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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Specialized Center (P50)
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Special Emphasis Panel (ZMH1-ERB-S)
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Harvard University
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Hayworth, Kenneth J; Morgan, Josh L; Schalek, Richard et al. (2014) Imaging ATUM ultrathin section libraries with WaferMapper: a multi-scale approach to EM reconstruction of neural circuits. Front Neural Circuits 8:68
Gogolla, Nadine; Takesian, Anne E; Feng, Guoping et al. (2014) Sensory integration in mouse insular cortex reflects GABA circuit maturation. Neuron 83:894-905
Hensch, Takao K (2014) Bistable parvalbumin circuits pivotal for brain plasticity. Cell 156:17-9
Lichtman, Jeff W; Pfister, Hanspeter; Shavit, Nir (2014) The big data challenges of connectomics. Nat Neurosci 17:1448-54
Tomassy, Giulio Srubek; Berger, Daniel R; Chen, Hsu-Hsin et al. (2014) Distinct profiles of myelin distribution along single axons of pyramidal neurons in the neocortex. Science 344:319-24
Kobayashi, Yohei; Hensch, Takao K (2013) Germline recombination by conditional gene targeting with Parvalbumin-Cre lines. Front Neural Circuits 7:168
Spatazza, Julien; Lee, Henry H C; Di Nardo, Ariel A et al. (2013) Choroid-plexus-derived Otx2 homeoprotein constrains adult cortical plasticity. Cell Rep 3:1815-23