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

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
5DP1OD003699-03
Application #
7667960
Study Section
Special Emphasis Panel (ZGM1-NDPA-G (P2))
Program Officer
Jones, Warren
Project Start
2007-09-30
Project End
2012-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
3
Fiscal Year
2009
Total Cost
$845,000
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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