Top-down medial prefrontal cortex-to-hypothalamic paraventricular nucleus circuit regulates social avoidance and conditioned fear in male mice

Abstract Compromised cortical inhibition during threat processing contributes to individual vulnerability to stress-related psychiatric disorders. However, the precise underlying neurobiological circuits remain elusive. Here, by combining monosynaptic viral tracing, electrophysiology, in vivo calcium imaging, and functional manipulations in mice, we elucidated a functionally specialized monosynaptic pathway originating from glutamatergic pyramidal neurons in the ventromedial prefrontal cortex (vmPFC Glu ) to corticotropin-releasing hormone (CRH)-expressing neurons in the paraventricular nucleus of the hypothalamus (PVN CRH ). We found that activating medial prefrontal cortex (mPFC)-driven CRH “pacemaker” cells propagated calcium signals within the local CRH network of the PVN. Hyperactivity of this vmPFC Glu -PVN CRH circuit promoted persistent social avoidance, consolidated threat memory, facilitated auditory-cued fear acquisition, and impaired extinction. Conversely, inhibition of this circuit selectively reduced social stress‑induced avoidance. Our findings define a novel top-down circuit that specifically controls psychosocial stress responses and amplifies susceptibility to conditioned fear.