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, using both mice and rats, 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.