Drug Reinforcement Impairs Cognitive Flexibility by Inhibiting Striatal Cholinergic Interneurons

Abstract

Addictive drugs, including illegal ones like cocaine and heroin, and prescription ones like opioids and benzodiazepines, produce strong cravings. Addiction is a chronic condition that affects behavior, brain function, and physical health, leading to issues such as anxiety, depression, liver and heart diseases, and respiratory problems, as well as social and financial difficulties. Treatment involves medication, therapy, and family support, with early intervention improving recovery prospects. Addiction also alters the brain's reward system, leading to inflexibility and poor decision-making. Over time, addiction can significantly impact a person's well-being, making it harder to adapt to new challenges. Cognitive flexibility refers to the ability to adapt and switch between different mental tasks, thoughts, or strategies in response to changing situational demands or environmental cues. It involves the capacity to modify behavior or actions in response to novel or conflicting information, and to switch between multiple concepts, rules, or perspectives. Addictive substance use reduces cognitive flexibility, but the underlying mechanisms are unknown. The reinforcement of substance use is mediated by substance-induced synaptic plasticity in the striatal direct-pathway medium spiny neurons (dMSNs) that project to the substantia nigra (SNr). Cognitive flexibility is mediated by striatal cholinergic interneurons (CINs), which receive extensive local striatal inhibition. Therefore, we hypothesized that substance-induced potentiation of dMSN activity inhibits CINs and reduces cognitive flexibility. In my graduate thesis, we report that cocaine administration and reinforcement behaviors caused long-lasting potentiation of local inhibitory dMSN→CIN transmission and reduced CIN firing in the dorsomedial striatum (DMS), a brain region critical for cognitive flexibility. Furthermore, chemogenetic and time-locked optogenetic inhibition of DMS CINs suppressed cognitive flexibility in an instrumental reversal learning task. An instrumental reversal learning task is a type of cognitive task used in psychology and neuroscience research to assess an individual's ability to adapt their behavior in response to changes in the contingencies between actions and outcomes. 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. In summary, my thesis work demonstrates that the local inhibitory dMSN→CIN circuit mediates the reinforcement-induced reduction in cognitive flexibility.

The findings of my thesis work has been submitted to Nature Communications as an original article and the paper is currently under revision.