Stressed Microglia: Neuroendocrine-Neuroimmune Interactions in the Stress Response

Abstract

Stressful life experiences are associated with the development of neuropsychiatric disorders like depression. Emerging evidence indicates that microglia, the specialized resident macrophages of the brain, may be a key mediator of the relationship between psychosocial stressor exposure and adaptive or maladaptive responses at the level of synaptic, circuit, and neuroimmune alterations. Here, we review current literature regarding how psychosocial stressor exposure changes microglial structure and function, thereby altering behavioral and brain outcomes, with a particular focus on age- and sex-dependent effects. We argue that additional emphasis should be placed in future research on investigating sex differences and the impacts of stressor exposure during sensitive periods of development, as well as going beyond traditional morphological measurements to interrogate microglial function. The bidirectional relationship between microglia and the stress response, particularly the role of microglia in the neuroendocrine control of stress-related circuits, is also an important area for future investigation. Finally, we discuss emerging themes and future directions that point to the possibility of the development of novel therapeutics for stress-related neuropsychiatric disorders.

Keywords: age; early-life adversity; microglia; neuroendocrine; neuroimmune; sex; stress.

Figure 1.

Microglia and the stress response. (A) The HPA axis interacts with microglia to modify their structure and function across the brain, which in turn can modify the stress response. (B) Stressor exposure can alter the microglial immune response, as well as interactions with synapses, such as synaptic pruning. These alterations are dependent on factors such as age, sex, stressor type and duration, and the brain region measured. HPA, hypothalamic–pituitary–adrenal; CRH, corticotropin-releasing hormone); ACTH, adrenocorticotropic hormone; CORT, corticosterone; LPS, lipopolysaccharide; IL, interleukin; NLRP3, nucleotide-binding domain, leucine-rich–containing family, pyrin domain-containing 3; BDNF, brain-derived neurotrophic factor; MerTK, Mer tyrosine kinase; C3R, complement receptor C3; CX3CR1, CX3C motif chemokine receptor 1; CSF1R, colony stimulating factor 1 receptor. Created with BioRender.com.