Essoh, A. | Search bioRxiv

bioRxiv2025

Alcohol Attenuates CRF-Induced Excitatory Effects from the Extended Amygdala to Dorsostriatal Cholinergic Interneurons

Alcohol relapse is associated with corticotropin-releasing factor (CRF) signaling and altered reward pathway function, though the precise mechanisms remain unclear. Here, we investigated how CRF modulates cholinergic interneurons (CINs) in the dorsal striatum, a region critical in mediating cognitive flexibility and action selection. Using monosynaptic and retrograde circuit tracing, we identified direct inputs from CRF-expressing (CRF) neurons in the central amygdala (CeA) and bed nucleus of the stria terminalis (BNST) to dorsal striatal CINs. We showed that CINs express CRF receptor 1 (CRFR1) and established their functional connectivity with CeA/BNST CRF projections. Functional recordings revealed that CRF enhanced CIN excitability and promoted acetylcholine release in the dorsal striatum. However, acute alcohol exposure and withdrawal attenuated the excitatory effect of CRF on CIN firing, suggesting a mechanism by which alcohol disrupts CRF-dependent neuromodulation. These findings reveal a previously unrecognized CRF-CIN pathway linking the extended amygdala to the dorsal striatum and provide new insight into how CRF and alcohol interact to impair striatal function. This work highlights CRF signaling as a potential target for understanding stress-induced changes to the reward pathway. HighlightsO_LIDorsal striatal CINs receive monosynaptic CRF+ inputs from CeA and BNST neurons. C_LIO_LICRFR1 is expressed in striatal CINs, and CRF+ fibers are present in the dorsal striatum. C_LIO_LICRF enhances dorsal striatal CIN activity via CRFR1 signaling. C_LIO_LIAcute alcohol exposure impairs CRF-induced cholinergic activity. C_LI Significance StatementThe dorsal striatum regulates goal-directed behavior and is implicated in alcohol use disorder (AUD). Within this region, cholinergic interneurons (CINs) support cognitive flexibility and receive input from limbic areas, including the central amygdala (CeA) and bed nucleus of the stria terminalis (BNST). In this study, we identified direct projections from CRF-producing neurons in the CeA and BNST to dorsal striatal CINs, a subset of which express CRF receptor 1 (CRFR1). Electrophysiological recordings confirmed these projections provide functional input that is disrupted by acute alcohol exposure. These findings lay the groundwork for future studies on how CRF and alcohol interact to impair striatal function.

neuroscience↗

bioRxiv2022

Drug Reinforcement Impairs Cognitive Flexibility by Inhibiting Striatal Cholinergic Neurons

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

neuroscience↗