The Neuroscience of Insatiable Hunger

A newly-discovered subset of neurons plays a major role.

Posted November 20, 2021 |  Reviewed by Vanessa Lancaster



  • Having a healthy appetite and consuming enough calories each day to sustain life is vital to every human and animal’s survival.
  • But having an insatiable appetite or never feeling satiated—even after consuming plenty of calories―can lead to obesity and poor health.
  • A “satiation network” rooted in the cerebellum sends satiety signals to other brain regions that alert humans (and mice) when to stop eating.

Both hemispheres of the human cerebellum (Latin for “little brain”) are tucked underneath the larger cerebral hemispheres. Cerebellar is the sister word to cerebral and means “relating to the cerebellum.”Source: SciePro/Shutterstock

Not so long ago, the human cerebellum was viewed by most experts as a brain region that’s primary job was simply to coordinate muscle movements. Most 20th-century neuroscientists didn’t think that cerebellar neurons were involved in non-motor cognitive processes or reward-driven behaviors. But this antiquated “motor-function-only” view of the cerebellum has been radically updated over the past two decades.

Increasingly, new research is uncovering previously unknown ways that the cerebellum works with vast neural networks to optimize whole-brain functions and shows how our so-called “little brain” drives a wide range of unconscious behaviors.

This week, a study by an international team of researchers led by the University of Pennsylvania’s Nicholas Betley sheds light on how a specific subset of neurons in the cerebellum sends signals related to hunger and satiety that let us know when to stop eating. These findings (Low et al., 2021) were published on November 17 in the peer-reviewed journal Nature.

The discovery and identification of what first author Aloysius Low et al. are calling “a cerebellar satiation network” could lead to new interventions that help people eat less and lose weight.

Mohamed Hassan/Pixabay

Source: Mohamed Hassan/Pixabay

Notably, the Betley Lab‘s recent identification of this satiation network was inspired by previous research in patients with Prader-Willi syndrome, a genetic disorder marked by an insatiable appetite (i.e., hyperphagia) and the inability to experience satiety—even after eating a huge meal.

Based on previous research into Prader-Willi syndrome, Betley and Low began to speculate that the cerebellum might be playing a heretofore unknown role in insatiable hunger.

So, they reached out to Laura Holsen at Harvard Medical School’s Brigham and Women’s Hospital, who had a rare set of fMRI data from about a decade ago (Holsen et al., 2011) that tracked blood flow in the brain’s of Prader-Willi patients.

Holsen’s previous research focused on neural mechanisms underlying hyperphagia in Prader‐Willi syndrome and looked at “subcortical food motivation circuitry and prefrontal inhibitory circuitry functioning in response to food stimuli before and after eating.”article continues after advertisement

However, the initial analysis of this fMRI data didn’t take a close look at the cerebellum, which is tucked underneath the cerebral cortices. Surprisingly, when Betley and Low took a closer look at the fMRI images with the cerebellum top of mind, they noticed something unexpected.

Unearthing the cerebellum’s non-motor functions often catches neuroscientists off guard

In a news release, Bentley describes this moment of discovery and initial skepticism about what they were seeing: “The cerebellum pops out, and we were all looking at this, saying, ‘Is this real?’ [It] was mind-blowing. In fact, it was so mind-blowing I thought it had to be wrong.”

After this initial observation, Betley encouraged Low to conduct a series of experiments in mice to see if their hunch about what they’ve coined as a “cerebellar satiation network” was accurate. Over the next year, the researchers’ findings convinced them that this network does exist.

“It’s amazing that you can still find areas of the brain that are important for basic survival behaviors that we had never before implicated. And these brain regions are important in robust ways,” Betley noted.

Using a reverse-translational approach, Betley’s lab was able to identify and functionally characterize a neural ensemble that promotes satiation via a distinct subset of neurons in the anterior deep cerebellar nuclei (aDCN).

In mice, the researchers found that activating aDCN neurons hacked into dopamine-driven “reward pathways” in the brain’s ventral striatum. As the authors explain, “We found that aDCN activity terminates food intake by increasing striatal dopamine levels and attenuating the phasic dopamine response to subsequent food consumption.”

Interestingly, the researchers also discovered that when they activated the aDCN neurons in mice that they would automatically stop eating when they’d gotten enough calories. But if they were given less calorically dense food, mice would eat larger quantities than normal to equal their typical caloric intake. “That told us that this animal is calculating the number of calories it is taking in and stopping when it thinks it’s had enough,” Betley explains.article continues after advertisement

Hacking the “cerebellar satiation network” could be a new way to curb overeating by triggering satiety

The latest research (2021) suggests that neurons in the cerebellum’s anterior deep cerebellar nuclei are key to intuitively regulating portions and meal size. Pinpointing non-invasive ways to turn these aDCN cerebellar neurons “on” and “off” could be a game-changer for helping people eat less without constantly feeling hungry or craving more food.

Clinical studies involving people (not mice) are needed to see how this newly-discovered “cerebellar satiation network” works in humans. Forthcoming research into this satiation network by Betley and his colleagues will give us more details on how insatiable hunger and satiety are regulated in the human brain.

Facebook image: 1Roman Makedonsky/Shutterstock


Aloysius Y. T. Low, Nitsan Goldstein, Jessica R. Gaunt, Kuei-Pin Huang, Norliyana Zainolabidin, Alaric K. K. Yip, Jamie R. E. Carty, Ju Y. Choi, Alekso M. Miller, Helen S. T. Ho, Clara Lenherr, Nicholas Baltar, Eiman Azim, October M. Sessions, Toh Hean Ch’ng, Amanda S. Bruce, Laura E. Martin, Mark A. Halko, Roscoe O. Brady Jr, Laura M. Holsen, Amber L. Alhadeff, Albert I. Chen & J. Nicholas Betley. “Reverse-Translational Identification of a Cerebellar Satiation Network.” Nature (First published: November 17, 2021) DOI: 10.1038/s41586-021-04143-5

Laura M. Holsen et al. “Importance of Reward and Prefrontal Circuitry in Hunger and Satiety: Prader–Willi Syndrome vs. Simple Obesity.” International Journal of Obesity (First published: October 25, 2011) DOI: 10.1038/ijo.2011.204

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