously shown that the proenkephalin enhancer is composed of two different elements, ENKCRE-1 and ENKCRE-2. We show here that one of these, ENKCRE-2, is structurally similar to elements found within the vasoactive intestinal polypeptide, somatostatin, and tyrosine hydroxylase genes and binds a trans-acting factor that is competed for both in cotransfection experiments (in vivo) and in DNase I footprint assays (in vitro) by these other elements. The c-fos element has similar structural requirements to confer transcriptional induction by cAMP but competes less strongly. Protein purified by affinity chromatography with the ENKCRE-2 sequence binds to each of these elements. A second element within the proenkephalin cAMP-inducible enhancer, ENKCRE-1, binds a factor that is not competed for by these other genes and is therefore distinct. This analysis suggests a potential mechanism of transcriptional coregulation of the neuronally expressed genes investigated in this study and also demonstrates that multiple factors are involved in transcriptional activation by cAMP. -
Hyman SE. 1988. Recent developments in neurobiology: Part II. Neurotransmitter receptors and psychopharmacology. Psychosomatics. 29(3):254-63. Pubmed: 2900534 Hyman SE. 1988. Recent developments in neurobiology: Part II. Neurotransmitter receptors and psychopharmacology. Psychosomatics. 29(3):254-63. Pubmed: 2900534 -
Comb M, Mermod N, Hyman SE, Pearlberg J, Ross ME, Goodman HM. 1988. Proteins bound at adjacent DNA elements act synergistically to regulate human proenkephalin cAMP inducible transcription. The EMBO journal. 7(12):3793-805. Pubmed: 2850173 Comb M, Mermod N, Hyman SE, Pearlberg J, Ross ME, Goodman HM. 1988. Proteins bound at adjacent DNA elements act synergistically to regulate human proenkephalin cAMP inducible transcription. The EMBO journal. 7(12):3793-805. Pubmed: 2850173 Synthesis of the endogenous opioid precursor, proenkephalin, is regulated by neurotransmitters and membrane depolarization. These events act through second messenger dependent signal transduction pathways via a short inducible DNA enhancer to regulate transcription of the proenkephalin gene. Two DNA elements located within this enhancer are essential for the transcriptional response to cAMP and phorbol ester. Inactivation of either element by mutation or by alteration of their stereospecific alignment eliminates inducible enhancer activity. The promoter distal element, ENKCRE-1, in the absence of a functional adjacent ENKCRE-2 element, has no inherent capacity to activate transcription. However, in the presence of a functional ENKCRE-2 element, this element synergistically augments cAMP and phorbol ester inducible transcription. The promoter proximal element, ENKCRE-2, is essential for both basal and regulated enhancer function. Four different protein factors found in HeLa cell nuclear extracts bind in vitro to the enhancer region. ENKTF-1, a novel enhancer binding protein, binds to the DNA region encompassing ENKCRE-1. The transcription factors AP-1 and AP-4 bind to overlapping sites spanning ENKCRE-2, and a fourth transcription factor, AP-2, binds to a site immediately downstream of ENKCRE-2. The binding of ENKTF-1 to mutant ENKCRE-1 sequences in vitro correlates with the in vivo inducibility of the mutant elements suggesting that ENKTF-1 acts in combination with factors that recognize the ENKCRE-2 domain to regulate cAMP inducible transcription. Together, the two DNA elements, ENKCRE-1 and ENKCRE-2 and the protein factors with which they interact, play a critical role in the transduction and reception of signals transmitted from cell surface receptors to the proenkephalin nuclear transcription complex. 1987
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Schalling M, Dagerlind A, Brene S, Petterson R, Kvist S, Brownstein M, Hyman SE, Mucke L, Goodman HM, Joh TH. 1987. Localization of mRNA for phenylethanolamine N-methyltransferase (PNMT) using in situ hybridization. Acta physiologica Scandinavica. 131(4):631-2. Pubmed: 3442246 Schalling M, Dagerlind A, Brene S, Petterson R, Kvist S, Brownstein M, Hyman SE, Mucke L, Goodman HM, Joh TH. 1987. Localization of mRNA for phenylethanolamine N-methyltransferase (PNMT) using in situ hybridization. Acta physiologica Scandinavica. 131(4):631-2. Pubmed: 3442246 -
