Corticotropin-releasing factor-dependent synaptic plasticity in acute stress: From rapid signaling to circuit...

Stress enables organisms to adapt to changing environments, but repeated or poorly resolved stress can shift adaptive plasticity toward maladaptive overload. Corticotropin-releasing factor (CRF), also termed corticotropin-releasing hormone (CRH) in endocrine contexts, plays an established role in the hypothalamic-pituitary-adrenal (HPA) axis. Beyond this endocrine role, CRF acts as a neuromodulator in limbic brain circuits, where it can rapidly regulate neuronal communication. Evidence from hippocampal and related limbic circuits shows that CRF can increase neuronal excitability, regulate neurotransmitter release, remodel dendritic spines, and influence long-term synaptic plasticity. These effects suggest that CRF helps establish cellular conditions required for stress-related learning and circuit adaptation. Current models support a temporally layered view of the stress response, in which rapid CRF-dependent signaling interacts with slower glucocorticoid-dependent transcriptional and structural remodeling. Understanding when acute CRF signaling supports adaptive plasticity and when it instead contributes to allostatic load may clarify the transition from resilience to pathology. This review frames CRF not as a generalized stress signal, but as a temporally and spatially organized modulator whose effects depend on circuit architecture, stressor type, receptor context, developmental and experiential history, and interactions with other neuropeptide systems.