Distinct populations of corticotropin-releasing factor (CRF) neurons mediate divergent yet complementary defensive behaviors in response to a threat.

Defensive behaviors in response to a threat are shared across the animal kingdom. Active (fleeing, sheltering) or passive (freezing, avoiding) defensive responses are adaptive and facilitate survival. Selecting appropriate defensive strategy depends on intensity, proximity, temporal threat threshold, and past experiences. Hypothalamic corticotropin-releasing factor (CRF) is a major driver of an acute stress response, whereas extrahypothalamic CRF mediates stress-related affective behaviors. In this review, we shift the focus from a monolithic role of CRF as an anxiogenic peptide to comprehensively dissecting contributions of distinct populations of CRF neurons in mediating defensive behaviors. Direct interrogation of CRF neurons of the central amygdala (CeA) or the bed nucleus of the stria terminalis (BNST) show they drive unconditioned defensive responses, such as vigilance and avoidance of open spaces. Although both populations also contribute to learned fear responses in familiar, threatening contexts, CeA-CRF neurons are particularly attuned to the ever-changing environment. Depending on threat intensities, they facilitate discrimination of salient stimuli predicting manageable threats, and prevent their generalization. Finally, hypothalamic CRF neurons mediate initial threat assessment and active defense such as escape to shelter. Overall, these three major populations of CRF neurons demonstrate divergent, yet complementary contributions to the versatile defense system: heightened vigilance, discriminating salient threats, and active escape, representing three legs of the defense tripod. Despite the 'CRF exhaustion' in the field of affective neuroscience, understanding contributions of specific CRF neurons during adaptive defensive behaviors is needed in order to understand the implications of their dysregulation in fear- and anxiety-related psychiatric disorders. This article is part of the Special Issue on "Fear, Anxiety and PTSD".