Dissecting Non-coding RNA Function in Critical Period Brain Development and Disor

Boston Children'S Hospital, Boston MA

Investigators

Linked publications & trials

Abstract

How does early experience shape ourselves? We have shown such critical period brain[unreadable] development is triggered by specific parvalbumin (PV)-positive GABA cells, then hard-wired by[unreadable] sequential re-configuration of spines and inputs upon pyramidal cell dendrites. At a genomic level,[unreadable] a far more widespread world of non-coding RNA (ncRNA) has been identified than previously[unreadable] anticipated. Accelerated regions of change in ncRNA sequences expressed in strategic cell types[unreadable] appear vital to human brain evolution. By rapidly regulating mRNA translation even distally,[unreadable] ncRNAs may be particularly adapted to respond to constantly changing environments, defining a[unreadable] unique milieu for maintaining the identity of individual neurons.[unreadable] Strikingly, the role of ncRNAs in brain function (and dysfunction) remains virtually unknown. We[unreadable] will explore their contribution to the onset and permanence of critical period brain development.[unreadable] Using replication-defective adenoviral vectors, we will develop ?pulse gene transfer? into specific[unreadable] progenitor cells in a neuronal birthdate-specific manner in mice. By covalently linking magnetic[unreadable] beads, innovative constructs containing specific ncRNA sequences or inducible Crerecombinases[unreadable] will be focused in utero for late over-expression or deletion of endogenous[unreadable] ncRNAs in PV-cells. Virally infected pyramidal cell cohorts will similarly be manipulated[unreadable] postnatally by their canonical inside-out laminar origins. An integrated assessment of[unreadable] electrophysiological, optical imaging, anatomical and behavioral measures of vision, audition and[unreadable] social behaviors will be performed on these various mouse models.[unreadable] We will then test the hypothesis that ncRNAs act as molecular switches to regulate gene[unreadable] networks within neural networks. By coordinating maturation of PV-cells and the propagation of[unreadable] well-orchestrated changes across cortical layers, ncRNA may establish the timecourse of[unreadable] experience-dependent brain plasticity. Behavioral and physiological reactivation in adulthood[unreadable] would elucidate the purpose of critical periods. Importantly, our work will identify novel methods[unreadable] and therapeutic targets for developmental brain disorders, like autism or schizophrenia, which[unreadable] tragically incarcerate the mind.[unreadable]