Striatal ensemble plasticity in alcohol use disorder

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Relapse is a major clinical challenge in the treatment of alcohol use disorder. Relapse is driven in part by alcohol-induced synaptic plasticity at the corticostriatal circuit. The dorsomedial striatum (DMS) has been implicated in alcohol seeking and relapse. The DMS contains direct-pathway medium spiny neurons (dMSNs) and indirect-pathway MSNs (iMSNs), which positively and negatively regulate alcohol seeking, respectively. Alcohol-associated behaviors such as operant self-administration activate only a relatively small subset of neuronal ensembles in the striatum. Although alcohol-induced plasticity is much studied in bulk tissue, it is unknown whether it is induced in dMSN ensembles. Characterizing synaptic mechanisms of the ensemble neurons is especially vital to reconcile with the decades of evidence for drug-induced synaptic changes detected in bulk tissue analysis. In addition, extinction training yields greater suppression of alcohol seeking relative to abstinence alone, but the mechanism is poorly understood. The absence of alcohol delivery during extinction likely stimulates thalamic inputs to the DMS and reduces striatal dopamine levels, concurrently inducing thalamostriatal long-term potentiation (LTP) in DMS iMSNs; this enhances “NoGo” actions, suppressing alcohol seeking during relapse. LTP in iMSNs is also likely to directly or indirectly suppress dMSN activity by reducing dopaminergic activity. This application aims to elucidate how extinction training reduces alcohol- induced corticostriatal plasticity in the DMS ensembles and thereby persistently reduces relapse, with the long- term objective of determining how such strategies can be used to treat alcohol use disorder. They hypothesize that alcohol-induced corticostriatal plasticity in dMSN ensembles drives relapse and that extinction training promotes thalamostriatal plasticity in iMSN ensembles to directly or indirectly, via counteracting dMSN activity, suppress relapse. Three specific research aims will: 1) test the hypothesis that operant alcohol self- administration causes long-lasting corticostriatal plasticity in DMS dMSN ensembles, promoting relapse; 2) test the hypothesis that extinction-mediated thalamostriatal plasticity in DMS iMSN contributes to reduced relapse to alcohol seeking; and 3) test the hypothesis that extinction training potentiates the inhibitory outputs from iMSNs to dMSNs or the disinhibitory effects of iMSNs on habenula-projecting globus pallidus neurons, suppressing relapse. This application is highly innovative because it applies state-of-the-art approaches, including a combination of ArcTRAP, Cal-Light, and dual-channel optogenetic stimulation, allowing us for the first time to determine how extinguishing alcohol-evoked synaptic plasticity in specific molecularly defined neuronal ensembles alters their activities in vivo and thus persistently decreases relapse behavior; these critical questions cannot be addressed using conventional methodologies. Knowledge generated from this proposal will provide novel strategies for the long-term treatment of alcohol use disorder.