Microglial deletion induces despair-like behavior associated with astrogliosis
Abstract
Microglia, the brain’s resident immune cells, are increasingly recognized as key regulators of brain physiology and behavior. However, their specific role in affective states remains controversial, with studies reporting conflicting depression-like outcomes following their removal. Using the colony stimulating factor-1 receptor (CSF1R) inhibitor PLX5622 in adult mice of both sexes, we found that microglial deletion selectively induced despair-like behavior (increased immobility in the forced swim test and the tail suspension test) in either sex, without affecting locomotion, anxiety, sociability, anhedonia, or cognition. This effect was accompanied by reactive astrogliosis in the medial prefrontal cortex (mPFC). Unexpectedly, microglial deletion induced a predominant A2-like astrocyte reactivity. Notably, both the despair-like and A2-like phenotypes resolved upon microglia repopulation. Critically, pharmacological inhibition of these hyperactive mPFC astrocytes with fluorocitrate reversed the despair-like phenotype, indicating that microglial loss triggers maladaptive astrocyte reactivity that drives behavioral despair. Our results reveal an essential role for microglia in maintaining emotional homeostasis, possibly through interaction with astrocytes.
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BibTeX
@article{wang2026microglial,
title = {{Microglial deletion induces despair-like behavior associated with astrogliosis}},
author = {Xun Wang and Shi-Han Liao and Nan Wang and Ya-Ting Chen and Rui-Han Huang and Di-Ji Li and Wen-Ying Jiang and Xiao-Wen Li and Tian-Ming Gao and Jian-Ming Yang},
journal = {Translational Psychiatry},
year = {2026},
month = jul,
doi = {10.1038/s41398-026-04325-7},
url = {https://doi.org/10.1038/s41398-026-04325-7},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Microglial deletion induces despair-like behavior associated with astrogliosis
AU - Xun Wang
AU - Shi-Han Liao
AU - Nan Wang
AU - Ya-Ting Chen
AU - Rui-Han Huang
AU - Di-Ji Li
AU - Wen-Ying Jiang
AU - Xiao-Wen Li
AU - Tian-Ming Gao
AU - Jian-Ming Yang
PY - 2026
DA - 2026/07/29
JO - Translational Psychiatry
DO - 10.1038/s41398-026-04325-7
UR - https://doi.org/10.1038/s41398-026-04325-7
AB - Microglia, the brain’s resident immune cells, are increasingly recognized as key regulators of brain physiology and behavior. However, their specific role in affective states remains controversial, with studies reporting conflicting depression-like outcomes following their removal. Using the colony stimulating factor-1 receptor (CSF1R) inhibitor PLX5622 in adult mice of both sexes, we found that microglial deletion selectively induced despair-like behavior (increased immobility in the forced swim test and the tail suspension test) in either sex, without affecting locomotion, anxiety, sociability, anhedonia, or cognition. This effect was accompanied by reactive astrogliosis in the medial prefrontal cortex (mPFC). Unexpectedly, microglial deletion induced a predominant A2-like astrocyte reactivity. Notably, both the despair-like and A2-like phenotypes resolved upon microglia repopulation. Critically, pharmacological inhibition of these hyperactive mPFC astrocytes with fluorocitrate reversed the despair-like phenotype, indicating that microglial loss triggers maladaptive astrocyte reactivity that drives behavioral despair. Our results reveal an essential role for microglia in maintaining emotional homeostasis, possibly through interaction with astrocytes.
SN - 2158-3188
ER -