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Updated: Nov 1, 2025
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Microglia contribute to social behavioral adaptation to chronic stress
Sami Piirainen1,2, Keerthana Chithanathan2, Kanchan Bisht3,4
1Neuroscience Center, HiLIFE, University of Helsinki, Helsinki, Finland.
Abstract:
Microglial activation has been regarded mainly as an exacerbator of stress response, a common symptom in psychiatric disorders. This study aimed to determine whether microglia contribute to adaptive response of the brain and behavior toward stress using a mild and adaptive stress model - chronic restraint stress (CRS) - with wild type (WT) and CX3CR1-GFP (CX3CR1[G]) mice and human schizophrenia patients' data. Our results revealed that CRS did not exacerbate anxiety and depressive-like behaviors, but instead strengthened social dominance and short-term spatial learning in WT mice. Compared to WT and CX3CR1(+/G) heterozygous mice, CX3CR1(G/G) homozygotes were subordinate in social interaction before and after CRS. Microglia in WT mice underwent a series of region-specific changes involving their phagocytosis of presynaptic vesicular glutamate transporter 2 protein, contacts with synaptic elements, CD206+ microglial proportion, and gene expressions such as Cx3cr1. By contrast, CX3CR1-deficient microglia showed decreased CD206+ while increased MHCII+ subpopulations and hypo-ramification in the hippocampus, as well as sensitized polarization and morphological change in response to CRS. Furthermore, CD206+ microglial abundancy was positively correlated with social dominancy and microglial ramification in CX3CR1-GFP mice. Moreover, CX3CR1 mRNA level was reduced in CRS-treated mouse brains and showed a smaller interactome with other brain genes in the dorsal-lateral prefrontal cortices of patients with schizophrenia. Our findings overall highlight microglia and its receptor CX3CR1 as key contributors in regulation of social behavioral adaptation to chronic stress.
Insights
Microglia, particularly through the CX3CR1 receptor, play a crucial role in adapting social behaviors to chronic stress. This research reveals their involvement in strengthening social dominance and learning, not just exacerbating stress responses.
Area of Science:
- Neuroscience
- Immunology
- Behavioral Science
Background:
- Microglial activation is typically viewed as worsening stress responses in psychiatric disorders.
- The role of microglia in adaptive brain and behavioral responses to stress remains underexplored.
Purpose of the Study:
- To investigate the contribution of microglia to adaptive responses to chronic restraint stress (CRS).
- To examine the role of the CX3CR1 receptor in microglial function during stress adaptation.
Main Methods:
- Utilized a chronic restraint stress (CRS) model in wild-type (WT) and CX3CR1-GFP mice (including homozygotes and heterozygotes).
- Analyzed behavioral outcomes (social dominance, anxiety, depression, spatial learning).
- Examined microglial morphology, phagocytosis (VGLUT2), synaptic contacts, cell surface markers (CD206, MHCII), and gene expression (Cx3cr1).
- Correlated microglial markers with behavioral phenotypes.
- Analyzed CX3CR1 mRNA levels and gene interactions in human schizophrenia patient data.
Main Results:
- CRS enhanced social dominance and spatial learning in WT mice, without increasing anxiety or depressive behaviors.
- CX3CR1-deficient mice exhibited social subordination and altered microglial responses (decreased CD206+, increased MHCII+, hypo-ramification) to CRS.
- CD206+ microglial abundance correlated positively with social dominance and microglial ramification.
- Reduced CX3CR1 mRNA levels were observed in stressed mouse brains and in the prefrontal cortex of schizophrenia patients.
Conclusions:
- Microglia, via the CX3CR1 receptor, are key regulators of social behavioral adaptation to chronic stress.
- CX3CR1 signaling in microglia promotes adaptive social behaviors and influences brain gene interactomes relevant to psychiatric disorders.
