Brain function is shaped by genes and environment during critical periods of neuronal circuit development. Mental illness may arise when the complex convergence of these factors results in aberrant wiring. Here, we propose to meet this challenge by sophisticated, whole genome and neural circuit analyses at single-cell resolution in developing systems. We unite recent insights by the PIs regarding the true magnitude of genomic imprinting, which may underlie parent-of-origin effects in a variety of disorders;the identification of specific cell-types that trigger the re-wiring of circuits in response to early life experience;and innovative technologies to visualize and reconstruct all synaptic inputs and outputs of an individual neuron in the mammalian cortex. Taking advantage of vastly improved computational power and methods, our goal in this project is to use a suite of new neuronal circuit analysis tools to attain a rather simple, but heretofore unattainable goal: the complete connectional diagram and imprinted gene expression profile of a pivotal cell type implicated in multiple cognitive developmental disorders. To begin, we focus strategically on the parvalbumin (PV)-positive GABA neuron in medial prefrontal cortex (mPFC). This inhibitory cell type plays a critical role in timing normal brain development and processing, and is particularly vulnerable to a broad spectrum of genetic and environmental stressors, as are imprinted genes. Shared features of neural circuit dysregulation across animal models are likely to inform the human disorder being modeled. The pipeline to obtain such data will then be very similar for other cases, so that once it is established for one cell-type, age, sex, or mutant, it will be straight forward to repeat for others. Our collective goal is to establish a paradigm for the systematic dissection of developmental 'connectopathies,'which should inspire novel circuit-based therapies for mental illness.

Public Health Relevance

The convergence of epigenetic imprinting (Dulac), connectomics (Lichtman), critical period brain plasticity (Hensch), super-resolution imaging (Zhuang) and informatics methods (Cuff) in one Conte Center on the Harvard University undergraduate campus not only offers state-of-the-art training in basic neuroscience, but also provides unparalleled access to a broad audience for informing the public about mental illness.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZMH1-ERB-S (02))
Program Officer
Panchision, David M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Harvard University
Schools of Arts and Sciences
United States
Zip Code
Fang, Tao; Lu, Xiaotang; Berger, Daniel et al. (2018) Nanobody immunostaining for correlated light and electron microscopy with preservation of ultrastructure. Nat Methods 15:1029-1032
Berger, Daniel R; Seung, H Sebastian; Lichtman, Jeff W (2018) VAST (Volume Annotation and Segmentation Tool): Efficient Manual and Semi-Automatic Labeling of Large 3D Image Stacks. Front Neural Circuits 12:88
Takesian, Anne E; Bogart, Luke J; Lichtman, Jeff W et al. (2018) Inhibitory circuit gating of auditory critical-period plasticity. Nat Neurosci 21:218-227
Lee, H H C; Bernard, C; Ye, Z et al. (2017) Genetic Otx2 mis-localization delays critical period plasticity across brain regions. Mol Psychiatry 22:680-688
Sheu, Shu-Hsien; Tapia, Juan Carlos; Tsuriel, Shlomo et al. (2017) Similar synapse elimination motifs at successive relays in the same efferent pathway during development in mice. Elife 6:
Cameron, Judy L; Eagleson, Kathie L; Fox, Nathan A et al. (2017) Social Origins of Developmental Risk for Mental and Physical Illness. J Neurosci 37:10783-10791
Morgan, Josh L; Lichtman, Jeff W (2017) Digital tissue and what it may reveal about the brain. BMC Biol 15:101
Quadrato, Giorgia; Nguyen, Tuan; Macosko, Evan Z et al. (2017) Cell diversity and network dynamics in photosensitive human brain organoids. Nature 545:48-53
Babcock, Hazen P; Zhuang, Xiaowei (2017) Analyzing Single Molecule Localization Microscopy Data Using Cubic Splines. Sci Rep 7:552
Steullet, P; Cabungcal, J-H; Coyle, J et al. (2017) Oxidative stress-driven parvalbumin interneuron impairment as a common mechanism in models of schizophrenia. Mol Psychiatry 22:936-943

Showing the most recent 10 out of 34 publications