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

Authors

Bence Pytel, Zsombor Márton, János Kocsa, Gergely Berta, László Ákos Kovács, József Farkas, Nóra Füredi, Zsófia Havasi, Viktória Kormos, Balázs Gaszner

Published in

GeroScience. Aug 10, 2026. Epub Aug 10, 2026.

Abstract

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.

PMID:
42576129
Bibliographic data and abstract were imported from PubMed on 11 Aug 2026.

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