Inhibitory corticostriatal circuit mechanisms underlying binge alcohol drinking

About This Grant

PROJECT SUMMARY The main risk factor for alcohol use disorder (AUD) is excessive alcohol consumption. However, there is a knowledge gap regarding how alcohol differentially alters synaptic function within the neural circuits that underlie AUD progression. Therefore, it is critical to better understand these synapse-specific neuroadaptations so more efficacious circuit-based therapeutics may be developed. One brain region central to this effort is the dorsal striatum, which plays an important role in goal-directed learning (by the dorsomedial striatum) and habit formation (by the dorsolateral striatum, DLS) behaviors that are key to the progression of AUDs. Our previous work indicates that alcohol induces changes in the anterior insular cortex (AIC) to the DLS (AICDLS) excitatory synaptic transmission, presynaptically with a loss of mu opioid receptor-mediated plasticity and postsynaptically by an increase in glutamate receptor function in medium spiny neurons (MSNs). Interestingly, the AIC is a key brain region involved in regulating addiction and AUD. Therefore, we evaluated the circuit using in vivo optogenetic, and we found that the activation of AICDLS glutamatergic synapses reduced binge-like alcohol consumption in males. These findings suggest that alcohol’s synapse-specific plasticity-ablating effects may be a mechanism regulating alcohol consumption. Importantly, MSNs in the DLS also receive long-range cortical GABAergic inputs. Recent studies, and our research, have demonstrated that long-range inhibitory projections from cortex directly target MSNs. Specifically, we demonstrated that parvalbumin-expressing (PV+) neurons in the AIC send direct inhibitory synapses to DLS, and that activation of this pathway increase binge alcohol drinking, opposite to the effects of excitatory AICDLS activation. Yet little is known about how alcohol regulates PV+ AICDLS circuit. Our central hypothesis is that inhibition from AIC PV+ GABAergic projections to specific MSNs subtypes in the DLS is imbalanced by alcohol increasing binge alcohol consumption. In specific aim 1, we will determine the effect of alcohol on anterior insular cortical parvalbumin-expressing GABAergic inputs to dorsolateral striatum. In specific aim 2, we will define the role of anterior insular cortex parvalbumin-expressing neuron projections to the dorsolateral striatum in regulating alcohol drinking behavior. By integrating state of the art research in electrophysiology, in vivo and ex vivo optogenetics and chemogenetics, binge alcohol and aversive drinking behavior, and the use of transgenic mice, we will determine the role of this specific inhibitory synaptic connection that is relevant for alcohol consumption behavior and potentially revealing novel circuit- based therapeutic targets for AUD.