Presynaptic modulation of corticostriatal transmission following chronic ethanol exposure

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Presynaptic modulation of corticostriatal transmission following chronic ethanol exposure Chronic ethanol exposure causes pathological changes in behavior, including alterations in cognition and a transition from flexible, goal-directed alcohol use to inflexible, habitual alcohol seeking. The dorsal striatum, which is responsible for motor activity, action learning, and habit formation, undergoes changes in synaptic modulation in response to chronic alcohol exposure. Inhibition of excitatory transmission by presynaptic G protein-coupled receptors (GPCRs) such as metabotropic glutamate receptor 2 (mGlu2) that couple to Gi/o proteins is impaired by chronic alcohol. I will explore how alcohol changes GPCR modulation of specific synapses, and relate these alterations to behavioral adaptations. My central hypothesis is that reductions in presynaptic GPCR function following chronic alcohol exposure disrupt normal cortical regulation of striatal function such that dorsolateral striatum-dependent learning is facilitated. Results of the following studies will provide insight into the therapeutic utility of targeting presynaptic GPCRs such as mGlu2 for AUDs. Aim 1. Determine the input-specificity of the disruption of mGlu2-mediated modulation of glutamatergic synaptic transmission in the dorsal striatum. I will use slice electrophysiology and optogenetic techniques to identify specific excitatory projections to the dorsal striatum that are impacted by chronic alcohol exposure. Aim 2. Evaluate the effect of alcohol-induced changes in corticostriatal Gi/o-coupled GPCR function on dorsal striatum-mediated learning. I will use an innovative, genetically-encoded, toxin-based technique to test the hypothesis that disruption of presynaptic GPCR function in corticostriatal circuits mimics the enhancing effect of chronic alcohol exposure on dorsal striatum-dependent learning. I will also test the hypothesis that activation of presynaptic Gi/o-coupled Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in corticostriatal circuits will reverse alcohol-induced enhancement of striatum-dependent learning. Aim 3. Assess the impact of presynaptic corticostriatal inhibition by Gi/o-coupled GPCRs on habitual alcohol seeking. I will use pharmacological and chemogenetic strategies to study effects of presynaptic GPCR activation (mGlu2 or DREADD) on habitual alcohol seeking. Training: I will gain extensive experience with models of chronic alcohol exposure, including chronic intermittent ethanol vapor exposure (CIE) (Aims 1 and 2) and operant ethanol self-administration (Aim 3). I will also learn sophisticated models of instrumental learning to look at alcohol-induced changes in cognition (Aim 2) and habitual alcohol seeking behavior (Aim 3). Training in behavioral assays will allow me to apply my interest in GPCR modulation of synaptic transmission to unanswered questions about how synaptic modulation influences animal behavior. I will also receive career development training that will maximize my ability to transition to an independent position and make significant scientific contributions to the alcohol field.