Investigating the role of BNST GluN2D subunit-containing NMDARs in ethanol-induced plasticity and behavior

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PROJECT SUMMARY/ABSTRACT Alcohol use disorder (AUD) is a chronic, relapsing disease, highly comorbid with anxiety and depression. In fact, these states of negative affect experienced during withdrawal are hypothesized to drive alcohol seeking and relapse behavior. The bed nucleus of the stria terminalis (BNST) is a key brain region responsible for the integration of negative affect and alcohol-related behaviors. Within this highly heterogeneous region, synaptic plasticity driven by ethanol exposure is a significant contributor to maladaptive behavior. N-methyl-D-aspartate receptors (NMDARs) are a major target of ethanol, known to modulate BNST synaptic plasticity and transmission following both acute and chronic exposure. However, to date, no work has investigated the role of GluN2D-subunit containing NMDARs in mediating ethanol’s effects in the BNST. Moreover, these subunits are expressed by corticotropin-releasing factor (CRF)-positive BNST neurons (BNSTCRF), a key subpopulation for driving anxiety-like and ethanol seeking behaviors. Together, these data suggest a role for GluN2D expression in regulating ethanol intake and reward following chronic ethanol exposure. Thus, I propose a series of experiments to investigate the role of BNST GluN2D-containing NMDARs in ethanol-induced plasticity and behavior, with a focus on BNSTCRF neurons. First, I will assess the ability of GluN2D expression to regulate ethanol sensitivity of BNSTCRF neurons. Second, I will dissect the contribution of GluN2D-containing NMDARs to altered glutamatergic plasticity of BNSTCRF neurons following chronic ethanol exposure. Lastly, I will test the hypothesis that abstinence following chronic ethanol exposure regulates GluN2D-containg NMDAR expression in a behaviorally relevant manner.