All mice prefer the company of females until they sense imminent danger

Humans owe a great deal to mice. Despite their seemingly vast differences, these small creatures share 85% of their genes with us, many of which perform essential functions inherited from a common ancestor that lived 125 million years ago. This genetic connection has enabled drugs for conditions like cancer and diabetes to be tested on rodents before going on to cure millions of people. However, their use as models for understanding neurological disorders such as Alzheimer’s or autism has been more controversial, as these conditions manifest quite differently in mice compared to humans. Similarly, using rodents to investigate the genetic foundations of human behavior has also been questioned.

On Thursday, the prestigious journal Science published a study on this type of research, which explored the social preferences of mice depending on the situation. Led by Changhe Wang from Jiaotong University in Xi’an, China, the study observed mice in normal conditions before putting them on alert by spraying their cages with trimethylthiazoline, a compound found in the feces and urine of predators such as foxes. Under normal circumstances, mice — both male and female — typically seek out the company of female mice. However, when they sensed danger, both sexes gravitated toward the males.

In addition to observing the change in social preferences, the researchers identified the neural circuits that underlie these shifts and found that they function differently in males and females. In both sexes, dopaminergic neurons — which regulate learning, pleasure, and emotions — activate in distinct ways depending on the priorities of the moment.

In males, when the situation is calm, these neurons release dopamine in the nucleus accumbens, and the mice to seek out females to copulate and fulfill a primary goal such as reproducing. However, when a predator is sensed nearby, an increased release of dopamine towards the medial preoptic area shifts their priorities towards survival. As a result, males seek out other males in the hopes of gaining protection.

In females, it is the activation of dopaminergic neurons that changes their responses. When no danger is perceived, the neurons fire in rapid bursts towards the nucleus accumbens, and they seek out the company of other females. However, in the presence of fear, the activation becomes more continuous, and their preference changes to males. The researchers suggest that females’ preference for same-sex company in non-threatening situations may stem from their more passive role in partner selection. This preference for female company could offer protection and social support, improving health and chances of survival, as well as a less confrontational environment than interacting with males. The scientists also demonstrated that they could manipulate the animal’s social preferences using drugs or light to alter neuron activation.

While acknowledging the differences between humans and mice, the study’s authors argue that the analogies are valid. “I think humans have similar preferences,” says Wang. “This is why it’s much easier for girls to make close friends, while boys tend to form deeper friendships by fighting or working together towards shared goals.”

Wang argues that the study sheds light on the central role of the dopamine system — the brain’s nerve center for reward, emotion, and motivation — in shaping sex preferences. According to the researcher, the findings also define the distinct mechanisms in males and females that explain sociosexual preference. This work “provides a new conceptual framework that explains how social decisions can be refined in a convergent manner by innate needs and the external environmental context to achieve the maximum benefits of social activity,” says Wang.

Felix Leroy, a researcher at the Institute of Neurosciences in Alicante in Spain, finds the study’s exploration of how dopamine regulates shifts in social preferences intriguing. He highlights how fundamental drives, such as the desire to reproduce, can be put on hold when more immediate threats arise.

However, Leroy, who was not involved in the research, warns: “We must be careful with anthropomorphization, with interpreting what mice do as if they were humans.” “In mice, females are more passive in their search for sex, but we are not going to assume that men only interact with women with the intention of reproducing,” he says.

Leroy has conducted research with mice to understand the neural circuits that govern social preferences for unfamiliar individuals versus familiar ones. In the early days of life, hormonal regulation drives offspring to prefer interacting with familiar mice, a behavior that enhances their chances of survival. However, as adults, mice must overcome this phase to expand their social networks. Leroy suggests that by uncovering the circuits controlling social preferences and identifying the molecular changes that encourage interaction with strangers or avoidance, it may become possible to develop drugs for individuals struggling with social anxiety or disorders like autism.

Wang also highlights the therapeutic potential of the findings. “Given the critical role of dopamine transmission in reward and emotion, this work also sheds new light on the development of gender-specific treatments or therapies for psychiatric disorders that show sex differences in their susceptibility [such as schizophrenia or depression],” he explains.

The distance between humans and mice — those 125 million years that separate us from a common ancestor — is both vast and narrow. It may seem trivial to believe that these small, seemingly insignificant rodents could offer insights into the nature of beings capable of sending rockets to the Moon. However, the persistent presence of certain deeply ingrained and seemingly irrational behaviors suggests that we may not have risen as far as we like to think.

“It was once believed that changing the environment or education could eliminate racism, but that hasn’t happened,” reflects Leroy.

In their biological simplicity, mice offer a humbling lesson: despite our towering technological and cultural achievements, we remain profoundly shaped by the same biological mechanisms that have ensured the survival of our genes for hundreds of millions of years.

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