Neuroscience – how your brain tells you when to stop eating

Your brain’s natural calorie counter

Clara Lenherr tells the story of how digging up decade-old data led researchers to discover how the brain tells you it’s time to stop eating.

The desire to consume food is one of the most primitive, universal, and powerful behaviors driving humans and animals alike. We rely on our ability to sense how satiated we are in order to regulate the amount of food we eat, and an imbalance in our sense of hunger can lead to overeating and obesity, a disorder that is becoming increasingly prevalent worldwide.

An international team of researchers recently discovered that the cerebellum (a brain region traditionally known for controlling movement) is involved in regulating food intake. The findings shed light on this seemingly underestimated region as a new target for therapies to treat insatiable hunger.

Led by Dr Nicholas Betley (University of Pennsylvania) and Dr Albert I. Chen (Scintillon Institute), the team published their results in Nature in November 2021. The paper showed a subset of neurons in the deep cerebellum are activated in response to food intake.

Cerebellar neurons responded to food by increasing the release of the “reward neurotransmitter'', dopamine, in a region deep within the brain. An increase in dopamine decreases the significance of later food-induced dopamine spikes, so the reward value of food diminishes along with the desire to consume it. This cerebellar circuit therefore controls the reward value of food to regulate how much of it we consume.

An insatiable appetite is one symptom of Prader-Willi syndrome, a rare genetic disorder which can lead to life-threatening overeating and obesity. The role of the cerebellum in hunger was first suspected when a rare set of neuroimaging (fMRI) data tracking blood flow in the brains of Prader-Willi syndrome patients was re-investigated after almost a decade.

The data unexpectedly revealed the deep cerebellum was the only brain region with significant differences in activity between controls and Prader-Willi patients. A lack of cerebellar activity in response to food cues was detected in patients experiencing insatiable hunger, calling for further investigation into the underlying mechanisms of the cerebellum.

The researchers studied mice to determine the precise cerebellar region activated by food intake. They carried out gene expression profiling and monitored brain activity in response to food to reveal that a discrete population of neurons in the anterior deep cerebellar nuclei (aDCN) became active in response to food intake.

Moreover, artificially inducing activity in aDCN neurons caused mice to consume less food. When animals were given food of different caloric densities, they adjusted the quantity of food consumed to obtain an equal number of calories overall. Together, these findings show the activity of aDCN neurons controls eating in a calorie-dependent manner.

The researchers tried activating both the aDCN neurons and the hypothalamus, a part of the brain known to regulate hunger according to need. While activation of the hypothalamus alone increased the amount of food the mice ate, activating both parts at the same time didn’t have the same effect. This demonstrated the cerebellum can override the hypothalamus.

The cerebellar neurons worked by reducing the reward value of food, making every mouthful less satisfying than the last. Activating the aDCN neurons led to a sustained release of dopamine, which strongly decreased food intake. Dopamine bursts normally occur after eating, but following cerebellar activation, the base level of dopamine was increased, meaning any spikes from further eating made less of a difference.

The finding that aDCN neurons tell the body when it is time to stop eating greatly expands our understanding of how dopamine is used as a reward, and already has significant clinical implications for the treatment of eating disorders. The approach of the study (beginning with data from human patients followed by experiments in mice) was also remarkable in its somewhat “backwards” approach compared to many studies.

Dr Betley’s lab has been investigating neural circuits that regulate food intake for several years, but this finding is most likely to lead to obesity treatments. Importantly, this study showed the mice that underwent aDCN activation did not compensate by eating more food later on. This makes it particularly attractive as a therapeutic target to control the desire for food.

With the right research, perhaps it will not be too long before brain stimulation of the deep cerebellum is used to cure extreme hunger in Prader-Willi syndrome patients and help reduce obesity.

Image (courtesy of Dr. Aloysius Low, lead author) depicting the neural circuit from the gut to the anterior cerebellum and downstream striatum. Food intake leads to the activation of the anterior cerebellum and consequent release of dopamine in the striatum, which signals that sufficient calories have been consumed to terminate food consumption.