The University of Tokyo identifies brain mechanism underlying aversion toward familiar individuals in mice: A step forward in understanding of social relationships

In human society, it is not uncommon to grow to dislike someone who was once close to you after a negative experience. What happens in the brain during such moments, and how does the brain update its evaluation of familiar individuals? Research addressing these questions has now been reported by a team led by Professor Teruhiro Okuyama of the University of Tokyo, whose work is well known in the field of neuroscience. Using mice, the group revealed that the mechanism by which we come to dislike someone involves the strengthening of neural circuit connections between the "hippocampus," which stores memories, and the "amygdala," which regulates emotions. If this can be applied to humans, it could lead to research into treatments for disorders related to interpersonal relationships, such as depression.

Okuyama has previously elucidated how the brain remembers other individuals and how it generates empathy toward them. This latest study demonstrates "how emotional evaluations of known individuals are updated through experience," and is drawing attention as a breakthrough that advances neuroscience research to understand human relationships. The paper was published in the July 10 issue of Science, a U.S. scientific journal.

Utilizing "optogenetics" technology

The study was conducted by a team including Professor Teruhiro Okuyama and Research Fellow Mu-Yun Wang (at the time of the research) from the University of Tokyo's Institute for Quantitative Biosciences, along with graduate student Narutoshi Suto and other researchers from the Graduate School of Medicine. The researchers first allowed a test mouse to interact with two other mice so that they became familiar with one another. This experience led to the formation of social memories, memories of other individuals, which were stored in a region of the test mouse's hippocampus.

Next, the researchers induced aggressive behavior in one of the mice by manipulating the activity of specific neurons in a region of the hypothalamus. This allowed them to turn one of the two familiar mice into an aversive social partner and observe how the test mouse responded.

After repeatedly being attacked by the now aggressive mouse, the test mouse began to avoid it. The researchers interpreted this behavioral change as evidence that the brain had updated the "emotional value" assigned to that specific individual.

After confirming the behavioral change, Okuyama and colleagues employed optogenetics to investigate the underlying neural mechanism. They performed experiments that either weakened the connection between the ventral CA1 region of the hippocampus, which stores memories of the aggressive mouse, and the amygdala, or suppressed activity within the circuit itself. Optogenetics is a technique in which neurons are engineered to express light-sensitive proteins, allowing their activity to be controlled with specific wavelengths of light.

The researchers found that strengthening the connection between the ventral CA1 and the amygdala caused the test mouse to avoid the aggressive individual, whereas weakening the connection abolished the avoidance behavior. The results suggest that feelings of aversion are regulated by the strength of the connection between hippocampal neurons that represent a specific individual and amygdala neurons involved in fear-related responses.

Potential new treatment strategies for Depression

According to Okuyama, the brain contains a region known as the nucleus accumbens, which plays a key role in motivation and behavior. Neural circuits also connect the amygdala to this region. Emotional evaluations of specific individuals, such as whether they are perceived positively or negatively, are thought to be updated through networks linking the ventral CA1 region of the hippocampus to the amygdala and, in turn, the amygdala to the nucleus accumbens.

In a separate experiment, the researchers used optogenetics to reactivate the memory of a particular mouse while simultaneously administering mild electric shocks to the test mouse, creating a fear response. Because neural connections are strengthened when two stimuli occur at the same time, this procedure reinforced the circuit linking ventral CA1 neurons that encoded memories of the other mouse with amygdala neurons involved in fear responses.

As a result, the test mouse began to avoid another mouse that had never attacked it and toward which it had previously shown no aversion. The findings indicate that linking memories of a familiar individual with fear-related neural activity can artificially alter emotional responses toward that individual by strengthening the underlying neural circuitry.

Okuyama noted that several established methods are already used to induce depression-like states in mice for research purposes. These include repeated social defeat, exposure to aggression through a wire barrier, and repeated encounters with an individual that had previously attacked the animal. While such experiments would be ethically unacceptable in humans, previous studies have reported elevated activity in both the amygdala and the nucleus accumbens in patients with depression.

According to Okuyama, the team's approach created an experimental situation in which a previously familiar companion suddenly became aggressive, establishing a new behavioral model for investigating how emotions toward specific individuals change. "We hope these findings will eventually lead to new treatment strategies for social anxiety disorder (SAD) and depression by targeting the neural circuit linking the ventral CA1 region of the hippocampus, the amygdala, and the nucleus accumbens," he said.

A decade of accumulated "research on the memories of others"

"My research began when I was a graduate student," Okuyama said at a press conference announcing the latest research findings. As a graduate student at the University of Tokyo, he discovered that female medaka fish tend to prefer familiar males around them as mating partners. This was published as a paper "A neural mechanism underlying mating preferences for familiar individuals in medaka fish" in Science in 2014.

Okuyama moved to the United States in 2013 after finishing writing this paper without waiting for its publication. He joined the laboratory of Dr. Susumu Tonegawa, a professor at the Massachusetts Institute of Technology (MIT) and Nobel laureate in Physiology or Medicine, who passed away on July 11 at the age of 86. There, Okuyama continued his research on the mechanism of memories of others and, together with Tonegawa, elucidated that "memories of others are stored in the hippocampal ventral CA1." The paper was published in Science in September 2016.

In 2017, he returned to the Institute of Molecular and Cellular Biosciences at the University of Tokyo (current Institute for Quantitative Biosciences). In 2023, he discovered neurons that hold information about both the self and others in the "prefrontal cortex" of the mouse brain, elucidating the brain mechanism underlying empathy.

In July 2024, he found that symptoms of autism spectrum disorder (ASD) stem from abnormalities in specific regions of the hippocampus and published his findings in Nature Communications, a British scientific journal. In August 2025, he also elucidated that memories of others involve combined action of different neurons—some responding to information of the other (individual) itself, some responding to information of attributes such as gender and lineage—and the paper was published in Science.

Brain science unravels "human connections"

In this way, Okuyama and his young colleagues have accumulated research findings centered on the concept of "memories of others (social memory)" for over 10 years. The latest research findings present a new perspective that memories of others and emotions, which are input into different areas of the brain, are refreshed and updated through neural circuits.

Although their research findings are based on animal experiments using mice, the research subject has evolved from "the brain that remembers others" to "the brain that develops likes and dislikes of others." This is the first time their research relates to the neural circuit network. The focus is clearly on "connections with people" and "human relationships."

In the future, advances in brain science are expected to contribute to solutions for various "mental issues" arising from the increasing complexity of society—ranging from basic human relationships such as friendship, romance, and family ties to conditions like ASD, PTSD (post-traumatic stress disorder), social anxiety disorder, and depression.

Carrying on Dr. Tonegawa's legacy

It was announced on July 15 that Tonegawa, Professor Okuyama's "mentor" who not only pioneered immunology, the field for which he was awarded the Nobel Prize, but also led global neuroscience research, had passed away. MIT posted a comment on its website stating, "We lost a giant. His scientific legacy will continue to shape neuroscience for years to come."

Upon hearing the news of his mentor's death, Okuyama said, "Professor Tonegawa taught me how to live as a scientist. I am truly grateful to him for making me who I am today. I hope to continue my research without ever losing my curiosity about biological phenomena, just like him."

The path pioneered by Tonegawa is certainly being carried on by young researchers.