Columbia scientists studying mice have identified specialized neurons that respond to a variety of cues to then instruct the animals to stop eating. Though many feeding circuits in the brain are known to play a role in monitoring food intake, the neurons in those circuits do not make the final decision to cease eating a meal. The neurons identified by the Columbia scientists, which represent a new element of these circuits, are located in the brainstem, the oldest part of the vertebrate brain. Their discovery could lead to new treatments for obesity.
“These neurons are unlike any other neuron involved in regulating satiation,” said Alexander Nectow, MD, PhD, a physician-scientist at Columbia University Vagelos College of Physicians and Surgeons. “Other neurons in the brain are usually restricted to sensing food put into our mouth, or how food fills the gut, or the nutrition obtained from food. The neurons we found are special in that they seem to integrate all these different pieces of information and more.”
Nectow, along with research co-lead Srikanta Chowdhury, PhD, an associate research scientist in the Nectow lab, and colleagues, reported on their findings in Cell, in a paper titled, “Brainstem neuropeptidergic neurons link a neurohumoral axis to satiation.” In their paper, the team concluded, “Together, these studies reveal important principles through which the brainstem regulates satiation and begin to shed light on the neural determinants of meal size … This work raises fundamental questions about how the brain is wired to terminate a meal and, beyond that, how innate, recurring behaviors are regulated.”
Hunger is evolutionarily hardwired to ensure that an animal has sufficient energy to survive and reproduce, the authors wrote. “Hunger and satiety are evolutionarily conserved functions that ensure survival … Just as important as knowing when to start eating is knowing when to stop eating.” The decision to stop eating is a familiar phenomenon. Nectow commented, “It happens every time we sit down to eat a meal: At a certain point while we’re eating, we start to feel full, and then we get fuller, and then we get to a point where we think, okay, that’s enough.”
How does the brain know when the body has had enough, and how does it act on that information to stop eating? “Satiation, a negative feedback process that ultimately leads to meal termination, arises from monitoring many metabolic and ingestive parameters …,” the investigators explained. “Satiation is also dissociable from hunger and satiety signaling and is thus controlled by a distinct set of neural circuits.”
Researchers had previously tracked the decision-making cells to the brainstem, but the leads ended there. “While hunger and satiety circuits are thought to originate in the hypothalamus, classical studies utilizing decerebrate rats localized the regulation of satiation to the brainstem,” the team explained. Such studies demonstrated that the brainstem, independent of the forebrain, could detect gastric loads and associated “satiety signals” and respond by reducing food intake. But as the authors noted, “This work left a broad swath of the brainstem as a set of potential sites and cell types regulating satiation, leaving a longstanding, unresolved question: how does the brainstem appropriately terminate an ongoing meal?”
For their newly reported study Nectow, Chowdhury, and team deployed spatially resolved single-cell phenotyping, a technique that makes it possible to look into a region of the brain and discern different types of cells that until now have been difficult to distinguish from one another. “This technique—spatially resolved molecular profiling—allows you to see cells where they are in the brainstem and what their molecular composition looks like,” Nectow said.
While profiling a brainstem region—the dorsal raphe nucleus (DRN)—known for processing complex signals, the researchers spotted previously unrecognized cells that had similar characteristics to other neurons involved in regulating appetite. Nectow continued, “We said, ‘Oh, this is interesting. What do these neurons do?’” To see how the neurons might influence eating, the researchers engineered the neurons so they could be turned on and off using light.
Tests in mice using optogenetics showed that when these identified neurons were activated by the light, the mice ate much smaller meals. The intensity of the activation determined how quickly animals stopped eating. “Interestingly, these neurons don’t just signal an immediate stop; they help the mice to slow down their eating gradually,” Chowdhury explained.
Nectow and Chowdhury also looked at how other eating circuits and hormones affected the neurons. The researchers found that the neurons were silenced by a hormone that increases appetite, and activated by a GLP-1 agonist, a class of drugs used for treating obesity and diabetes. Tests indicated that these inputs helped the neurons track each bite the mice took. “Together, these results indicate that CCK neurons track food intake on a bite-to-bite basis and use this information to terminate meals through a delayed and sustained anorexigenic signal operating on the order of tens of minutes,” the team stated.
“Essentially these neurons can smell food, see food, feel food in the mouth and in the gut, and interpret all the gut hormones that are released in response to eating,” Nectow said. “And ultimately, they leverage all of this information to decide when enough is enough.” The authors further noted, “Using single-cell, spatially resolved molecular profiling, we find that DRN neurons expressing cholecystokinin (CCK) comprise a unique neuropeptidergic subpopulation, with a molecular composition enabling them to sense and respond to diverse metabolic cues … Together, these studies demonstrate that CCK neurons can detect diverse non-aversive neurohormonal signals over broad timescales to adaptively regulate feeding.”
They say their collective findings make a number of key advances. One is the finding that CCK neurons can track diverse neurohormonal cues to signal food intake on a “bite-to-bite basis,” and that this then allows for what they describe as the “passive encoding of meal size.” Secondly, these neurons convert the information into a sustained signal with “a built-in delay to ultimately terminate a meal.” Thirdly, the CCK neurons are positioned at what the team describes as “the intersection of multiple negative feedback loops” that are central to integrated control of satiation. “… this work demonstrates how DRN CCK neurons regulate satiation and identifies a likely conserved cellular mechanism that transforms diverse neurohumoral signals into a key behavioral output.”
Though the specialized neurons were found in mice, Nectow says their location in the brainstem, a part of the brain that is essentially the same in all vertebrates, suggests that it is highly likely that humans have the same neurons.
“We think it’s a major new entry point to understanding what it means to be full, how that comes about, and how that is leveraged to end a meal,” Nectow added. “And we hope that it could be used for obesity therapies down the road.”
