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.