Drug Reinforcement Impairs Cognitive Flexibility by Inhibiting Striatal Cholinergic Neurons

Abstract

The mechanisms underlying the reduction in cognitive flexibility associated with reinforcement of addictive substance use are unknown. This reinforcement is mediated by substance-induced synaptic plasticity in direct-pathway medium spiny neurons (dMSNs) that project to the substantia nigra (SNr). Cognitive flexibility is mediated by cholinergic interneurons (CINs), which receive extensive local inhibition from the striatum. Here, we report that cocaine or alcohol administration caused a long-lasting potentiation of local inhibitory dMSN[->]CIN transmission in the dorsomedial striatum (DMS), a brain region critical for goal-directed behavior and cognitive flexibility. This dMSN[->]CIN potentiation reduced CIN firing activity. Furthermore, chemogenetic and time-locked optogenetic inhibition of DMS CINs suppressed cognitive flexibility in an instrumental reversal learning task. Importantly, rabies-mediated tracing and physiological studies revealed that SNr-projecting dMSNs, which mediate reinforcement, sent axonal collaterals to inhibit DMS CINs, which mediate flexibility. Our findings demonstrate that the local inhibitory dMSN[->]CIN circuit mediates a reinforcement-induced reduction in cognitive flexibility. HIGHLIGHTSO_LICocaine reinforcement inhibits striatal cholinergic interneurons (CINs) and impairs cognitive flexibility. C_LIO_LIOptogenetic and chemogenetic CIN inhibition impairs cognitive flexibility. C_LIO_LIReinforcement behaviors potentiate inhibitory transmission from direct-pathway medium spiny neurons (dMSNs) to CINs. C_LIO_LISubstantia nigra-projecting dMSNs mediate reinforcement and also send collaterals that inhibit CINs. C_LI