As any dieter can relate to, when an animal gets too little food or water, it typically makes up for it when the next chance to eat or drink arises. This kind of compensation also applies to social interaction—and is underpinned by a similar brain mechanism, according to a study published today in Nature.
“People thought there must be something like this, but no one had found it,” says Steve Chang, associate professor of psychology and neuroscience at Yale University, who was not involved in the work.
The idea that people and other animals balance their social needs in the same way they regulate hunger and thirst gained traction in recent years, particularly after the COVID-19 pandemic highlighted the negative effects of social distancing; chronic loneliness tracks with long-term brain changes. But the mechanisms by which an animal adjusts its sociability after a brief bout of solitude were unclear, says Catherine Dulac, professor of molecular and cellular biology at Harvard University and investigator at the Howards Hughes Medical Institute, who led the study.
“Some type of ‘counter’ tells you how much you need to restore either your metabolic need or your sleep or your water intake,” Dulac says. The counter for hunger, for example, consists of dueling sets of hypothalamic neurons, one of which senses food intake and the other deprivation.
In the new study, Dulac and her colleagues have identified a similar counter for social homeostasis: a hypothalamic circuit formed by one group of neurons that detects isolation and another that responds to reunion. The reunion neurons activate after solitary mice experience touch, lessening the animals’ need for companionship, the team discovered.
The findings highlight the importance of touch in fulfilling the animals’ social needs, Dulac says. “Animals need to perceive others through touch, and that tells them whether they are alone or together,” she says. “We think that touch is also very relevant to social society.”
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emale FVB/NJ mice and C57BL/6J mice, two widely used strains, show an increase in social-interaction time—or a “rebound”—after a period of isolation, Dulac and her colleagues discovered. That suggested that, just as in hunger, thirst and sleep, part of the animal’s brain must monitor its social needs and work to restore the balance. The team did not study male mice because of the competing drives of mating and aggression that arise when the males socialize with females and other males, she says.A population of neurons in the medial preoptic nucleus (MPN) of the hypothalamus activates soon after an animal is left alone and becomes silent when the animal is reunited with other mice, the team found. Optogenetically activating those neurons in socially satiated mice resulted in an increase in the animals’ time spent socializing with others, whereas inactivating them decreased the rebound time after isolation.
A separate MPN cell population, on the other hand, activates once a mouse is reunited with other mice, Dulac and her colleagues also found. These cells inhibit the activity of isolation neurons and fall silent during quarantine. Optogenetic activation of these neurons during intermingling periods decreased an animal’s rebound time. And mice preferred to spend time in a chamber of their cage in which their reunion neurons had previously been activated, suggesting that they have positive associations with that activity.
The reunion neurons project to the ventral tegmental area, which is involved in social reward, whereas isolation neurons project to regions linked to appetite suppression and negative emotions. Isolation neurons also activate oxytocin-positive neurons in the lateral septum, which may enhance the animals’ social drive, Dulac says.
That dual signaling parallels the push-pull mechanism thought to identify hunger or thirst and satiety, says Yuki Oka, professor of biology at the California Institute of Technology, who was not involved in the study. “Under a thirst condition, homeostatic pressure accumulates. Then one neuronal population starts firing, and that drives an increased desire to drink water or eat food.”
For hunger and thirst, food and water deliver the satiety signals. But Dulac and her colleagues wanted to understand what it is about being reunited with other mice that satisfies a mouse’s social needs.
After social isolation, mice that are able to see, smell or hear other mice still show typical levels of social rebound once reunited with the group, the team found. But mice given access to a soft, fuzzy tunnel while being socially isolated showed decreased social rebound times—suggesting that “some of their social need is somehow partially fulfilled by this soft touch,” Dulac says.
When the mice were inside the soft tunnel, the majority of MPN isolation neurons became silent, and a subset of the reunion neurons activated, the team discovered.
“It’s almost like you can override the system by providing sensory cues,” Chang says. “That’s a signal that you’re in a group again.”
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nlike deprivation of food, water or sleep, a lack of social interaction will not cause a mouse to die, even though such interactions are useful for the animal’s long-term survival, Oka says. That key difference puts social homeostasis in “a slightly different category, but many of the homeostatic regulation principles are shared,” he adds.Whether the same mechanisms exist in people remains to be seen, Chang says. “The hypothalamus is a pretty well-conserved area,” he says. “A lot of other hypothalamic functions we learn about—osmolarity, blood pressure, all these kinds of things—are conserved in humans.”
Dulac says that she and her colleagues next plan to investigate the heterogeneity in social needs that exists across mouse strains. “Some mouse strains were extraordinarily sensitive to social isolation—way more than the typical C57 [strain] that everyone uses,” she says. Others, such as BALB/c mice, were insensitive to isolation. “What is it that is different? It may be something very simple—it could be that the excitability of the neurons is different, or that the connectivity is different. We don’t know.”
Those findings may have implications for conditions that affect social behaviors in people, Dulac says. Autism model mice, for example, seem to have social homeostasis neurons that function differently from those of controls, preliminary data from Dulac and her colleagues suggest.
The team also aims to explore the sex differences that exist in this hypothalamic circuit, Dulac says. Although females showed the strongest rebound effect, typical males still have a social drive, she says. “There are differences, and where the difference is coming from is something we are very interested in pursuing.”
