Chronic stress enhances threat responding and impacts fear extinction.

Chronic stress is a major risk factor for psychiatric disorders. Previous work from our laboratory has demonstrated that chronic stress exposure disrupted network activity in the basolateral amygdala (BLA) and altered the activity of projection-specific neurons in the BLA to bias information processing to favor negative valence processing. Although the BLA is well established as a critical hub for fear memory encoding and retrieval, it remains unclear how chronic stress alters ensemble recruitment within the BLA and its downstream circuit dynamics to shape fear and extinction learning. To answer this question, we used retrograde tracing combined with immunohistochemistry in adult male mice to examine how chronic unpredictable stress (CUS) during adulthood alters the activity of the BLA and its projections to the nucleus accumbens (NAc) or bed nucleus of the (BNST) following fear extinction. Here we demonstrate that CUS produced a shift toward persistent threat responding and alters extinction learning, accompanied by reduced recruitment within the lateral nucleus of the BLA (LA) and in BLA-NAc projecting neurons. These findings provide circuit-level evidence for how chronic stress disrupts information flow from BLA, biasing valence processing toward extinction-resistant fear states and potentially contributing to the persistence of maladaptive fear in stress-related psychiatric disorders.