A newly discovered brain cluster acts as an on and off switch for sex differences

Researchers have discovered a distinct cluster of brain cells in mice that behaves like an on and off switch for sex-specific social behaviors, turning on permanently in females but remaining quiet in adult males until they mate. This strictly binary brain feature offers fresh insight into how social and reproductive life stages physically alter the brain. The findings were recently published in the Proceedings of the National Academy of Sciences.

Male and female bodies show obvious physical differences in anatomy and hormones. Biologists refer to these sex-based physical differences as sexual dimorphism. In the brain, these physical distinctions are usually much less obvious and much harder to categorize.

Most brain differences between sexes appear as overlapping gradients rather than a strict presence or absence of a feature. A specific brain region might be slightly larger or have a few more connections in one sex, but the two groups still share many similarities. Truly binary differences in the brain are exceptionally rare.

Tamar Licht and Dan Rokni from the Hebrew University of Jerusalem wanted to find out if there were absolute differences in how brain cells behave at rest. They led a research team to look for neurons that were active in one sex but entirely quiet in the other.

The researchers focused on a region called the medial amygdala. This is a small structure deep inside the brain that helps animals process emotions, interpret social signals, and manage reproductive behaviors. It acts as a central hub for integrating smells and other sensory cues from the environment, allowing the animal to respond appropriately to rivals or potential mates.

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To see which cells were active, the team tracked specific genes that turn on immediately after a neuron fires. These genes act like a genetic signpost that indicates a cell has recently communicated with other cells. Biologists often use these genes to map which parts of the brain are working during a specific behavioral task.

The scientists used a genetic tracking tool to permanently tag active neurons in live mice. When the mice received a specific triggering drug, any brain cell firing at that exact moment became permanently labeled with a bright red fluorescent protein.

This technique allowed the team to look at slices of the brain under a microscope weeks later. They could easily spot which cells had been active during the tagging process, even if the cells had since gone quiet.

When examining the medial amygdala, Licht and her colleagues noticed a dense, circular cluster of glowing cells in the female mice. They named this cluster DIMPLE, partly because it resembled bilateral facial dimples when viewing the brain slices.

This glowing cluster appeared in every single female mouse they tested. In contrast, it was completely absent in almost one hundred adult virgin male mice. The cell activity represented a perfect binary split between the sexes.

“Most sex differences in the brain are subtle and distributed,” said Dr. Licht. “What surprised us here was the clarity of the signal. This is a discrete group of neurons that behaves almost like a biological switch, reflecting sex and social state in a very robust way.”

The researchers then tested whether removing adult reproductive hormones would change this pattern. They surgically removed the ovaries from female mice and the testes from male mice.

After waiting a month for hormone levels to drop, they tagged the brain cells again. The glowing DIMPLE cluster still appeared in all the females and none of the males, showing that baseline adult sex hormones do not maintain this difference.

Next, the team looked at younger mice to see when this difference develops. They tagged the brains of adolescent mice before the pups were separated from their mothers.

At this young age, the DIMPLE cluster was active in both males and females. The activity in males only faded away after they grew older and were separated from their family unit, suggesting the social environment influences the cells.

The team then investigated whether social and reproductive experiences could turn the cluster back on in adult males. They placed adult virgin males in cages with females and allowed them to mate.

When the researchers tagged the male brains right after mating, the DIMPLE cluster was suddenly glowing. The cells had turned back on after a single reproductive encounter.

The researchers ran several tests to see exactly what triggered this change in the males. Letting a male smell female bedding or interact with a female through a clear barrier did not activate the brain cells.

The cluster only turned on when the male had physical sexual contact with the female. The cells remained active as long as the male stayed in the cage with his pregnant partner.

If the male was removed from the cage a few days after mating, the cluster went dark again. The brain activity required the continuous presence of the female, showing that the cluster reacts dynamically to an animal’s current social status.

Because mating triggers the release of certain chemicals in the body, the researchers suspected a hormone might be responsible. They focused on prolactin, a hormone well known for stimulating milk production and encouraging parental behaviors.

In a normal physiological setting, prolactin levels naturally spike in male mice immediately after mating. When the scientists injected virgin male mice with prolactin, the DIMPLE cluster turned on without any female contact. This suggested that prolactin alone was capable of activating these specific brain cells.

The team then tried to block prolactin in mating males and in females to see if the cluster would turn off. They added a drug to the mice’s drinking water that stops the pituitary gland from releasing prolactin.

The drug failed to turn off the brain cluster in both groups. The researchers noted that either the drug did not lower the hormone enough, or other chemical signals are also involved in keeping the cells active.

These results provide a clear example of a biological switch, but the exact behavioral purpose of the DIMPLE cluster remains unproven. The researchers suspect it might help stop adult males from attacking newborn pups.

Male mice typically exhibit aggressive behavior toward infants, but this behavior shifts to protective parenting after they mate. The sudden activation of the DIMPLE cluster lines up perfectly with this behavioral change.

Testing this idea will be technically difficult. The cell cluster is located deep within the brain and lacks a unique molecular marker, making it incredibly hard to target with current laboratory tools.

Future studies will need to find ways to selectively turn these cells on and off to observe how the mice behave. Scientists also need to look into other hormones and genes to fully understand how this brain region operates.

For now, the discovery shows how deeply social experiences can rewire the male brain. It provides a new starting point for understanding how animals adapt to different stages of life.

The study, “A sexually dimorphic neuronal cluster in the mouse medial amygdala responds to male sexual status,” was authored by Tamar Licht, Adan Akarieh, Aya Dhamshy, Amit Zeisel, Osnat Ophir, and Dan Rokni.