In the cerebellum there is a new target for suppressing hunger
Scientists have identified a completely new way in which the brain signals satiety after meals. The findings set a target for therapies that could dramatically reduce overeating.
People with Prader Willi syndrome, a genetic disorder, have an insatiable appetite. They never feel full, even after a hearty meal, and the consequences can be overeating and obesity, which endangers health and even life. According to a new study, their constant hunger partially results in disordered signaling in the cerebellum of the brain, a region responsible for motor control and learning.
An international research team from 12 institutions, led by J. Nicholas Betley, an assistant professor of biology at the School of Arts and Sciences, and Albert I. Chen, an associate professor at the Scintillio Institute in San Diego, used clues from patients with Prader Willi to guide investigations in mice. Thus, they discovered a subset of cerebellar neurons that signal satiety after meals. When the researchers activated these neurons, the magnitude of the effect “was enormous,” according to Betley. The animals ate as often as ordinary mice, but each of their meals was 50-75% smaller.
“It was amazing,” he said. “In fact, it was so amazing that I thought it must be wrong.” Betley encouraged Aloysius Low, a postdoctoral researcher in his laboratory and the first author of the study, to perform a series of other experiments to make sure the effect was real. In almost a year, they were convinced. “It’s amazing that you can still find areas of the brain that are important for basic survival behaviors that we’ve never involved or researched before,” says Betley. “And these regions of the brain are important in robust ways.”
Since its inception, Betley’s lab has revealed a variety of neural circuits related to how the brain regulates food intake. This work, as well as other research, involved areas of the posterior brain and hypothalamus in this control. “But we also know that drugs that target the hypothalamus and the posterior brain are not really good therapies for obesity,” according to Betley.
Returning to mice, unicellular transcriptomic analysis confirmed that a small subset of glutamatergic neurons in aDCN (neurons in the deep anterior cerebellar nuclei) were those activated in food. Their activation caused the animals to dramatically reduce their meal size, regardless of whether they were deprived of food or given as much food as they previously wished. When the researchers did the opposite, inhibiting the same neurons, the mice ate larger-than-normal meals. Reducing food intake can often cause humans and animals to compensate by eating more food later, but animals stimulated by aDCN did not do so, and metabolic activity measures remained constant. While mice normally have an increase in dopamine levels after being fed, mice activated by aDCN have had an increase in dopamine growth.
“It has been observed that when you activate dopamine neurons with dopamine or eliminate dopamine, the animal will eat less,” says Betley. “Too much dopamine blocks the subsequent growth of dopamine in rewards, eventually changing behavior.” These findings may guide therapeutic strategies to reduce the “reward” that patients with Prader Willi syndrome get from their diet, helping them to manage their uncontrollable hunger.
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