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

Alcohol relapse is linked to corticotropin-releasing factor (CRF) signaling and is caused by dysfunction within reward pathway circuitry, yet the underlying mechanisms guiding this process remain unclear. Here, we investigated how CRF modulates cholinergic interneurons (CINs) in the dorsal striatum, a region critical for 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 uncover a novel CRF-mediated circuit linking the extended amygdala to the dorsal striatum and provide insight into how CRF and alcohol interact to impair striatal function. This work highlights CRF signaling as a potential target for uncovering the mechanism of stress-induced changes to the reward pathway.