ALTERED BNST<SUP >CRF</SUP> CIRCUIT DYNAMICS IN STRESS-INDUCED COMPULSIVE BEHAVIOR

Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric condition characterized by intrusive thoughts, repetitive behaviors, and anxiety^1-2. First-line treatments such as SSRIs are often ineffective, with ~40% of patients failing to respond, highlighting the need to better understand the neural mechanisms linking anxiety and compulsivity^3-5. Here, we investigate how stress and anxiety regulate compulsive behavior using a novel paradigm that induces acute stress while enabling high-resolution behavioral tracking alongside neural recording and manipulation. Exposure to 10 minutes of acute stress robustly increased corticosterone levels in both wild-type (WT) and Sapap3 knockout (KO) mice and induced grooming behavior in WT mice. In contrast, Sapap3-KO mice, an established OCD model⁶, exhibited elevated compulsive grooming both before and after stress exposure. Multi-region c-Fos analysis identified stress-activated brain regions, revealing that activity in the bed nucleus of the stria terminalis (BNST) was positively correlated with stress-induced grooming in WT mice but negatively correlated in Sapap3-KO mice, indicating altered stress-compulsion coupling. To probe circuit dynamics, we used fiber photometry to monitor BNST corticotropin-releasing factor (BNST^CRF) neurons. In WT mice, BNST^CRF activity increased before grooming bouts and during stress exposure, whereas Sapap3-KO mice lacked both pre-grooming modulation and stress-induced activation. Together, our behavioral, endocrine, and neural activity findings demonstrate that: (1) BNST^CRF neuronal activity is tightly linked to both stress exposure and stress-induced grooming behavior; and (2) despite intact stress hormone release, Sapap3-KO mice exhibit impaired stress-related modulation at both the behavioral and circuit levels, highlighting a disrupted link between stress and compulsive behavior in this model.