Linking input- and cell-type-specific synaptic plasticity to the reinforcement of alcohol-seeking behavior.

The reinforcement of voluntary alcohol-seeking behavior requires dopamine-dependent long-term synaptic plasticity in the striatum. Specifically, the long-term potentiation (LTP) of direct-pathway medium spiny neurons (dMSNs) in the dorsomedial striatum (DMS) promotes alcohol drinking. However, it remains unclear whether alcohol induces input-specific plasticity onto dMSNs and whether this plasticity directly drives instrumental conditioning. In this study, we found that voluntary alcohol intake selectively strengthened glutamatergic transmission from the medial prefrontal cortex (mPFC) to DMS dMSNs in mice. Importantly, mimicking this alcohol-induced potentiation by optogenetically self-stimulating mPFC→dMSN synapse with an LTP protocol was sufficient to drive the reinforcement of lever pressing in operant chambers. Conversely, induction of a post-pre spike timing-dependent LTD at this synapse time-locked to alcohol delivery during operant conditioning persistently decreased alcohol-seeking behavior. Our results establish a causal relationship between input- and cell-type-specific corticostriatal plasticity and the reinforcement of alcohol-seeking behavior. This provides a potential therapeutic strategy to restore normal cortical control of dysregulated basal ganglia circuitries in alcohol use disorder.