Role of Neural Activity and Perineuronal Nets in Adolescent Intermittent Ethanol-Induced Social Anxiety

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Project Summary Our research group has revealed long-lasting behavioral impairments associated with adolescent intermittent ethanol (AIE) exposure, with male rats exposed to ethanol during adolescence demonstrating social deficits indexed via decreases in social preference and social investigation. Our preliminary data point to the prelimbic (PrL) cortex as a region associated with this social inhibition. AIE has been reported to increase glutamatergic signaling in the PrL, potentially due to alterations in GABAergic transmission. PrL activity is heavily regulated by inhibitory parvalbumin (PV) interneurons that are often encompassed by extracellular matrix components, perineuronal nets (PNNs). This proposal is designed to test the hypothesis that AIE-induced dysfunction of the PrL is a result of PNN-dependent decreases of PV interneuron inhibitory control, a neural alteration that might directly contribute to social deficits evident in adult rats following AIE. This hypothesis will be tested in Aim 1 by determining whether inactivation of specific neural ensembles associated with responding to a social stimulus within the PrL can reverse AIE-induced social deficits. In Aim 2, we will assess the impact of AIE on PNN expression within the PrL and investigate whether AIE-dependent PNN alterations are associated with changes in glutamatergic and GABAergic inputs onto PV interneurons. For evaluation of the relationship between PNN upregulation and social alterations after AIE, we will test whether an enzymatic degradation of PNNs following AIE is able to reverse social deficits in AIE-exposed animals. Collectively, these studies will characterize specific neural mechanisms in the PrL that are disrupted following AIE and further our understanding of how these alterations contribute to social deficits. Through this training mechanism I will gain invaluable skills to build my technical tool kit, expand my theoretical framework, and further develop my conceptual research skillset, all of which will aid in my progression into postdoctoral training and eventually becoming an independent investigator.