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Neurobiological and behavioral influences of chronic stress (CS; 2\u00a0h\/day restraint for 2 wks) were studied in male C57Bl\/6 mice fed a control diet (CD; 12% kcal as fat\/65% carbohydrate\/23% protein) or Western diet (WD; 32% kcal fat\/57% carbohydrate\/11% protein) for 20 wks. CS induced weight loss and anxiety-like behavior, associated with reduced frontal cortex (FC) brain-derived neurotrophic factor (BDNF) and \u03b3-aminobutyric acid (GABA)\n                    <jats:italic>vs<\/jats:italic>\n                    . elevated glutamate; and mitochondrial dysfunction, including reduced complex I (CI), electron transport system (ETS) and spare respiratory capacities. Hippocampus (HPC) appeared less responsive (CI flux selectively inhibited). Proteomics supports CS disruption of synaptogenesis and mitochondrial pathways, together with \u201cadaptive\u201d changes, including activation of neuroprotective chaperone-mediated autophagy (CMA), reelin and eukaryotic initiation factor 2 (EIF2) paths. The WD alone (inducing weight gain, insulin-resistance and reduced sucrose preference) had no independent effects on FC neurochemistry, FC or HPC respiratory function. Co-morbid CS in WD mice induced anxiety-like behavior and anhedonia, coupled with WD-related reductions in FC GABA and HPC BDNF not evident in un-stressed mice. A co-morbid WD also limited CS-dependent changes in ETS and spare respiratory capacities. Proteomics supports reduced CS activation of reelin and EIF2 pathways, and a switch from CMA activation to suppression, in co-morbid CS\u2009+\u2009WD mice.\n                    <jats:italic>Summary<\/jats:italic>\n                    : Mild anxiogenic stress disrupts mitochondrial function, glutamate:GABA balance and BDNF\/synaptogenesis signaling, primarily in FC\n                    <jats:italic>vs.<\/jats:italic>\n                    HPC. Co-morbid CS\u2009+\u2009WD exaggerates neurochemical disturbances, and disrupts adaptive pathway responses, in association with anhedonia and anxiety-like behaviors.\n                  <\/jats:p>","DOI":"10.1007\/s11011-026-01855-3","type":"journal-article","created":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T07:19:39Z","timestamp":1777274379000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Neurobiology of co-morbid stress and a western diet in mice: mitochondrial, proteomic and behavioral outcomes"],"prefix":"10.1007","volume":"41","author":[{"given":"Tessa","family":"Helman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makayla","family":"Nicholas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brock","family":"Lyon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saba","family":"Naghipour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chul-Kyu","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trissha","family":"Ybanez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Robertson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tia A.","family":"Griffith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason N.","family":"Peart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas J. 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