Work

PPARγ in microglia helps protect adolescent male mice from harmful effects of stress during early development

Year: 2026

Type: article

Abstract: • Early maternal separation triggers stress susceptibility in male adolescent mice by suppressing PPARγ signaling in the mouse hippocampus. • Microglia-specific knockout of PPARγ is sufficient to induce stress susceptibility and depressive-like behaviors in adolescent mice. • Pharmacological activation of PPARγ with pioglitazone reverses behavioral deficits and restores hippocampal neurogenesis in stressed mice. • Single-cell RNA sequencing reveals that microglial PPARγ knockout disrupts neuronal gene expression networks linked to psychiatric disorders. Deficiency in the expression or activity of the nuclear hormone receptor peroxisome proliferator-activated receptor γ (PPARγ) has been observed in autism spectrum disorder, bipolar disorder and Alzheimer’s disease. Here we showed that separating mouse pups from their mothers for three hours daily during the first two weeks of life downregulated PPARγ, leading to pro-inflammatory polarization and activation of microglia in the hippocampus, which results in more severe responses to subsequent chronic restraint stress in adolescent animals. These effects of maternal separation were reversed by activating PPARγ with pioglitazone at 30 mg/kg/day for one week, which also stimulated hippocampal neurogenesis. Knocking out PPARγ specifically in microglia reduced neural activity and dendritic spine density in the cortex and hippocampus and led to depressive-like behaviors in mice. These results suggest that PPARγ expression enables microglia to “remember” previous exposure to stress and thereby influence responses to future stress. The findings may help guide interventions against stress and related psychological disorders.

Source: Brain Behavior and Immunity

DOI: 10.1016/j.bbi.2026.106483