Arlotta Lab

The molecular logic that generates, maintains, and wires into circuits the multitude of cell types found in the mammalian brain is poorly understood, yet these processes are critical for complex brain function, and their disruption leads to neurodevelopmental disease. Focusing on the mammalian cerebral cortex, our laboratory is interested in decoding the mechanistic principles by which the vast diversity of cortical cell types is established, integrated, and subsequently maintained for the lifespan of the organism. We have identified molecular programs that shape cell-identity acquisition, and were the first to challenge the notion that the identity of postmitotic neurons in the central nervous system is irreversibly set, by showing that they can be reprogrammed from one class into another in vivo. We discovered that cortical neuron class identity also informs the development and functionality of glia, in particular oligodendrocytes and microglia, putting forward a new conceptual framework for the role of neuronal diversity in instructing local connectivity, immune-neuron balance, and the establishment of myelin maps.

Building on this work in the embryo, we have more recently pioneered the development of stem cell-derived brain organoids that model the human cortex, to study previously-inaccessible mechanisms of human neurodevelopment and disease. We demonstrated that human brain organoids in long-term culture (grown for many years in the lab) can generate extensive cellular diversity, following similar developmental trajectories as the endogenous brain, with unprecedented levels of organoid-to-organoid reproducibility. These organoids can achieve advanced neuronal maturation and the generation of spontaneously-active neuronal networks sensitive to sensory stimuli. By creating organoids bearing mutations in different risk genes for Autism Spectrum Disorder (ASD), we have uncovered cell-type-specific neurodevelopmental abnormalities that are shared across ASD genetic risk. In very recent work, we have shown that we can generate chimeric organoids (chimeroids) incorporating cells of many individual donors, and we recently applied this human brain chimeroid model to uncover inter-individual variation in response to disease triggers. In the future, we are excited to bring these discoveries to bear for unearthing poorly understood mechanisms of human brain development and disease.

Selected recent awards:

• 2024 Elena Leucrezia Cornaro Piscopia International Prize for Italian Women in Science
• 2024 Pradel Research Award, National Academy of Sciences
• 2023 Cowan Award in Comparative Developmental Neuroscience, Wiley Press
• 2023 FASEB Excellence in Science Mid-career Investigator Award
• 2023 Gutenberg Award for Distinction in Science, Gutenberg Res. College, Meinz, Germany
• 2019 Harvard College Professorship, Harvard University
• 2019 Instructional Moves, Spotlighted Faculty, Harvard College
• 2018 Fannie Cox Prize, Harvard University
• 2017 George Ledlie Prize, Harvard University

Selected recent publications:

1. Velasco, S., Kedaigle, A.J., Simmons, S.K., Nash, A., Rocha, M., Quadrato, G., Paulsen, B., Nguyen, L., Adiconis, X., Regev, A., Levin, J.Z., and Arlotta, P.  Individual brain organoids reproducibly form cell diversity of the human cerebral cortex.  Nature. 2019; 570(7762):523-527. https://doi.org/10.1038/s41586-019-1289-x
2. Jin, X., Simmons, S.K., Guo, A., Shetty, A.S., Ko, M., Nguyen, L., Jokhi, V., Robinson, E., Oyler, P., Curry, N., Deangeli, G., Lodato, S., Levin, J.Z., Regev, A*., Zhang, F*., and Arlotta, P*. In vivo Perturb-Seq reveals neuronal and glial abnormalities associated with autism risk genes. Science. 2020; 370(6520):eaaz6063. doi: https://doi.org/10.1126/science.aaz6063.
3. Yang, S.M., Michel, K., Jokhi, V., Nedivi, E., and Arlotta, P. Neuron-class specific responses govern adaptive myelin remodeling in the neocortex. Science. 2020; 18;370(6523):eabd2109. doi: https://doi.org/10.1126/science.abd2109. With “Perspective article”.
4. Di Bella, D.J., Habibi, E., Yang, S-M., Stickels, R.R., Brown, J.R., Yadollahpour, P., Chen, F., Macosko, E.Z., Regev, A.*, and Arlotta, P*. Molecular Logic of Cellular Diversification in the Mammalian Cerebral Cortex.  Nature. 2021; 595(7868):554-9. doi: https://doi.org/10.1038/s41586-021-03670-5
5. Paulsen, B.*, Velasco, S.*, Kedaigle, A.J.*, Pigoni, M.*, Quadrato, G., Deo, A.J., Adiconis, X., Uzquiano, A., Sartore, R., Yang, S.M., Simmons, S.K., Symvoulidis, P., Kim, K., Tsafou, K., Podury, A., Abbate, C., Tucewicz, A., Smith, S.N., Albanese, A., Barrett, L., Sanjana, N.E., Shi, X., Chung, K., Lage, K., Boyden, E.S., Regev, A., Levin, J.Z., and Arlotta, P. Autism genes converge on asynchronous development of shared neuron classes. Nature 2022; 602(7896):268-273. doi: https://doi.org/10.1038/s41586-021-04358-6.
6. Stogsdill, D. J., Kim, K., Binan, L., Farhi, L.S., Levin, Z.J., and Arlotta, P. Pyramidal neuron subtype diversity governs microglia states in the neocortex. Nature 2022; doi: https://doi.org/10.1038/s41586-022-05056-7.
7. Uzquiano, A.*, Kedaigle, A.J.*, Pigoni, M., Paulsen, B., Adiconis, X., Kim, K., Faits, T., Nagaraja, S., Antón-Bolaños, N., Gerhardinger, C., Tucewicz, A., Murray, E., Jin, X., Buenrostro, J., Chen, F., Velasco, S., Regev, A., Levin, J.Z., and Arlotta, P. Proper acquisition of cell class identity in organoids allows definition of fate specification programs of the human cerebral cortex. Cell, 2022; 185(20):3770-3788.e27. doi: https://doi.org/10.1016/j.cell.2022.09.010.
8. Anton Bolanos, N.,*, Faravelli, I.*, Faits, T., Andreadis, S., Sartore, R., Adiconis, X., Levin, J.Z., Kim, K., Nehme, R., Regev, A., and Arlotta, P. Multi-donor human cortical Chimeroids reveal individual susceptibility to neurotoxic triggers. BioRxiv: doi: https://doi.org/10.1101/2023.10.05.558331. Nature (in press).