How the brain drives mice to seek social contact

In efforts to understand the neural basis for loneliness — something most people have experienced during the COVID-19 pandemic — researchers at Japan’s RIKEN Center for Brain Science (CBS) have found a molecular indicator and regulator of social isolation in female mice. They found that social contact-seeking behaviour in mice is driven by the peptide amylin in the medial preoptic area (MPOA) of the forebrain, and that being alone decreases the amount of amylin in this brain region.

Previous research by the CBS group has shown that in mammals, the drive for maternal care also comes from the MPOA; specifically, the amylin-responsive neurons in the central MPOA (cMPOA) are required for maternal motivation. Yet the initial connection between amylin and loneliness was inadvertent, with research leader Kumi Kuroda revealing, “While studying amylin signalling in maternal care, we noticed that the amount of amylin in the cMPOA depended on the housing conditions of the mice.”

That observation led the researchers to examine behavioural and neural responses to social isolation and social reunion in female mice. Their results were published in the journal Nature Communications.

The researchers found that six days of isolation led to an almost complete disappearance of amylin, which returned to normal two weeks after the mice were reunited with their cage-mates. This was true even when the mice were separated from cage mates by a windowed divider within the same cage, indicating that female mice needed to make free physical contact with other mice to maintain amylin expression in the cMPOA.

The researchers then carefully eliminated the possibility that amylin levels were regulated by other factors such as boredom, general stress, physical contact with humans, or contact with other mice for defensive purposes. They also found that amylin-expressing neurons in the cMPOA are deactivated upon isolation, and activated upon reunion.

Top: The three housing conditions — in a group, isolated for six days, and six days after being reunited with the group. Bottom: Amylin (blue stains) in the medial preoptic area disappears after being isolated and returns after being reunited with the group.

When female mice were separated from their cage-mates by the windowed divider, they first bit the bars of the divider vigorously. This biting behaviour was only observed when other mice were across the divider, and thus the mice seemed like they were trying to break the window and reunite with the other mice. This contact-seeking behaviour was increased by specifically activating amylin-expressing neurons using chemogenetics, a biotechnology that allows artificial control of neuronal activity. In contrast, contact-seeking behaviour decreased after knocking down amylin in the cMPOA.

“Among other reported molecules, amylin is the one that responds the most to isolation and reunion, and itself facilitates contact-seeking behaviours,” Kuroda said. “With all these results, we became confident that amylin is the major player in the brain that is needed for sensing and seeking social contacts.”

Since Darwin’s time, scientists have postulated that social affiliation among adults originally evolved from parental care. This study provides molecular evidence that supports this notion.

“Both parental care and female–female social contact depend on amylin and augment its expression,” Kuroda said. “This synergy might facilitate cooperative parenting, in which multiple females care for young together, as is observed in mice and humans.”

Top image caption: After somatic isolation from the group by the windowed divider, the mouse on the left exhibits contact-seeking behaviour. This behaviour increased when amylin neurons were chemogenetically activated and decreased in amylin knockdown mice.

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