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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
5P50MH094271-03
Application #
8545209
Study Section
Special Emphasis Panel (ZMH1-ERB-S (02))
Program Officer
Panchision, David M
Project Start
2011-09-05
Project End
2016-06-30
Budget Start
2013-09-16
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$1,640,980
Indirect Cost
$669,986
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138
Mierau, Susanna B; Patrizi, Annarita; Hensch, Takao K et al. (2016) Cell-Specific Regulation of N-Methyl-D-Aspartate Receptor Maturation by Mecp2 in Cortical Circuits. Biol Psychiatry 79:746-54
Morgan, Josh Lyskowski; Berger, Daniel Raimund; Wetzel, Arthur Willis et al. (2016) The Fuzzy Logic of Network Connectivity in Mouse Visual Thalamus. Cell 165:192-206
Perez, Julio D; Rubinstein, Nimrod D; Dulac, Catherine (2016) New Perspectives on Genomic Imprinting, an Essential and Multifaceted Mode of Epigenetic Control in the Developing and Adult Brain. Annu Rev Neurosci 39:347-84
Kobayashi, Yohei; Ye, Zhanlei; Hensch, Takao K (2015) Clock genes control cortical critical period timing. Neuron 86:264-75
Perez, Julio D; Rubinstein, Nimrod D; Fernandez, Daniel E et al. (2015) Quantitative and functional interrogation of parent-of-origin allelic expression biases in the brain. Elife 4:e07860
Kaynig, Verena; Vazquez-Reina, Amelio; Knowles-Barley, Seymour et al. (2015) Large-scale automatic reconstruction of neuronal processes from electron microscopy images. Med Image Anal 22:77-88
Santoro, Stephen W; Dulac, Catherine (2015) Histone variants and cellular plasticity. Trends Genet 31:516-27
Sigal, Yaron M; Speer, Colenso M; Babcock, Hazen P et al. (2015) Mapping Synaptic Input Fields of Neurons with Super-Resolution Imaging. Cell 163:493-505
Morishita, Hirofumi; Cabungcal, Jan-Harry; Chen, Ying et al. (2015) Prolonged Period of Cortical Plasticity upon Redox Dysregulation in Fast-Spiking Interneurons. Biol Psychiatry 78:396-402
Do, Kim Q; Cuenod, Michel; Hensch, Takao K (2015) Targeting Oxidative Stress and Aberrant Critical Period Plasticity in the Developmental Trajectory to Schizophrenia. Schizophr Bull 41:835-46

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