Dorsal Raphe VIP Neurons Are Critical for Survival-Oriented Vigilance.

Defensive behaviors are essential for survival, relying on risk assessment to detect and respond to threats. The dorsal raphe nucleus (DRN), a brain region involved in sleep-wake regulation, contains dopaminergic neurons (DRN(DA)) with unclear roles in threat evaluation. A subset of these neurons expresses vasoactive-intestinal-peptide (VIP) and projects to two key regions for adaptive threat responses: the central amygdala (CeA) and the oval nucleus of the bed nucleus of the stria terminalis (ovBNST). We hypothesized that DRN(VIP) neurons modulate sleep-wake regulation and play a pivotal role in coordinating activity between the CeA and ovBNST, thereby influencing risk assessment and defensive response. We found that DRN(VIP) neurons form a distinct feedback loop with PKC-δ neurons in the CeA and ovBNST. These DRN(VIP) neurons release glutamate and modulate excitability in target regions. Selective ablation of DRN(VIP) neurons disrupts active-phase sleep architecture, enhances risk assessment behaviors that may reflect dysfunctional processing, and impairs defensive responses. Fiber-photometry revealed direct activation of the DRN(VIP) neurons during presentation of the visual threat-predictive cue in behaving mice. These results suggest that DRN(VIP) neurons regulate specific sleep phases and control defensive behaviors, acting as a neuronal alarm system that responds to threats.