Small cells with big implications: Microglia and sex differences in brain development, plasticity and behavioral health

Abstract

Brain sex differences are programmed largely by sex hormone secretions and direct sex chromosome effects in early life, and are subsequently modulated by early life experiences. The brain's resident immune cells, called microglia, actively contribute to brain development. Recent research has shown that microglia are sexually dimorphic, especially during early life, and may participate in sex-specific organization of the brain and behavior. Likewise, sex differences in immune cells and their signaling in the adult brain have been found, although in most cases their function remains unclear. Additionally, immune cells and their signaling have been implicated in many disorders in which brain development or plasticity is altered, including autism, schizophrenia, pain disorders, major depression, and postpartum depression. This review summarizes what is currently known about sex differences in neuroimmune function in development and during other major phases of brain plasticity, as well as the current state of knowledge regarding sex-specific neuroimmune function in psychiatric disorders.

Keywords: Astrocyte; Autism; Behavior; Development; Hormone; Immune; Inflammation; Microglia; Mood disorders; Sex; Sex differences; Stress.

Figure 1:. Sexual differentiation of the brain and behavior.

Male typical (top; blue) and female typical (bottom; pink) sexual differentiation. Sex chromosome complement (XX in females; XY in males) leads to sex determination. The Y-chromosome gene, SRY, codes for the protein testicular determining factor (TDF), which programs the bi-potential gonads to differentiate into testes (left). In rodents, the testes begin secreting androgens during the late embryonic period, and these androgens lead to sexual differentiation of the brain and other tissues (middle). In the rodent brain, androgens are converted into estrogens, and estrogens masculinize the brain. In genetic females, the gonads differentiate into ovaries, and the ovaries are largely quiescent in the perinatal period (middle), thus brain feminization occurs largely in the absence of active hormonal signals. At puberty, both male and female gonads produce sex-typical hormone secretions, namely high androgen levels and high but pulsatile estrogen and progestin levels in females. Both early life (organizational) and post-pubertal (activational) hormones contribute to sex differences in behavior, most notably male mounting behavior (blue rat) and female lordosis behavior (pink rat) (right). Sex chromosomes can also have independent effects on brain organization as well as adult sex differences in behaviors (dashed lines). Anthony S. Baker, CMI, Reproduced with the permission of The Ohio State University.

Figure 2:. Sex differences in microglia across different developmental windows and conditions.

(A) During the perinatal period (left panel), males have more microglia than females, and the microglia are in a more activated and immature form. Microglia in the male preoptic area respond to the masculinizing hormone, estradiol, by releasing the inflammatory lipid, prostaglandin E2 (PGE2), and PGE2 is responsible for programming male-typical dendritic spine genesis/maintenance that is necessary to display adult copulatory behavior. During the perinatal-juvenile period (middle panel), female microglia appear to show a higher level of phagocytic activity in the hippocampus than male microglia. Female microglia target neural progenitor cells at a higher rate than males, and higher phagocytosis in females is also correlated with reduced dendritic spines in the hippocampus at this time, though they have not been causally linked to date. In adulthood (right), female microglia are hormone responsive and show hyper-ramification relative to males. (B) Studies in which microglia have been depleted early in life demonstrate lifelong behavioral changes in both males and females, with sex-specific effects being seen in some outcomes. (C) Studies in which microglia are stimulated early in life show that male microglia are more responsive than female microglia. Male microglia depicted in blue and female microglia in pink throughout. Figure based on data from Bollinger et al., 2016; ; Hanamsagar et al., 2017; Hui et al., 2018; Lenz et al., 2013; Makinson et al., 2017; Nelson & Lenz, 2016; Nelson et al., 2017; Schwarz et al., 2011; Van Ryzin et al., 2016, Weinhard et al., 2018b). Anthony S. Baker, CMI, Reproduced with the permission of The Ohio State University.