Sex-specific Microglia Activation Induced By Stress Relate To CX3CR1 Signaling

Epidemiological studies have shown that there are widespread gender differences in the incidence,clinical manifestations and drug responsiveness of depression.It is of great significance to explore the biological mechanism of gender differences in depression for the targeted treatment of gender depression.Many of the gender-based transcriptional changes associated with stress and depression involve the immune system,and microglia are innate immune cells that reside in the central nervous system.Under stress or pathological conditions,microglia cells regulate neurogenesis through phenotypic transformation and secretion of various factors regulating the neurogenic microenvironment,thus promoting or slowing the occurrence and development of depression.CX3CR1/CX3CL1 is an important signaling molecule mediating the interaction between neuro progenitor cells and microglia,and this pathway has been shown to be involved in sex-specific activation of hypothalamic microglia.In this paper,we will further explore the role of microglia CX3CR1 in mediating gender differences in stress susceptibility in male and female mice.In this thesis,the subthreshold three-week chronic mild stress(CMS)model was used to evaluate the gender differences of depression-like and anxiety-like behaviors in male and female mice after stress.Immunohistochemical experiments were conducted to explore the morphological and phenotypic changes of male and female microglia after stress and its effects on neurogenesis.The correlation between CX3CR1/CX3CL1 expression and behavior was investigated by Western blot.Inhibition of CX3CR1 signals in microglia in vivo demonstrated that CX3CR1 was involved in sex differences in stress susceptibility.The results showed that there were gender differences in post-stress behavior of male mice.Male mice showed depression and anxiety like behavior,while female mice showed stress resistance.Stress induced male microglia to change into pro-inflammatory phenotype and release more inflammatory factors to damage neurogenesis.CX3CR1 mediates stress resistance in female mice,and female microglia transform into anti-inflammatory phenotype,releasing anti-inflammatory factors to protect neurogenesis.The stress resistance of females disappeared after CX3CR1 inhibition.Meanwhile,In vitro showed that female microglia CX3CR1 showed higher reactivity to s CX3CL1 recombinant protein under stress.In this thesis,data suggest that that different CX3CR1 reactivity in male and female mice mediates different inflammatory phenotypes of microglia of both sexes in a subthreshold stress model,thus regulating neuroinflammation and affecting neurogenesis,and thus mediating gender differences in post-stress behaviors of male and female mice.