Developmental origins of mental illness: evolution and reversibility

点击翻译按钮获取中文摘要

Abstract: Altered network dynamics (brain rhythms) underlie most if not all brain disorders, yet we know almost nothing about how such dynamics evolve in functional relationship to normal behavior. Leveraging existing physiological data from the parent Conte grant to generate biophysically detailed computational models, the proposed project constructs a circuit-based strategy for tracking interneuron function and targeted intervention that involves network dynamics. We will construct models of critical period dynamics to understand the essential mechanisms underlying the transition from a predominantly inhibitory dynamic to the emergence of networks involving pyramidal cells and interneurons, characteristic of cortical network processing in the adult brain. Previous data suggests that the transformation is begun with a gamma oscillation provided by networks of only inhibitory cells (ING). We hypothesize that ING is the initial stage in the transformation of the immature cortical network, in which sensory input is ubiquitously processed, to a more adult-like network state in which sophisticated, cortical processing of sensory input occurs, including gating and working memory. We hypothesize the transformation involves changes in network interactions between thalamus and cortex. We will perform data analysis on existing data to investigate how this process normally evolves over time and how it is derailed in the MeCP2 mouse model of Rett Syndrome and rescued by cell-specific gene restoration. We anticipate this pioneering computational psychiatry approach to be broadly applicable to many neurodevelopmental disorders beyond the parent Conte center.