Brain plasticity at the right time and place is of paramount importance during development with lasting consequence throughout life. Just as sensory input in early life shapes primary sensory cortex, emotional experience may shape the limbic-cortical relay system. Fibers from the BLA actively sprout within the mPFC during the post-weanling period, forming increased contacts with GABAergic interneurons as late as the early adult period. This connectivity requires further evaluation ultrastructurally (with Lichtman), and the identity of the receptors at these appositions merits investigation (with Zhuang). Here, we focus on the shift of neural circuit mechanisms from amygdala to mPFC underlying fear extinction across development. Using these stages as a milestone, we will measure developing synaptic inputs onto individual PV-cells of the mPFC by whole-cell recording techniques in slices from PV-EGFP mice crossed to various mouse models. The maturational state of afferents from the BLA in particular, will be examined by optogenetic tagging of this projection. Ultimately, we aim to determine whether dynamic epigenetic regulation (such as by imprinted genes identified by Dulac) dictates the functional maturation of these pivotal cortical inhibitory circuits. Identifying cell-specific mechanisms that underlie epigenetic regulation of critical periods may provide valuable insight into potential circuit-based therapies for pathologies arising from aberrant environment-gene interactions.

Public Health Relevance

We will identify functional alterations of mPFC PV-cell inputs / outputs across development that may be altered in mouse models of mental illness. These behavioral and synaptic measures will inform the genomic (Dulac) and connectomic (Lichtman) approaches, as well as provide the brain samples at the relevant stages.

Agency
National Institute of Health (NIH)
Type
Specialized Center (P50)
Project #
5P50MH094271-04
Application #
8737969
Study Section
Special Emphasis Panel (ZMH1)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Harvard University
Department
Type
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02138
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Perez, Julio D; Rubinstein, Nimrod D; Dulac, Catherine (2016) New Perspectives on Genomic Imprinting, an Essential and Multifaceted Mode of Epigenetic Control in the Developing and Adult Brain. Annu Rev Neurosci 39:347-84
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Santoro, Stephen W; Dulac, Catherine (2015) Histone variants and cellular plasticity. Trends Genet 31:516-27
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Morishita, Hirofumi; Cabungcal, Jan-Harry; Chen, Ying et al. (2015) Prolonged Period of Cortical Plasticity upon Redox Dysregulation in Fast-Spiking Interneurons. Biol Psychiatry 78:396-402
Do, Kim Q; Cuenod, Michel; Hensch, Takao K (2015) Targeting Oxidative Stress and Aberrant Critical Period Plasticity in the Developmental Trajectory to Schizophrenia. Schizophr Bull 41:835-46

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