An MIT study identified how the cytokine IL-1B activates a brain circuit that induces social isolation during infections, separating it from physical lethargy.
MADRID, Dec 1 (EUROPA PRESS).- It is logical that, when we fight against a infectionlet’s lose the desire to be with others. This protects them from get sick and allows us to rest, something we need so much. What is not so clear is how this change in behavior occurs.
In fact, in much of the animal kingdom, when infection occurs, social contact is interrupted. Now this new study details how the immune and central nervous systems implement this behavior disease.
How the body tells us that it is time to isolate ourselves
Researchers at the Massachusetts Institute of Technology (MIT) discovered how an immune system molecule activates neurons in a specific brain circuit to stop social behavior in mice that model infection.
In research published in Cellscientists at MIT’s Picower Institute for Learning and Memory and their collaborators used multiple methods to causally show that when the immune system cytokine interleukin-1 beta (IL-1B) reaches IL-1 receptor 1 (IL-1R1) on neurons in a region of the brain called the dorsal raphe nucleus, it activates connections with the intermediate lateral septum to stop social behavior.
“Our findings show that social isolation following an immunological challenge is self-imposed and driven by an active neural process, rather than being a secondary consequence of the physiological symptoms of the disease, such as lethargy,” says study co-senior author Gloria Choi, an associate professor in the Picower Institute and the Department of Brain and Cognitive Sciences at MIT.
Jun Huh, associate professor of immunology at Harvard Medical School, is co-senior author of the paper. The long collaboration between Choi and Huh has identified other cytokines that affect social behavior by binding to their receptors in the brain. Therefore, in this study, his team hypothesized that the same type of dynamics could cause social isolation during infection.
To start, Yang and his collaborators injected 21 different cytokines into the brains of mice, one by one, to see if any triggered social isolation in the same way as LPS administration (a standard method for simulating infection).
Only IL-1B injection completely replicated the same social withdrawal behavior as LPS. That said, IL-1B also made the mice slower.
IL-1B affects cells by binding to IL-1R1, so the team proceeded to explore the brain to determine where this receptor is expressed. They identified several regions and examined individual neurons in each. The dorsal raphe nucleus (DRN) stood out among the regions, both for its ability to modulate social behavior and for its location next to the cerebral aqueduct, which would give it high exposure to incoming cytokines in the cerebrospinal fluid.
The experiments identified populations of DRN neurons that express IL-1R1, including many involved in the production of serotonin, a crucial neuromodulator.
From there, Yang and his team demonstrated that IL-1B activates these neurons and that this activation promotes social withdrawal. Furthermore, they demonstrated that inhibition of such neuronal activity prevented social withdrawal in mice treated with IL-1B, and that inactivation of IL-1R1 in DRN neurons also prevented social withdrawal behavior after IL-1B injection or exposure to LPS. Importantly, these experiments did not modify lethargy following IL-1B or LPS, demonstrating that social withdrawal and lethargy occur by different mechanisms.
“Our findings implicate IL-1B as a primary effector that drives social withdrawal during systemic immune activation,” the researchers write in Cell.
The brain circuit that makes us withdraw
After identifying the DRN as the site where neurons receiving IL1B drove social withdrawal, the next question was through which circuit this behavioral change occurred. The team tracked where neurons make their circuit projections and found several regions with a known role in social behavior.
Using optogenetics, a technology that modifies cells so that they are controllable with flashes of light, the scientists managed to activate the connections of the DRN neurons with each descending region.
Only activation of DRN connections with the intermediate lateral septum elicited the social withdrawal behaviors observed with IL-1B injection or LPS exposure.
In a final test, they replicated their results by exposing some mice to salmonella. “Taken together, these results reveal a role for IL-1R1-expressing DRN neurons in mediating social isolation in response to IL-1B* during systemic immune challenge,” the researchers wrote. Although the study revealed in detail the cytokine, neurons and circuitry responsible for social isolation in mice, and demonstrated causality, the results still raise new questions. One is whether IL-1R1 neurons affect other illness behaviors. Another is whether serotonin influences social isolation or other illness behaviors.
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