Impaired microglia fractalkine signaling affects stress reaction and coping style in mice

• Published in: Behavioural brain research 2017-09, Vol.334, p.119-128
• Main Authors: Winkler, Zsuzsanna, Kuti, Dániel, Ferenczi, Szilamér, Gulyás, Krisztina, Polyák, Ágnes, Kovács, Krisztina J.
• Format: Article
• Language: English
• Subjects: Adaptation, Psychological - physiology; Adrenocorticotropic Hormone - blood; Anhedonia - physiology; Animals; c-Fos; Calcium-Binding Proteins - metabolism; Chemokine CX3CL1 - metabolism; Chronic stress; Corticosterone - blood; CX3C Chemokine Receptor 1 - deficiency; CX3C Chemokine Receptor 1 - genetics; CX3CR1; Depression; Energy expenditure; Escape Reaction - physiology; Male; Mice, Inbred C57BL; Mice, Knockout; Microfilament Proteins - metabolism; Microglia; Microglia - metabolism; Microglia - pathology; Paraventricular Hypothalamic Nucleus - metabolism; Paraventricular Hypothalamic Nucleus - pathology; Proto-Oncogene Proteins c-fos - metabolism; Signal Transduction; Stress, Psychological - metabolism; Stress, Psychological - pathology
• ISSN: 0166-4328; 1872-7549
• DOI: 10.1016/j.bbr.2017.07.023

[Display omitted] •Mice with impaired microglia fractalkine signaling display exacerbated HPA reactivity to acute stress.•Fractalkine receptor KO mice display active escape strategy.•Active escape behavior of CX3CR1-/- mice might be related to improved metabolic performance.•Fractalkine receptor KO mice do not develop chronic stress-induced anhedonia. 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.