Implication of orexin transmission in chronic stress, hyperarousal, and neuroplasticity deficits: a mechanistic framework for depression and anxiety.

Stress is a major risk factor for depression- and anxiety-related disorders and produces neuroplastic adaptations within brain regions that regulate emotion, cognition, and stress responsivity. These adaptations include dendritic retraction in the medial prefrontal cortex (mPFC), suppression of plasticity and neurogenesis in the hippocampus (HIPP), and hypertrophic remodeling of circuits within the amygdala (AMY), promoting emotional dysregulation and maladaptive behavior. Although these alterations are well-documented, the mechanisms that coordinate their emergence across multiple neural systems remain unknown. The orexin (OX; hypocretin) system is anatomically and functionally positioned to serve as a key mediator of stress-induced neuroplasticity. Indeed, OX neurons receive direct corticotropin-releasing factor (CRF) input from the hypothalamic paraventricular nucleus (PVN) and project broadly to brain regions involved in arousal, motivation, emotional regulation, and reward processing (e.g., mPFC, HIPP, and AMY). Chronic activation of CRF-sensitive OX pathways may therefore sustain OX-dependent hyperarousal beyond the presence of an acute stressor, increasing excitatory drive throughout emotion-regulation circuits. This prolonged activation may contribute to maladaptive plasticity through alterations in neuronal excitability, impaired homeostatic regulation, and reductions in brain-derived neurotrophic factor (BDNF)-related signaling. In this review, we propose a mechanistic framework in which CRF-mediated recruitment of hypothalamic OX neurons contributes to neuroplasticity deficits in the mPFC, HIPP, and AMY. We discuss how developmental stage, biological sex, and genetic variation influence vulnerability to these adaptations and examine therapeutic strategies aimed at reducing hyperarousal and restoring neural plasticity. Collectively, this theoretical framework positions OX transmission as a potential link between chronic stress and mood-related psychopathology.