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.
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.
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