Abstract
Chronic stress (CS) and hyper-caloric diets promote affective disorders, however pathobiological interactions await definition. Neurobiological and behavioral influences of chronic stress (CS; 2 h/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 γ-aminobutyric acid (GABA) vs. 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 “adaptive” 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 + WD mice. Summary: Mild anxiogenic stress disrupts mitochondrial function, glutamate:GABA balance and BDNF/synaptogenesis signaling, primarily in FC vs. HPC. Co-morbid CS + WD exaggerates neurochemical disturbances, and disrupts adaptive pathway responses, in association with anhedonia and anxiety-like behaviors. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11011-026-01855-3.