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Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Impaired microglia fractalkine signaling affects stress reaction and coping style in mice
Zsuzsanna Winkler1, Dániel Kuti1, Szilamér Ferenczi2
1Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Budapest, Hungary; János Szentágothai Doctoral School of Neurosciences, Semmelweis University, Budapest, Hungary.
Abstract:
Microglia, resident immune cells of the CNS are sensitive to various perturbations of the environment, such as stress exposure, and may be involved in translating these changes to behavior. Among the pathways mediating stress-related neuronal cues to microglia, the fractalkine-fractalkine receptor (CX3CR1) signaling plays a crucial role. Using mice, in which the CX3CR1 gene was deleted, we explored hormonal and behavioral responses to acute and chronic stress along with changes in hypothalamic microglia. CX3CR1-/- animals display active escape in forced swim- and tail suspension tests, exaggerated neuronal activation in the hypothalamic paraventricular nucleus and increased corticosterone release in response to restraint. Analysis of Iba1 immunostaining of hypothalamic sections revealed stress-related reduction of microglia in CX3CR1-/- mice. Because microglia also contribute to energy balance regulation, we characterized metabolic phenotype of CX3CR1-/- mice. Comparison of respiratory exchange ratio did not show genotype effect on fuel preference, however, the energy expenditure was increased in CX3CR1-/- mice, which may be related to their active coping behavior. Microglia and fractalkine signaling has been repeatedly shown to be involved chronic stress-induced depressive state. CX3CR1-/- mice did not become anhedonic in the "two hit" chronic stress paradigm, confirming resistance of these animals to chronic stress-induced mood alterations. However, there was no difference in stress hormone levels, open field performance and hypothalamic microglia distribution between the genotypes. These results highlight differential involvement of microglia fractalkine signaling in controlling/integrating hormonal-, metabolic and behavioral responses to acute and chronic stress challenges.
Insights
Mice lacking fractalkine receptor (CX3CR1) show altered stress responses and increased energy expenditure. These mice are resistant to chronic stress-induced mood changes, highlighting CX3CR1
Area of Science:
- Neuroimmunology
- Neuroendocrinology
- Behavioral Neuroscience
Background:
- Microglia, the CNS immune cells, are sensitive to environmental stressors like stress.
- Fractalkine-fractalkine receptor (CX3CR1) signaling is a key pathway for stress-related neuronal signals to microglia.
- Microglia also play a role in regulating energy balance.
Purpose of the Study:
- To investigate the role of CX3CR1 signaling in mediating hormonal, behavioral, and metabolic responses to acute and chronic stress.
- To examine the impact of CX3CR1 deletion on hypothalamic microglia.
Main Methods:
- Utilized CX3CR1 knockout (CX3CR1-/-) mice.
- Assessed hormonal (corticosterone) and behavioral responses to acute stress (restraint, forced swim, tail suspension tests).
- Analyzed hypothalamic microglia using Iba1 immunostaining and evaluated metabolic parameters (respiratory exchange ratio, energy expenditure).
- Investigated responses to chronic stress using a "two hit" paradigm and assessed anhedonia, stress hormones, and open field performance.
Main Results:
- CX3CR1-/- mice exhibited heightened neuronal activation in the paraventricular nucleus and increased corticosterone release during acute stress.
- A reduction in hypothalamic microglia was observed in CX3CR1-/- mice following stress.
- While fuel preference was unaffected, CX3CR1-/- mice showed increased energy expenditure, potentially linked to active coping behaviors.
- CX3CR1-/- mice were resistant to chronic stress-induced anhedonia, but other stress parameters remained similar between genotypes.
Conclusions:
- Microglia and CX3CR1 signaling play a differential role in modulating hormonal, metabolic, and behavioral outcomes in response to acute and chronic stress.
- CX3CR1 signaling influences stress coping mechanisms and energy expenditure.
- The findings suggest a complex interplay between microglia, CX3CR1, and stress adaptation.
