Stress-responsive neuronal ensembles and β-adrenergic signaling in the basolateral amygdala modulate the infra-limbic cortical activity and govern the delayed stress-induced fear extinction deficit.

Stress is a critical risk factor for the development of psychological disorders, including anxiety and post-traumatic stress disorder (PTSD). Key brain regions, including the basolateral amygdala (BLA) and the infralimbic cortex (IL-mPFC), play crucial roles in fear regulation. Our previous research demonstrated that neuronal genomic activity of glucocorticoid receptors in the BLA during a 2-hour acute restraint stress is essential for inducing anxiety-like behavior 10 days later. Additionally, blocking BLA β-adrenergic signaling during the elevated plus maze is crucial for preventing this stress-induced delayed anxiety-like behavior. Here, we utilized adult male Wistar rats to expand on these findings, revealing that a single acute restraint stress session increases the activity of BLA neurons and their projections to the IL-mPFC, while decreasing the activity of IL-mPFC neurons and their projections to the BLA during fear extinction. This finding highlights the key role of the BLA↔IL-mPFC circuitry in fear extinction and its susceptibility to acute stress-induced changes. Notably, the delayed stress-induced fear extinction deficit and decreased IL-mPFC activity during fear extinction depend on the stress-responsive BLA neuronal ensemble and BLA β-adrenergic signaling during contextual fear conditioning 10 days post-stress. Our findings demonstrate the significance of BLA β-adrenergic signaling during contextual fear conditioning, as it induces delayed stress-induced impairments in extinction and regulates IL-mPFC activity during fear extinction. Furthermore, this study indicates that the BLA is a pivotal regulator of delayed stress effects at both the circuitry and behavioral levels, thus shedding new light on the mechanisms underlying stress-related psychiatric conditions. Significance statement We uncover how stress reshapes brain circuits that regulate fear, offering new insights into the neurobiology of stress-related disorders. Stress powerfully triggers mental health conditions like anxiety and PTSD, making it crucial to understand its effects on the brain. We focused on two key players in fear regulation: the BLA, which processes emotional responses, and the IL-mPFC, which helps manage them. By examining how a single acute stress experience alters communication between these regions during fear extinction, we identified the significance of BLA β-adrenergic signaling and stress-responsive neuronal ensembles in influencing behavior. Our findings enhance our understanding of how stress shapes fear-related behaviors and highlight the BLA↔IL-mPFC pathway as a promising target for developing better treatments for stress-related disorders.