ESTRADIOL ENHANCES INFLAMMATION DURING PUBERTAL DEVELOPMENT IN FEMALE MICE

There is a dynamic interaction between the immune, endocrine, and central nervous systems. The main function of the immune system is to protect the organism from pathogens by engaging a network of organs, cells and signaling molecules. Recently, the resident-immune cells of the brain have been found to be critical in supporting the full development of neural circuits during sensitive periods of development. However, over-activation of the immune system during this period can alter the typical trajectory of maturing neural circuits. LPS (lipopolysaccharide) administration decreases hormone-induced adult sexual behavior in mice when administered during puberty, but not when it is administered in other developmental periods. In addition to this, pubertal females show increased microglial reactivity in hypothalamic areas associated with reproduction, compared to adult females receiving the same treatment. Interestingly, removing the ovaries of pubertal animals prior to LPS treatment ‘protects’ females from the decrease in sexual behavior. Together, these data suggest that the ovaries are a key factor in conferring vulnerability to LPS during puberty. Microglia express estrogen receptors, which suggest that estradiol can modulate microglial reactivity. However, it is unknown if estradiol regulates microglial reactivity during the pubertal sensitive period. The work presented in this dissertation was designed to test the hypothesis that estradiol confers vulnerability to LPS by regulating microglial reactivity. We manipulated estradiol levels by: (a) ovariectomy, (b) by estradiol capsule implantation, and (c) administration of an aromatase inhibitor. We discovered that: (1) estradiol affects microglial reactivity by increasing microglial outgrowth, (2) there is microglial heterogeneity between brain regions, (3) there is heterogeneity in microglial reactivity within brain regions, (4) LPS causes a strong hypothermic response only in the presence of estradiol, and (5) LPS induces higher levels of pro-inflammatory cytokines in the presence of estradiol. The present work suggests that estradiol enhances immune surveillance during the pubertal sensitive period and adds to the mounting evidence involving microglia in normal developmental processes. Understanding the interaction between the endocrine, immune and central nervous systems in females may shed light into factors that promote a sex bias in the prevalence of mood-related disorders