Stress, mood, and Parkinson's disease: selective dysregulation of corticotropin-releasing hormone and urocortin neurocircuits.

Parkinson's disease (PD) is an age-associated neurodegenerative disorder in which affective non-motor symptoms substantially contribute to disease burden, yet their neurobiological basis remains incompletely understood. We investigated region-specific alterations of corticotropin-releasing hormone (CRH) family neuropeptides in a rotenone-induced rat model of PD and evaluated the effects of combined dopaminergic (benserazide/L-DOPA) and antidepressant (fluoxetine) treatment. Motor performance, anhedonia-like behavior, dopaminergic neurodegeneration, and CRH-, urocortin 1 (UCN1)-, urocortin 2 (UCN2)-, and urocortin 3 (UCN3)-related molecular changes were assessed using behavioral testing, immunohistochemistry, and RNAscope in situ hybridization. Rotenone treatment induced robust motor impairment, nigral dopaminergic neurodegeneration with α-synuclein-positive Lewy body-like inclusions, and anhedonia-like behavior. Combined dopaminergic-antidepressant therapy improved affective deficits without reversing dopaminergic neuronal loss. Region-specific analyses revealed pronounced dysregulation of hypothalamic and midbrain stress-related neuropeptide systems, including the paraventricular nucleus/CRH, paraventricular nucleus/UCN2, lateral hypothalamic area/UCN3, and centrally projecting Edinger-Westphal nucleus/UCN1, whereas CRH- and UCN3-expressing populations within the extended amygdala remained largely unaffected. Correlation analyses further supported coordinated regulation among hypothalamic CRH-family systems and their association with affective behavioral alterations. These findings identify selective vulnerability of hypothalamic stress-regulatory neuropeptide circuits in experimental PD and suggest that aging-related impairment of stress resilience may contribute to affective non-motor symptoms. Beyond providing a comprehensive neuroanatomical characterization of CRH-family peptide alterations, this work highlights region-specific neuropeptide signaling as a potential framework for developing more precise biomarkers and targeted therapeutic strategies for PD-associated mood disturbances.