Endocrine Abstracts (2016) 42 IL2 | DOI: 10.1530/endoabs.42.IL2

Neuro-inflammatory origins of the sexual differentiation of the brain

Christopher Wright


Program in Neuroscience, Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland, USA


During development, surges in testosterone (T) organize the bipotential anlage of the periphery into the male phenotype. The same T surges also act on the preoptic area (POA) and hypothalamus of the brain to prevent the expression of female sex behavior and promote male behavior in adulthood so that the behavioral and anatomical phenotypes match. In the rodent, T actually serves as a prohormone. Once in the brain, T is aromatized to the quintessential female hormone estradiol (E2) to initiate a two-fold increase in dendritic spines, post-synaptic specializations through which an estimated 95% of the excitatory neurotransmission flow. In adulthood, glutamate and dopamine excitatory neurotransmission in the POA are necessary for the ongoing expression of male behavior. The question of what cellular processes trigger this spine formation continues to be surprising. In the periphery, injury and innate immune responses recruit the prostaglandin PGE2 to mediate inflammatory and febrile responses by increasing the levels of PGE2’s synthesizing enzymes cyclooxygenase-1 & -2 (COX-1 & -2). During the masculinization of the brain and behavior, perinatal exposure to E2 increases COX-1 & -2 two-fold and PGE2 seven-fold in the POA. PGE2 then mediates the cellular process that forms spines and organizes adult male sex behavior. In fact, as little as one post-natal dose of the labile PGE2 can permanently masculinize a female’s adult behavior. Co-administration of the COX inhibitor indomethacin with PGE2 can prevent the behavioral masculinization. Given that PGE2 is involved in a feed-forward mechanism in the brain and given PGE2’s peripheral role in inflammation and innate immunity, my colleagues asked whether masculinization could recruit the brain’s own resident innate immune cells, microglia. Normally, microglia are implicated in neurodevelopment for their role in cleaning up or phagocytosing errant synapses and cells but they are not known for being in a pro-inflammatory state, at least not at this age and not without injury. My colleagues found that POA microglia change in numbers and morphology across sexes and in response to exposure to hormones post-natally. Males have more ameboid microglia, which are typically known as being their pro-inflammatory state. Females in contrast have more ramified microglia, known for being quiescent sentinels. Neonatal treatment with a microglial inhibitor, minocycline, kept them quiescent, and prevented the formation of spines and the expression of adult male behavior. Post-natal minocycline administration also prevented the increases in PGE2 that would otherwise have been triggered by hormone exposure. This suggests that the ameboid microglia are the source of the feed-forward mechanism. Thus, immune cells and inflammation are crucial for the endocrine system’s restructuring of brain circuitry during development.

DOI: 10.1530/endoabs.42.IL2

Biographical details: Christopher Wright obtained his Ph.D. at the University of Maryland, School of Medicine in 2009. After a brief Post-Doctoral Fellowship at the Johns Hopkins University, School of Medicine, he served as Visiting Assistant Professor at Loyola University from 2009 to 2011. Since 2011, he has worked in the laboratory of Margaret McCarthy in the Department of Pharmacology at the University of Maryland, School of Medicine as a Post-doctoral Fellow and Research Associate. The lab’s research focuses on the influence of hormones in the developing brain, particularly the cellular mechanisms differentiating the brain into the male and female behavioral phenotypes. He has a particular interest in the role of inflammation and prostaglandin-E2 in affecting neuronal morphology, the organization of sexual behavior by the preoptic area of the brain, and the role of the cerebellum in affecting social behavior. He also received a New Investigator Award from the Organization for the Study of Sex Differences (2008) in addition to awards related to receiving his J.D. from the University of Maryland, Carey School of Law in 2014.

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