CRH neurons in the dorsal bed nucleus of the stria terminalis (dBNST) mediate contextual fear generalization

Contextual fear generalization is a hallmark of psychiatric disorders including post-traumatic stress disorder (PTSD), generalized anxiety disorder and panic disorder. Among these disorders, PTSD is particularly associated with contextual fear generalization. However, the mechanisms by which fear responses extend to similar contexts remain unclear. Here we tested whether corticotropin-releasing hormone (CRH) neurons in the dorsal bed nucleus of the stria terminalis (dBNST) contribute to contextual fear generalization. Using a contextual fear generalization paradigm with variable shock timing, we observed that intense foot shock conditioning enhanced freezing responses in both the training context and the generalization context in adult male mice, accompanied by elevated dBNST activity. Fiber photometry showed that dBNST CRH neurons were strongly engaged by foot shock and exhibited clear activity changes around freezing onset during both training and generalization tests. Functionally, chemogenetic inhibition of dBNST CRH neurons reduced freezing responses in the generalization test, whereas activation increased generalized freezing and promoted contextual fear generalization. Mechanistically, local pharmacological blockade of CRH receptor 1 (CRHR1) within the dBNST reduced freezing responses in the generalization test, indicating that CRHR1-dependent signaling within the dBNST contributes to fear generalization. Together, these findings identify dBNST CRH neurons and local CRHR1 signaling as key components underlying contextual fear generalization.