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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 \u03b1-synuclein-positive Lewy body-like inclusions, and anhedonia-like behavior. Combined dopaminergic\u2013antidepressant 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.<\/jats:p>","DOI":"10.1007\/s11357-026-02475-6","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T19:37:18Z","timestamp":1786390638000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Stress, mood, and Parkinson\u2019s disease: selective dysregulation of corticotropin-releasing hormone and urocortin neurocircuits"],"prefix":"10.1007","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-9903-5006","authenticated-orcid":false,"given":"Bence","family":"Pytel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsombor","family":"M\u00e1rton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e1nos","family":"Kocsa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gergely","family":"Berta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00e1szl\u00f3 \u00c1kos","family":"Kov\u00e1cs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f3zsef","family":"Farkas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N\u00f3ra","family":"F\u00fcredi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zs\u00f3fia","family":"Havasi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2830-2732","authenticated-orcid":false,"given":"Vikt\u00f3ria","family":"Kormos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bal\u00e1zs","family":"Gaszner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,10]]},"reference":[{"key":"2475_CR1","doi-asserted-by":"publisher","first-page":"1583","DOI":"10.1002\/mds.25945","volume":"29","author":"T Pringsheim","year":"2014","unstructured":"Pringsheim T, Jette N, Frolkis A, et al. 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