Sexual dimorphism in high-fat diet-induced depression-like phenotypes in mice: astrocyte-centered molecular, circuit, and microbiota associations

Metabolic disorders (MetD) are linked to depression, both of which exhibit sex differences in prevalence and clinical presentation; however, the mechanisms underlying sex-specific vulnerability to MetD-related depression remain unclear. Male and female C57BL/6 N mice were fed a high-fat diet (HFD) for 12 weeks (8 to 20 weeks of age) to induce MetD. Depression-like behaviors were assessed using the sucrose preference and forced swim tests. Ventral hippocampus (vHPC) astrocyte-centered molecular, structural, and circuit alterations were evaluated using Fluoro-Gold retrograde labeling, immunohistochemistry, and immunoblotting. Gut microbiota composition was characterized by full-length 16S rRNA sequencing and correlated with behavioral, metabolic, and neurobiological measures. Despite equivalent HFD exposure, male mice, but not females, developed pronounced metabolic dysfunction and depression-like behaviors. HFD-associated behavioral alterations in males were accompanied by sex-dependent impairments in vHPC astrocytic glutamate regulation and morphology, along with increased vHPC- nucleus accumbens (NAc) circuit activity. Peripheral insulin resistance and selective lipid abnormalities, rather than obesity or elevated glucocorticoids, showed the strongest associations with behavioral outcomes. HFD induced broadly similar gut microbiota remodeling across sexes, superimposed on distinct baseline microbial profiles, with sex-stratified analyses identifying specific taxa associated with FST performance in males but not females. These findings provide evidence for sex-dependent alterations in vHPC astrocytic morphology and vHPC-NAc circuit activity following HFD exposure, underscoring the importance of biological sex in the neurobiological responses associated with MetD-related depression.