Gender-specific behavior of mice guided by differences in brain gene activity | Information Center


An overview of neurological and psychiatric disorders

Some of the genes listed by the researchers are established risk factors for brain disorders that are more common in either sex. Of 207 genes already known to confer high risk for autism spectrum disorders, four times more common in men than in women, researchers identified 39 as being more active in the brain of either sex : 29 in males, 10 in females. They also identified genes linked to Alzheimer’s disease and multiple sclerosis, which tend to affect women more than men, as being more activated in female mice.

Researchers speculate that women need certain genes to work harder, and men need other genes to work harder – and that a mutation in a gene that needs high activation can do more less damage than a mutation in a gene that just sticks around.

“The frequency of migraines, seizures, and psychiatric disorders can vary across the menstrual cycle,” Shah said, “and our findings about differences in gene activation across the cycle suggest a biological basis for this change.”

Sex-typical social behaviors

Social behaviors typical of sex have been built into the brains of animals over millions of years of evolution.

Male mice, for example, quickly distinguish the sex of strangers who encroach on what they have considered their territory. If the intruder is another male, they attack him immediately. If it is a female, they, to put it politely, initiate a lightning courtship.

Female mice exhibit maternal rather than territorial aggression, attacking anything that threatens their young. They are much more likely than males to guard their young and retrieve those that stray. Their willingness to mate varies powerfully depending on the stage of their cycle.

“These primal behaviors are essential for survival and reproduction,” Shah said, “and they’re largely instinctual. If you need to learn how to mate or fight once the situation arises, it’s probably already too late.The evidence is pretty clear that the brain is not purely a blank slate just waiting to be shaped by environmental influences.

Previous attempts to find differences in gene activation between the brain cells of female and male rodents have only found around 100 – apparently too few, according to Shah’s group, to generate the many profound differences in behavior. known instinct.

“We ended up finding about 10 times more,” Shah said, “not to mention the 600 genes whose levels of activity in women vary by cycle stage. In total, that’s a solid 6% of genes of a mouse that are regulated by sex or cycle stage.

Needles in needles in a haystack

Shah compared the methods his team used to find needles in a haystack.

“The cells we have identified as mission-critical for these sex-typical behavioral displays of evaluation, courtship, mating, or hate probably represent less than 0.0005% of all brain cells in a mouse. “, did he declare. Determining what made these cells vibrate required separating them from surrounding cells and examining their genetic content, one cell at a time.

The researchers dramatically improved their outlook by focusing on rare but crucial estrogen-responsive cells, i.e. cells that have receptors for this major female sex hormone. (Estrogen is also present in men, although at lower levels). many mammals. In mice, ovulation and peak sexual receptivity, known as the estrus or heat stage, are marked by spikes in the levels of both hormones; the polar opposite, or diestrus stage, by dips in hormone levels.

These primary behaviors are essential for survival and reproduction.

Shah was able to purify the tissues of each of the four key brain structures in a way that enriched the resulting brain cell population for estrogen-responsive cells—the “needles,” in Shah’s analogy. By comparing males, females in estrus, and females in diestrus, the researchers discerned 1,415 genes with levels of activity that varied from group to group.

The estrogen-sensitive cells were far from alike. In a brain structure called the bed nucleus of the stria terminalis, they could be classified into 36 distinct cell types distinguished by the genes of each cell type that were particularly active in one or another group of mice. (The bed nucleus of the stria terminalis, or BNST, is also found in the human brain.)

Of these 36 types of estrogen-responsive cells in mice, scientists have shown that only one is critical to the ability of male mice to quickly recognize the sex of an unknown mouse and then behave characteristically towards it. .

Another brain structure, called the ventromedial hypothalamus, or VMH (also found in the human brain), contained 27 types of estrogen-responsive cells that differed in different patterns of gene activation. Eliminating the performance of just one of these cell types — but not the other 26 — turned women who would normally be sexually interested into those who rejected sexual advances even when in heat.

These BNST and VMH cell types that regulate male gender recognition and female sexual receptivity, respectively, were the “needles within needles” in the haystack that is the brain. What jobs each of the other 35 sex-hormone-responsive cell types in the BNST and the other 26 equivalent cell types in the VMH perform, whether sex-differentiated or not, are a mystery, Shah said.

‘The tip of the iceberg’

“That’s probably just the tip of the iceberg,” he said. “It’s likely that there are a lot more sex-differentiated features in these and other brain structures, if you know how to look for them.”

Stanford’s Office of Technology Licensing has filed a patent application on the intellectual property associated with the study.

Shah is a member of Stanford Bio-X and some Wu Tsai Institute for Neuroscience at Stanford and a member of the faculty of Stanford CHEM-H.

The study’s other co-authors at Stanford are researchers Sayaka Inoue, PhD, and Taehong Yang, PhD; postdoctoral fellows Daniel Bayless, PhD, and Nicole Leung, PhD; graduate students Adarsh ​​Tantry and Chung-ha Davis; undergraduate student Grace Wang; life science research professional Maricruz Alvarado; laboratory manager Charu Ramakrishnan; Lief Fenno, MD, PhD, professor of psychiatry and behavioral sciences; and Karl Deisseroth, MD, PhD, Professor of Bioengineering and Psychiatry and Behavioral Sciences and Professor DH Chen.

Researchers from Accent Therapeutics and Columbia University contributed to the work.

The study was sponsored by the National Institutes of Health (grants R01NS049488, R01NS083872, R01NS091144, F32MH125593, U01DA052783, R01HD104565, and R01MH123047), the National Science Foundation, the Paul and Daisy Soros Fellowship for New Americans Program, the AE Foundation, the Lucile Packard Foundation for Children’s Health, Chan-Zuckerberg Initiative, GG Gift Fund, Human Frontier Science Program, Bio-X Undergraduate Summer Research Program, and Stanford Vice Provost for Undergraduate Education.


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