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

Behav Brain Res. 2017 Sep 15:334:119-128. doi: 10.1016/j.bbr.2017.07.023. Epub 2017 Jul 20.

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.

Keywords: CX(3)CR1; Chronic stress; Depression; Energy expenditure; Microglia; c-Fos.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Psychological / physiology*
  • Adrenocorticotropic Hormone / blood
  • Anhedonia / physiology
  • Animals
  • CX3C Chemokine Receptor 1 / deficiency*
  • CX3C Chemokine Receptor 1 / genetics
  • Calcium-Binding Proteins / metabolism
  • Chemokine CX3CL1 / metabolism*
  • Corticosterone / blood
  • Escape Reaction / physiology
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microfilament Proteins / metabolism
  • 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

Substances

  • Aif1 protein, mouse
  • CX3C Chemokine Receptor 1
  • Calcium-Binding Proteins
  • Chemokine CX3CL1
  • Cx3cl1 protein, mouse
  • Cx3cr1 protein, mouse
  • Microfilament Proteins
  • Proto-Oncogene Proteins c-fos
  • Adrenocorticotropic Hormone
  • Corticosterone