Abstract
Exposure to addictive substances impairs flexible decision making. Cognitive flexibility is mediated by striatal cholinergic interneurons (CINs). However, how chronic alcohol drinking alters cognitive flexibility through CINs remains unclear. Here, we report that chronic alcohol consumption and withdrawal impaired reversal of instrumental learning. Chronic alcohol consumption and withdrawal also caused a long-lasting (21 days) reduction of excitatory thalamic inputs onto CINs and reduced pause responses of CINs in the dorsomedial striatum (DMS). CINs are known to inhibit glutamatergic transmission in dopamine D1 receptor–expressing medium spiny neurons (D1-MSNs) but facilitate this transmission in D2-MSNs, which may contribute to flexible behavior. We discovered that chronic alcohol drinking impaired CIN-mediated inhibition in D1-MSNs and facilitation in D2-MSNs. Importantly, in vivo optogenetic induction of long-term potentiation of thalamostriatal transmission in DMS CINs rescued alcohol-induced reversal learning deficits. These results demonstrate that chronic alcohol drinking reduces thalamic excitation of DMS CINs, compromising their regulation of glutamatergic transmission in MSNs, which may contribute to alcohol-induced impairment of cognitive flexibility. These findings provide a neural mechanism underlying inflexible drinking in alcohol use disorder.
Highlights
Alcohol use disorder is a chronic brain disorder characterized by an inability to stop drinking despite the resultant adverse consequences [1, 2]
In vivo optogenetic induction of long-term potentiation of thalamostriatal transmission in dorsomedial striatum (DMS) cholinergic interneurons (CINs) rescued alcohol-induced reversal learning deficits. These results demonstrate that chronic alcohol drinking reduces thalamic excitation of DMS CINs, compromising their regulation of glutamatergic transmission in
Having found that chronic alcohol consumption impaired CIN-mediated regulation of glutamatergic transmission in D1-medium spiny neurons (MSNs), we examined whether it altered CIN
Summary
Alcohol use disorder is a chronic brain disorder characterized by an inability to stop drinking despite the resultant adverse consequences [1, 2]. This inability is associated with impaired flexibility in decision-making, which contributes to compulsive alcohol use [1,2,3,4,5]. In the DMS, cholinergic interneurons (CINs) are the major source of acetylcholine and contribute to cognitive flexibility in response to salient stimuli [12,13,14]. CINs play an essential role in modulating striatal circuit activity, thereby regulating output from the striatum [15,16,17].
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