Abstract
Sexual differentiation is the early life process by which the brain is prepared for male or female typical behaviors, and is directed by sex chromosomes, hormones and early life experiences. We have recently found that innate immune cells residing in the brain, including microglia and mast cells, are more numerous in the male than female rat brain. Neuroimmune cells are also key participants in the sexual differentiation process, specifically organizing the synaptic development of the preoptic area and leading to male-typical sexual behavior in adulthood. Mast cells are known for their roles in allergic responses, thus in this study we sought to determine if exposure to an allergic response of the pregnant female in utero would alter the sexual differentiation of the preoptic area of offspring and resulting sociosexual behavior in later life. Pregnant rats were sensitized to ovalbumin (OVA), bred, and challenged intranasally with OVA on gestational day 15, which produced robust allergic inflammation, as measured by elevated immunoglobulin E. Offspring of these challenged mother rats were assessed relative to control rats in the early neonatal period for mast cell and microglia activation within their brains, downstream dendritic spine patterning on POA neurons, or grown to adulthood to assess behavior and dendritic spines. In utero exposure to allergic inflammation increased mast cell and microglia activation in the neonatal brain, and led to masculinization of dendritic spine density in the female POA. In adulthood, OVA-exposed females showed an increase in male-typical mounting behavior relative to control females. In contrast, OVA-exposed males showed evidence of dysmasculinization, including reduced microglia activation, reduced neonatal dendritic spine density, decreased male-typical copulatory behavior, and decreased olfactory preference for female-typical cues. Together these studies show that early life allergic events may contribute to natural variations in both male and female sexual behavior, potentially via underlying effects on brain-resident mast cells.
Highlights
Microglia, the primary resident immune cells of the brain, are both targets and effectors of the sexual differentiation process
Adult female rats were sensitized to the allergen ovalbumin (OVA), bred, and challenged intranasally with OVA in saline or saline vehicle on gestational day (GD) 15 of pregnancy (Fig. 1), which induced a significant acute Immunoglobulin E (IgE) response in maternal dams (t(4) = 2.20, p = 0.046; d = 0.74; Fig. 2A)
When offspring were assessed on postnatal day (PN)[4], we found that gestational allergic challenge significantly increased the number of mast cells in the female POA to male-typical levels (F(1,50) = 5.36; p = 0.025; η2p = 0.097; Fig. 2B)
Summary
The primary resident immune cells of the brain, are both targets and effectors of the sexual differentiation process. We have found that mast cells are more numerous and more activated within the neuropil of male rat POA during perinatal brain development, and that estradiol acts directly on these mast cells to stimulate the release of histamine[7] This histamine is in turn sufficient to activate neighboring microglia and set off the cascade of microglia activation and production of PGE2 that drives male-typical dendritic spine patterning in the POA. Pharmacologically activating mast cells leads to masculinization of dendritic spine patterning in the POA as well as the masculinization of copulatory behavior[7], suggesting that mast cell activation via non-pharmacological means could shift female sexual development toward a masculinized phenotype During this same critical period for brain sexual differentiation, perinatal exposure to many perturbations can independently alter the trajectory of brain development by activating immune cells in the brain. We report that allergic challenge of pregnant dams impacted the sexual differentiation of both the male and female POA, inducing masculinized brain and behavioral development in female offspring while dysmasculinizing brain and behavioral development in male offspring
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