Summary: Researchers report that mast cells—immune cells often overlooked in neuroscience—play a critical role in shaping whether an animal’s sexual behavior develops with more male-typical or female-typical patterns. Chemically activating mast cells in newborn female rats produced adult behavior more characteristic of males.
Source: Ohio State University.
Immune cells in the developing brain influence later sexual behavior, researchers report.
New research led by Kathryn Lenz, an assistant professor of psychology and neuroscience at Ohio State University, identifies mast cells as key players in organizing sex-specific brain development and adult sexual behavior. The study, conducted in rats, appears in the Journal of Neuroscience.
Historically, sex differences in brain and behavior have been attributed primarily to hormones acting during early development, but the specific cellular mechanisms have been unclear. This study shows that mast cells—immune cells usually associated with allergic responses—respond to estradiol (a form of estrogen) in the brain and, in turn, trigger a cascade of events that direct male-typical neural patterning and behavior.
To test the role of mast cells, the researchers used two complementary approaches. First, they inhibited mast cells in male fetal rats during the critical developmental window. Those males, when paired with a hormonally receptive female as adults, showed markedly reduced male-typical sexual behaviors such as chasing and mounting; their behavior resembled that of females more than typical males.
Second, the team activated mast cells in newborn female rats using a chemical stimulus. As adults, these females displayed behavior more typical of males, despite lacking male reproductive anatomy. “It’s striking to see females strongly motivated to perform male-type sexual behaviors,” Lenz said. “They don’t have the physical anatomy, but their behavior is clearly shifted.”
Cellular analysis revealed how this change occurs. Newborn males normally have more mast cells and a higher degree of mast cell activation in the preoptic area (POA) of the hypothalamus—a brain region essential for male copulatory and related social behaviors. Exposure of newborn females to a masculinizing dose of estradiol increased mast cell numbers and caused those cells to release histamine. The released histamine then stimulated microglia, another type of brain immune cell, to produce prostaglandins that drive male-typical synaptic patterning in the POA.
Previous work from the lab had established a role for microglia in sexual differentiation of the brain. The new findings place mast cells upstream of microglia in this pathway, identifying mast cells as a primary non-neuronal mediator by which estradiol sculpts sex-specific brain circuits.
These results suggest that relatively modest immune-related events during pregnancy—such as inflammation, allergic reactions, or injury—could influence the activity of mast cells in the developing brain and thereby bias sexual differentiation. Lenz noted it is conceivable that common medications taken during pregnancy that affect immune signaling, such as antihistamines or certain pain relievers, could have some impact, though direct evidence in humans is not established.
The discovery may also shed light on why some neurodevelopmental and psychiatric disorders show sex differences in prevalence. Because mast cells and immune signaling influence early brain development, differences in these pathways might help explain male-biased vulnerability in conditions such as autism spectrum disorder, though further research is needed.
“Mast cells are relatively sparse in the brain, yet they appear to be crucial for long-term, sex-specific brain development,” Lenz said. “This finding broadens our view of how immune cells interact with neurons and microglia to shape behavior and highlights the need to study multiple cell types when investigating brain development.”
The study specifically focused on the preoptic area (POA) of the hypothalamus because this region is highly involved in male reproductive behaviors such as mounting and in initiating maternal behaviors in females. The researchers documented both behavioral changes and the underlying cellular mechanisms connecting estradiol, mast cell activation, histamine release, microglial activation, prostaglandin production, and male-typical synaptic formation.
Source: Kathryn Lenz – Ohio State University
Publisher: Organized by Neuroscience News.
Image Source: Image credited to Ohio State University.
Original Research: “Mast Cells in the Developing Brain Determine Adult Sexual Behavior” by Kathryn M. Lenz et al., Journal of Neuroscience (published August 7, 2018).
DOI: 10.1523/JNEUROSCI.1176-18.2018
Abstract
Mast Cells in the Developing Brain Determine Adult Sexual Behavior
Many sex differences in brain structure and behavior are programmed by gonadal hormones during development, yet the cellular mechanisms are not fully understood. This study identifies mast cells—immune cells normally linked to allergic reactions—as primary targets of the masculinizing hormone estradiol and as critical mediators of brain sexual differentiation. Newborn male rats have more mast cells and greater mast cell activation in the preoptic area (POA) during the critical period for sexual differentiation. Stabilizing mast cells in males reduced masculinization of POA neuronal and microglial morphology and blunted adult male-typical sexual behavior. Conversely, activating mast cells in newborn females induced masculinization even though females naturally have fewer mast cells. Treating newborn females with estradiol increased mast cell numbers and triggered histamine release from these cells; histamine then stimulated microglia to release prostaglandins, which promoted male-typical synaptic patterning. These results reveal a novel, non-neuronal mechanism that contributes to sex differences in the brain and to motivated behaviors.
Significance Statement: Immune-derived mast cells are direct targets of estradiol and act as primary mediators of sexual differentiation in the developing brain. This work highlights a previously unrecognized non-neuronal source of brain sex differences and associated behaviors.