Hyman S, McComb JG, Megerdichian L, Weiss MH. 1987. Blood-cerebrospinal fluid barrier alteration following intraventricularly administered cholera toxin. Brain research. 419(1-2):104-11. Pubmed: 2445419 Hyman S, McComb JG, Megerdichian L, Weiss MH. 1987. Blood-cerebrospinal fluid barrier alteration following intraventricularly administered cholera toxin. Brain research. 419(1-2):104-11. Pubmed: 2445419 Cholera toxin (CT) has been reported to double cerebrospinal fluid (CSF) formation following its introduction into the ventricular system of cats and dogs. In our laboratory we noted that CT used in a similar fashion in rabbits and cats resulted in only a slight increase in CSF formation and was associated with a steadily rising protein content in the cisterna magna effluent. To further investigate this finding, rabbits and cats underwent ventriculo-cisternal perfusions, one group with CT introduced into the ventricles and the other without. In the rabbit only, radioiodinated serum albumin (125I-RISA) was given i.v. Other groups of rabbits had 125I-RISA or 125I-CT injected into the ventricles. The group of rabbits receiving intraventricular CT experienced a 4-10-fold elevation in the amount of both protein and 125I-RISA in the cisterna magna effluent compared with the control group. Electrophoretic pattern of the protein present in the effluent was similar to that of rabbit plasma. Autoradiography of the brains of those animals given intraventricular 125I-CT were found to have a very high uptake of 125I-CT in the choroid plexus and along all exposed ventricular surfaces, a finding not evident when 125I-RISA alone was given intraventricularly. It is concluded that CT altered the blood-CSF barriers allowing the reference marker to penetrate these barriers and plasma to leak into the CSF. These findings appear to account for most if not all of what was thought to be an increase in CSF formation in response to intraventricular CT. -
Pollack MH, Rosenbaum JF, Hyman SE. 1987. Calcium channel blockers in psychiatry. Psychosomatics. 28(7):356-60, 369. Pubmed: 3326023 Pollack MH, Rosenbaum JF, Hyman SE. 1987. Calcium channel blockers in psychiatry. Psychosomatics. 28(7):356-60, 369. Pubmed: 3326023 -
Wood M, Hyman S, Wood AJ. 1987. A clinical study of sensitivity to sodium nitroprusside during controlled hypotensive anesthesia in young and elderly patients. Anesthesia and analgesia. 66(2):132-6. Pubmed: 3028217 Wood M, Hyman S, Wood AJ. 1987. A clinical study of sensitivity to sodium nitroprusside during controlled hypotensive anesthesia in young and elderly patients. Anesthesia and analgesia. 66(2):132-6. Pubmed: 3028217 Aging has important effects on the cardiovascular system; baroreceptor reflex function decreases and the elderly are more resistant to both beta-receptor agonists and antagonists. The purpose of the present clinical study was to determine the relationship between age and sensitivity to sodium nitroprusside in 16 patients during deliberate hypotensive anesthesia by determining the blood pressure changes in young and elderly patients to incremental increases in dose of sodium nitroprusside. A dose-response curve relating change in mean blood pressure to dose of sodium nitroprusside (microgram X kg-1 X min-1) was constructed for each patient; the slope of this line is a measure of "sensitivity." The change in mean arterial blood pressure per microgram X kg-1 X min-1 nitroprusside dose (i.e., slope), showed a significant correlation with age (r = 0.766, P less than 0.001), demonstrating that sensitivity to sodium nitroprusside increases with advancing years. The maximum change in heart rate produced by nitroprusside showed a reciprocal correlation with age (r = -0.791, P less than 0.001). There was no significant correlation between age and maximum change in plasma norepinephrine or epinephrine concentrations during nitroprusside infusion. The increased sensitivity to nitroprusside might have been due to diminished baroreflex activity, resistance of cardiac adrenergic receptors to catecholamine stimulation, or alteration in sensitivity to the direct vasodilating effects of sodium nitroprusside. Whatever the mechanism, however, this clinical study has shown that lower doses of nitroprusside should be used in elderly patients to achieve the same degree of hypotension achieved in younger patients. 1984
