Cell: Typical sexual behavior in male and female mice guided by differences in brain gene activity

These differences may be reflected in the brains of men and women, the researchers said

The scientists studied four tiny structures in the mouse brain known to program "rating, dating, mating and hatred" behaviors

By analyzing tissue extracted from these brain structures, the scientists found that more than 1,000 genes were significantly more active in the brains of males and females than those of the other sex

The findings, published online Jan.

"Using these genes as entry points, we have identified specific populations of brain cells that coordinate specific sex-typical behaviors," said the study's senior author Nirao Shah, Ph.

Dr.

The researchers also found more than 600 differences in the level of gene activation in women during different stages of the estrous cycle

"In these four tiny brain structures, it was completely surprising to find that the activity levels of hundreds of genes depended solely on a woman's cycle phase," said Shah, who has devoted his career to understanding how sex hormones regulate typical sexual behavior

The brain structures the researchers focused on are shared among mammals, including humans

"Mice are not people," Shah said

Gain insight into neurological and psychiatric disorders

Some of the genes the researchers cataloged are established risk factors for brain disorders that are more common in men and women

The researchers speculate that men need some genes to work harder, and women need other genes to work harder—mutations in genes that require a high level of activation could do more damage than mutations in genes that do nothing

"The frequency of migraines, seizures, and psychiatric disorders may vary across the menstrual cycle," Shah said.

sexual social behavior

Over millions of years of evolution, typical gendered social behaviors have been implanted in animal brains

For example, male mice were able to quickly distinguish the gender of strangers who invaded their territory

The female mice displayed maternal rather than territorial aggression, attacking anything that threatened the pups

"These primitive behaviors are essential for survival and reproduction," Shah said, "and they are largely instinctive
.
If you need to learn how to mate or fight once the situation arises, it may be too late
.
The evidence is overwhelming.
Clearly, the brain is not just a blank slate waiting to be shaped by environmental influences
.
"

Previous attempts to find differences in gene activation between male and female rodent brain cells have found only about 100—and Shah's team believes that for many of the profound differences in known instinctual behavior, This seems too little
.

"We ended up finding about 10 times the number," Shah said, "not to mention that the activity level of 600 genes in women varies with the menstrual cycle
.
" Overall, these genes add up to 6 percent of mouse genes are regulated by sex or menstrual cycle
.
"

Looking for a needle in a haystack

Shah likens the method his team uses to finding a needle in a haystack
.

"We found that key cells associated with these typical sex evaluation, dating, mating or aversive behaviors may make up less than 0.
0005 percent of all cells in the mouse brain," he said
.
To determine what makes these cells tick To rattle, they need to be isolated from surrounding cells and examined individually for their genetic content
.

The researchers' focus on rare but vital cells that respond to estrogen has greatly improved their prospects
.
Estrogen refers to cells that have receptors for this primary female hormone
.
(Estrogen is also present in men, albeit in lower amounts
.
) Women's levels of estrogen and another hormone, progesterone, fluctuate roughly every month, like a full moon -- many mammals female behavior as well
.
In mice, both ovulation and maximal sexual receptivity, what we call estrus or febrile phase, are marked by peaks in the levels of both hormones; the trough of hormone levels is the polar opposite phase, or estrus period
.

Shah was able to distill tissue from four key brain structures, thereby enriching the number of brain cells that produce estrogen-responsive cells—Shah's analogy for "needles
.
" By comparing men in heat, women and women in menopause, the researchers found that 1,415 genes had different levels of activity across groups
.

The two types of estrogen-responsive cells are distinct
.
In a brain structure called the stria terminalis bed nucleus, they can be divided into 36 different cell types, each with genes that are particularly active in one or the other group of mice
.
(The nucleus of the bed of stria terminalis, or BNST for short, is also present in the human brain
.
)

Of the 36 types of estrogen-responsive cells in the mice, the scientists found that only one type of cell was critical to the male mice's ability to quickly identify the gender of an unfamiliar mouse and exhibit characteristic behaviors
.

Another brain structure, called the ventromedial hypothalamus, or VMH (also found in the human brain), contains 27 estrogen-responsive cell types that can be distinguished by distinct patterns of gene activation
.
Disrupting the performance of just one of these cells—and not the other 26—turned female cells that are normally sexually interested into female cells that reject sexual assault even in estrus
.

Those BNST and VMH cell types that regulate male gender cognition and female sexual receptivity, respectively, are like needles in a haystack, the brain
.
What tasks the other 35 sex hormone-responsive cells in the BNST and the other 26 equivalent cells in the VMH are performing, regardless of gender differentiation, Shah said
.

"tip of the iceberg"

"This may be just the tip of the iceberg," he said
.
"If you know how to look, you might find more sex-differentiated traits in these and other brain structures
.
"

Stanford University's Office of Technology Licensing has applied for a patent on the intellectual property related to this research
.

Shah is a member of Stanford Bio-X and the Wu Tsai Neuroscience Institute and an investigator at Stanford ChEM-H
.

Journal Reference :

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   Knoedler, Sayaka Inoue, Daniel W.
   Bayless, Taehong Yang, Adarsh ​​Tantry, Chung-ha Davis, Nicole Y.
   Leung, Srinivas Parthasarathy, Grace Wang, Maricruz Alvarado, Abbas H.
   Rizvi, Lief E.
   Fenno, Charu Ramakrishnan , Karl Deisseroth, Nirao M.
   Shah.
   A functional cellular framework for sex and estrous cycle-dependent gene expression and behavior .
   Cell , 2022; DOI: 10.
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   2021.
   12.
   031