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Developmental biology - Brain Development

Brain Immune Cells Influence Sexual Behavior

A surprising new explanation for how young brains are shaped for adult sexual behavior...

Immune cells usually ignored by neuroscientists appear to play an important role in determining whether an animal's sexual behavior will be more typical of a male or female. The study, which was done in rats, was led by Kathryn Lenz an assistant professor of psychology and neuroscience at The Ohio State University and appears in the Journal of Neuroscience.

To better understand the role of mast cells in sexual behavior, Lenz and her colleagues silenced mast cells in male fetal rats to observe their development later in the rat's life. Researchers paired one of these males with a female receptive to mating and watched to see whether the male sexually pursued the female - basically, whether he chased her and mounted her.

Experimental males were far less interested than typical males, acting almost like females.

Researchers also manipulated female newborn rats, activating their mast cells with a stimulating chemical - and as adults, they acted like males. Observes Lenz, in Ohio State's Institute for Behavioral Medicine Research, "Females appear to be strongly motivated to try to engage in male sexual behavior with other females."
Researchers also found that estrogen (which plays a major role in development of masculine traits in rats) activates mast cells in the brain and these mast cells drive the animal's sexual development.

Though scientists know that sex differences are programmed by hormones during early development, they had limited information about cell-level changes that contribute to the manner in which brain and behavior are formed. Lenz: "We're really interested in the fundamental mechanisms that drive brain development and sex-specific brain development. The study found that mast cells - immune cells involved in allergic responses - play a key role."
If human development mirrors what was seen in this animal study, it's possible that relatively minor influences - such as an allergic reaction, injury or inflammation during pregnancy - could steer how sexual behavior develops in offspring. It's even conceivable taking antihistamines or pain relievers during pregnancy could play a role! According to Lenz, this discovery could help explain risks for psychiatric and neurological disorders that are more common in males, including autism.

"These mast cells in the brain appear crucial for life-long brain development, even though there are relatively few of them, and this should really open our eyes to the potential role of immune cells in the human brain," Lenz adds. Her study focused on the pre-optic area of the brain, which is part of the hypothalamus. According to Lenz: "This is the most sexually dynamic area of the brain - we know that it's highly important for male-type reproductive and social behaviors such as mounting - as well as for initiating maternal behavior in female animals."

In a previous study by the group it was uncovered how a type of brain cell, microglia, also helps direct sexual behavior. In the new study, mast cells were found to activate microglia cells. Lenz: "This new mast cell discovery is really one of those "happy" accidents of science."

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, while 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.

Significance Statement
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.

Authors: Kathryn M. Lenz, Lindsay A. Pickett, Christopher L. Wright, Katherine T. Davis, Aarohi Joshi and Margaret M. McCarthy. Researchers from the University of Maryland School of Medicine also worked on the study.

The authors declare no competing financial interests.

We wish to acknowledge Shyama Patel from the Weill Cornell Medical College for assistance and training in brain mast cell isolations. We are also grateful to The Ohio State University Targeted Metabolomics Laboratory (metabolomics.osu.edu) for access to their LC-MS/MS equipment funded by the Translational Plant Sciences Targeted Investment in Excellence (TIE) and for performing LC-MS/MS analysis of histamine turnover in brain tissue. This work was supported by grant R01 MH052716 to MMM, F31NS093947 to LAP, and F32NS076327, R21MH105826 and The Ohio State University Startup Funds to KML. The authors have no conflicts of interest to declare.

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Aug 21, 2018   Fetal Timeline   Maternal Timeline   News   News Archive

New study finds that mast cells - immune cells involved in allergic responses - play a key role directing brain sexual behavior. Image Credit: Professional Institute of Medical Excellence

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