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Updated: Feb 13, 2026
Chronic Social Defeat Stress in Early Adolescent Male Mice
Published on: January 24, 2025
PPARγ in microglia helps protect adolescent male mice from harmful effects of stress during early development
Zhe Liu1, Jiutai Wang2, Yan Ge3
1Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Health Science Center, Xi'an Jiaotong University, 710061 Xi'an, China.
Abstract:
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.
Insights
Early life stress downregulates the nuclear hormone receptor PPARγ (peroxisome proliferator-activated receptor gamma), impacting microglia and stress responses. Activating PPARγ reversed these effects, suggesting a role in stress-related disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Psychiatry
Background:
- Deficiency in peroxisome proliferator-activated receptor γ (PPARγ) is linked to autism, bipolar disorder, and Alzheimer's disease.
- Early life stress can have long-lasting effects on brain function and behavior.
Purpose of the Study:
- To investigate the role of PPARγ in the neurobiological effects of early life stress.
- To explore PPARγ's influence on microglia activation and stress reactivity.
Main Methods:
- Maternal separation model in mice to induce early life stress.
- Pharmacological activation of PPARγ with pioglitazone.
- Genetic knockout of PPARγ in microglia.
- Assessment of microglial polarization, neurogenesis, neural activity, dendritic spine density, and behavioral responses to stress.
Main Results:
- Maternal separation downregulated hippocampal PPARγ, promoting pro-inflammatory microglia and heightened stress responses.
- Pioglitazone treatment reversed these effects and stimulated neurogenesis.
- Microglial PPARγ knockout impaired neural activity, reduced dendritic spine density, and induced depressive-like behaviors.
Conclusions:
- PPARγ expression in microglia is crucial for regulating responses to stress, potentially by enabling a cellular memory of prior stress exposure.
- PPARγ activation may offer a therapeutic strategy for stress-related psychological disorders.
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