Imprinting a Connectome: Developmental Circuit Approach to Mental Illness

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, wepropose to meet this challenge by sophisticated, whole genome and neural circuit analyses at single-cellresolution in developing systems. We unite recent insights by the PIs regarding the true magnitude ofgenomic imprinting, which may underlie parent-of-origin effects in a variety of disorders; the identification ofspecific cell-types that trigger the re-wiring of circuits in response to early life experience; and innovativetechnologies to visualize and reconstruct all synaptic inputs and outputs of an individual neuron in themammalian cortex. Taking advantage of vastly improved computational power and methods, our goal in thisproject is to use a suite of new neuronal circuit analysis tools to attain a rather simple, but heretoforeunattainable goal: the complete connectional diagram and imprinted gene expression profile of a pivotal celltype implicated in multiple cognitive developmental disorders. To begin, we focus strategically on theparvalbumin (PV)-positive GABA neuron in medial prefrontal cortex (mPFC). This inhibitory cell type plays acritical role in timing normal brain development and processing, and is particularly vulnerable to a broadspectrum of genetic and environmental stressors, as are imprinted genes. The pipeline to obtain such datawill then be very similar for other cases, so that once it is established for one cell-type, age, sex, or mutant,it will be straightforward to repeat for others. Shared features of neural circuit dysregulation across animalmodels are likely to inform the human disorder being modeled. Moreover, the convergence of methods inone Conte Center on the Harvard University undergraduate campus for critical period brain plasticity (TKHensch), epigenetic imprinting (C Dulac), connectomics (JW Lichtman), super-resolution imaging (XZhuang) and informatics (J Cuff) not only offers state-of-the-art training in basic neuroscience, but alsoprovides unparalleled access to a broad audience for informing the public about mental illness.