Sex and region-specific effects of variable stress on microglia morphology
Mariya Tsyglakova1,2, Alisa M Huskey3, Emily H Hurst1
1School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.
Abstract:
Major Depressive Disorder (MDD) is a common and debilitating mood disorder that is more prevalent in women than men. In humans, PET imaging of microglia activation is currently being explored as a potential biomarker of MDD and suicidal ideation. Stress is a trigger for many mood disorders, including MDD. Microglial changes in morphology and activation state in response to stress has been reported in various brain regions, but most studies only examined male subjects. Here we report changes in microglia morphology in the nucleus accumbens (NAc) and subregions of the hippocampus (HPC) in both male and female mice following variable stress of 6 or 28 days in duration. Our data demonstrate that after 6 days of stress, microglia in the female NAc and dentate gyrus have a reduction in homeostatic associated morphology and an increase in primed microglia. After 28 days some of these sex specific stress effects were still present in microglia within the NAc but not the dentate gyrus. There were no effects of stress in either sex at either timepoint in CA1. In female mice, anti-inflammatory activation of microglia using rosiglitazone promoted sociability behavior after 6 days of stress. Furthermore, both drug and stress have impact on microglia morphology and activation state in the NAc. These data suggest that microglia morphology and activation state are altered by 6 days of variable stress in a region-specific manner and may contribute to, or potentially compensate for, the onset of stress susceptibility rather than impacting long term exposure to stress.
Insights
Stress alters microglia morphology and activation in specific brain regions, particularly in females, potentially contributing to Major Depressive Disorder (MDD) susceptibility. These changes may be transient, with some effects persisting in the nucleus accumbens after 28 days.
Area of Science:
- Neuroscience
- Neuroinflammation
- Psychiatry
Background:
- Major Depressive Disorder (MDD) is more common in women and linked to stress.
- Microglia activation is a potential biomarker for MDD, but research often overlooks sex differences.
- Stress impacts microglial morphology and activation, yet studies predominantly focus on males.
Purpose of the Study:
- To investigate sex-specific changes in microglia morphology and activation in response to variable stress.
- To examine these changes in the nucleus accumbens (NAc) and hippocampus (HPC) over 6 and 28 days.
- To explore the therapeutic potential of targeting microglia in stress-induced behavioral changes.
Main Methods:
- Variable stress applied to male and female mice for 6 or 28 days.
- Analysis of microglia morphology and activation state in NAc and HPC subregions (dentate gyrus, CA1).
- Assessment of sociability behavior in stressed female mice treated with rosiglitazone.
Main Results:
- Six days of stress induced sex-specific microglial changes in the female NAc and dentate gyrus (reduced homeostatic, increased primed morphology).
- These sex-specific effects persisted in the NAc after 28 days but not in the dentate gyrus; no effects were observed in CA1.
- Rosiglitazone treatment improved sociability in stressed female mice, indicating a role for microglia in stress response.
Conclusions:
- Short-term stress (6 days) alters microglia morphology and activation in a region- and sex-specific manner.
- These microglial alterations may contribute to stress susceptibility rather than long-term stress effects.
- Targeting microglia, such as with rosiglitazone, may offer therapeutic benefits for stress-related mood disorders.