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Little FM, Gomer CJ, Hyman S, Apuzzo ML. 1984. Observations in studies of quantitative kinetics of tritium labelled hematoporphyrin derivatives (HpDI and HpDII) in the normal and neoplastic rat brain model. Journal of neuro-oncology. 2(4):361-70. Pubmed: 6241630 Little FM, Gomer CJ, Hyman S, Apuzzo ML. 1984. Observations in studies of quantitative kinetics of tritium labelled hematoporphyrin derivatives (HpDI and HpDII) in the normal and neoplastic rat brain model. Journal of neuro-oncology. 2(4):361-70. Pubmed: 6241630 Increasing interest has developed in the use of the photodynamic agent, Hematoporphyrin derivative (HpD) for photoradiation therapy (PRT) as adjunctive therapy of malignant glial tumors of the brain. HpD, injected systemically, is preferentially taken up and retained by neoplastic tissue. Early studies of such uptake have largely relied on gross fluorescence as evidence of tissue uptake. In this study HpD was labelled with a tritiated radioisotope (3H) in order to quantify tissue uptake in visceral and in normal and neoplastic brain tissues in a rat brain model. 3H-HpD was injected intravenously at a 10 mg/kg dose into 30 Sprague-Dawley rats (Group A) without tumors in order to clarify method. Separately, 3H-HpD of like dosage was injected into 20 Fischer-344 rats (Group B), 5 control and 15 with a 9L gliosarcoma implanted in the left anterior cerebral cortex. Post injection sacrifice occurred at 6, 24 and 48 hours. From the Sprague-Dawley group multiple somatic and cerebral specimens were assayed. Differential areas within the brain showed no significant difference in uptake. The tumor area, peritumoral margin, and distant uninvolved areas of the Fischer-344 9L rats were likewise assayed. Definite uptake of normal visceral and cerebral tissue occurred with a markedly higher uptake differential in tumor areas. Such differential was relatively consistent from trial to trial, but multiple separate values obtained in the respective study groups were often unreliabe in their reproducibility and at variance with previously reported tissue level studies. These findings implied an instability of 3H-HpD, subsequently confirmed chromatographically as contamination probably due to time related degradation and exchange. Therefore, 3H-HpD appears to inherently carry such a risk for contamination. The compound Photofrin II (HpDII) represents a chromatographic fraction of HpD (HpDI), currently considered its most photodynamically active and purest component. Tritiated Photofrin II was used for quantification. An assay was performed with 5 Fischer-344 9L brain tumor rats (Group C), sacrificed at 24 hours. Photofrin II provided results more reliably reproducible. Contamination, degradation, and exchange of 3H-Photofrin II did not appear to occur. Neoplastic brain levels of the Photofrin II isotope were higher than in the HpD studies, and highly fluorescent. Normal brain values were consistently minimal and without fluorescence. The differential tumor/brain ratio in Photofrin II was consequently much higher. The isolated active substrate of HpDI and HpDII (Photofrin II) appears to be the compound DiHematoporphyrin Ether (DHE).(ABSTRACT TRUNCATED AT 400 WORDS) 1972
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Oldendorf WH, Hyman S, Braun L, Oldendorf SZ. 1972. Blood-brain barrier: penetration of morphine, codeine, heroin, and methadone after carotid injection. Science (New York, N.Y.). 178(4064):984-6. Pubmed: 5084666 Oldendorf WH, Hyman S, Braun L, Oldendorf SZ. 1972. Blood-brain barrier: penetration of morphine, codeine, heroin, and methadone after carotid injection. Science (New York, N.Y.). 178(4064):984-6. Pubmed: 5084666 Labeled morphine, codeine, heroin, or methadone was injected as a bolus into the common carotid artery of the rat, and the rat was decapitated 15 seconds later. The brain uptake of the drug was calculated by measurement of the brain content of the drug as a percentage of a labeled, highly diffusible reference substance simultaneously injected. The uptake of morphine was below measurability; the uptake of codeine was 24 percent; heroin, 68 percent; and methadone, 42 percent. Brain uptakes of morphine and codeine were also studied after intravenous injection and correlated well with uptakes after carotid injection; the uptake of codeine being nearly complete by 30 seconds. These studies indicate that brain uptake of certain of these drugs is very rapid and that uptake of heroin injected intravenously is probably limited by the regional flow of blood in the brain. The possible relation of this rapid penetration of the blood-brain barrier by heroin to its strongly addictive properties is discussed. 1963
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HYMAN S, VILLA F, STEIGMANN F. 1963. Mimetic aspects of ascites. JAMA. 183:651-5. Pubmed: 13956014 HYMAN S, VILLA F, STEIGMANN F. 1963. Mimetic aspects of ascites. JAMA. 183:651-5. Pubmed: 13956014 1961
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CAPOS NJ, HYMAN S. 1961. Cancer in the residual stomach after gastric resection for duodenal ulcer. JAMA. 177:448-9. Pubmed: 13690597 CAPOS NJ, HYMAN S. 1961. Cancer in the residual stomach after gastric resection for duodenal ulcer. JAMA. 177:448-9. Pubmed: 13690597