Mast Cells in the Developing Brain Determine Adult Sexual Behavior

Abstract

Many sex differences in brain and behavior are programmed during development by gonadal hormones, but the cellular mechanisms are incompletely understood. We found that immune-system-derived mast cells are a primary target for the masculinizing hormone estradiol and that mast cells are in turn primary mediators of brain sexual differentiation. Newborn male rats had greater numbers and more activated mast cells in the preoptic area (POA), a brain region essential for male copulatory behavior, than female littermates during the critical period for sexual differentiation. Inhibiting mast cells with a stabilizing agent blunted the masculinization of both POA neuronal and microglial morphology and adult sex behavior, whereas activating mast cells in females, even though fewer in number, induced masculinization. Treatment of newborn females with a masculinizing dose of estradiol increased mast cell number and induced mast cells to release histamine, which then stimulated microglia to release prostaglandins and thereby induced male-typical synaptic patterning. These findings identify a novel non-neuronal origin of brain sex differences and resulting motivated behaviors. We found that immune-system-derived mast cells are a primary target for the masculinizing hormone estradiol and that mast cells are in turn primary mediators of brain sexual differentiation. These findings identify a novel non-neuronal origin of brain sex differences and resulting motivated behaviors.

Microglia and sexual differentiation of the developing brain: A focus on extrinsic factors

“…The response to local cues is exemplified in the developing preoptic area (POA) where, in males, testosterone is locally aromatized to estradiol and causes POA‐resident mast cells—another immune cell type—to degranulate and release histamine (Lenz et al, ). Estradiol‐induced histamine release occurs during the critical period and is essential for appropriate sexual differentiation of the developing POA.…”

Neuroimmunology of the female brain across the lifespan: Plasticity to psychopathology

“…Higher rates of developmental cell survival in the AVPV underlie this sex difference (Waters and Simerly, 2009), and the neuroimmune mediators, tumor necrosis factor (TNF) receptor 2 as well as nuclear factor κ-B (NFκB) protect neurons from cell death to lead to this brain region developing in a female-typical manner (Krishnan et al, 2009). In the nearby medial preoptic area (POA) of the hypothalamus, females have fewer activated microglia (microglia that are hypo-ramified, phagocytic, and inflammatory (Davalos et al, 2005;Nimmerjahn et al, 2005;Sominsky et al, 2018)) and mast cells than males, and active signaling by neuroimmune cells contributes to brain masculinization (Lenz et al, 2013;Lenz et al, 2018). But it is entirely possible that these cells are also crucial for the feminization process, given that the POA regulates maternal behavior and female hormonal cycling.…”

Sexually Dimorphic Formation of the Preoptic Area and the Bed Nucleus of the Stria Terminalis by Neuroestrogens

“…release, which then stimulates microglia in the POA to release prostaglandin E2, which triggers POA neurons to increase dendritic spine synapses via induction of glutamate receptor signaling (Wright et al, 2008;Wright and McCarthy, 2009;Lenz et al, 2011Lenz et al, , 2013Lenz et al, , 2018. Thus, microglia and mast cells have critical roles in the masculinization of dendritic spine patterning.…”

“…The male-biased sex difference in ameboid microglia is regulated by neuroestrogens of testicular origin, because treatment with estradiol increased ameboid microglia in the POA of postnatal females (Lenz et al, 2013). The male POA has more activated mast cells than the female POA in the perinatal period, and approximately half of the mast cells in both sexes express ERα (Lenz et al, 2018). Additionally, astrocytes in the POA of postnatal rats exhibit a sex difference in morphology: astrocytes in males have longer and more primary processes, and the astrocyte morphology is masculinized by neuroestrogens in the postnatal period (Amateau and McCarthy, 2002b).…”