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Your Environment. Your Health.

HIGH THROUGHPUT MOLECULAR SCREEN FOR ENVIRONMENTAL EPIGENETIC MODIFIERS IN BRAIN DEVELOPMENT AND ASD

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Principal Investigator: Eyring, Katherine
Institute Receiving Award University Of California Los Angeles
Location Los Angeles, CA
Grant Number K00ES032608
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 01 Jul 2018 to 29 Feb 2024
DESCRIPTION (provided by applicant): Oxytocin is a peptide and hormone known to be involved in myriad social behaviors. Dysfunction of the oxytocinergic signaling has also been implicated in the etiology of social deficits and neuropsychiatric disease. The mechanisms of oxytocin signaling in the brain, however, are incompletely understood. In this proposal, we dissect oxytocinergic signaling in the hippocampal subregion CA2, which is known to be a locus of oxytocin signaling and has, itself, been implicated in social behavior. Aim 1 of the proposal describes our lab's recent work elucidating the mechanism of oxytocin-driven excitation in hippocampal neurons. Activation of the oxytocin receptor (OXTR) depolarizes CA2 pyramidal cells by activation of a Gq-coupled signaling pathway that ultimately inhibits a potassium current known the M-current, or IM. Described most thoroughly in CA2 pyramidal cells, this mechanism appears to generalize to interneurons in CA1 and CA2. Joint regulation of excitatory and inhibitory neurons in CA2 shapes the propagation of activity from CA2 to its primary downstream target CA1. In addition to excitation, OXTR stimulation can cause hyperpolarization of hippocampal neurons. Experiments described in Aim 2 deconstruct the two opposing mechanisms downstream of the OXTR, with particular emphasis on how they produce the complex dynamics recorded in vitro. Moreover, we build upon the observation that there at least two subpopulations of CA2 pyramidal cells, only one of which expresses the OXTR. We propose experiments to compare the inputs, outputs and intrinsic properties of these two subpopulations. Aim 2 concludes with behavioral experiments driven by the hypothesis that oxytocin is necessary for CA2-mediated social behavior. Aim 3 describes work to be completed in the postdoctoral training period, using ethologically relevant behaviors to drive in vitro mechanistic studies. In vivo recordings will bridge biophysical and behavioral observations. This methodology will be applied to the investigation of social behaviors, with particular emphasis on how neural dynamics are modulated.
Science Code(s)/Area of Science(s) Primary: 61 - Neurodevelopmental
Secondary: 03 - Carcinogenesis/Cell Transformation
Publications No publications associated with this grant
Program Officer Cindy Lawler
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