Summary: Researchers have identified a specific brain region and a connected neural circuit that help produce the sensation of being full after a meal.
Source: University of Arizona
Feeling full, or satiated, after eating is a healthy and essential signal, but the exact brain mechanisms that produce that sensation remain incompletely understood. New research led by the University of Arizona and published in Molecular Metabolism identifies a brain region and a disynaptic neural circuit that mediate satiation. These findings improve our understanding of how the gut communicates fullness to the brain and could ultimately inform more targeted approaches for treating eating disorders and managing weight.
Currently, six medications are approved by the U.S. Food and Drug Administration for weight management, yet many of these drugs have significant side effects. Precisely targeting the brain systems that produce satiation could reduce unwanted effects while preserving therapeutic benefit.
“If we can more precisely identify and target the brain circuits responsible for satiation, we can develop treatments that work with fewer side effects,” said lead author Haijiang Cai, an associate professor in the Department of Neuroscience.
Earlier work had traced the neural pathways that contribute to satiation to the central amygdala, a brain structure known for its role in emotion, fear and pain as well as feeding. Because the central amygdala houses many different neuron types, however, it has been difficult to determine how the satiation signal travels onward from that region.
Cai and colleagues discovered that signals originating in a defined subset of central amygdala neurons travel next to a cluster of neurons in the parasubthalamic nucleus (PSTh). Activity in these PSTh neurons appears to be required for the feeling of fullness triggered by the gut hormone cholecystokinin (CCK).
The researchers started with two established facts: the gut hormone CCK is released after a meal and signals fullness to the brain, and a defined group of central amygdala neurons—those expressing protein kinase C-delta (PKC-δ)—mediate CCK’s satiation effects by inhibiting other inhibitory neurons within the central amygdala. From those observations, the team reasoned that neurons downstream of the PKC-δ-expressing central amygdala neurons should show increased activity both when CCK is present and when PKC-δ neurons are activated.
Using mouse models, the team identified neurons in the PSTh that are activated by peripheral CCK and by activation of central amygdala PKC-δ neurons. The investigators demonstrated that PKC-δ neurons inhibit a subset of central amygdala neurons that project to the PSTh, which results in a disinhibition and activation of PSTh neurons. In other words, activation of PKC-δ neurons produces a two-step pathway—disinhibiting PSTh-projecting neurons in the central amygdala and thereby activating PSTh neurons themselves.
The PSTh was first reported by researchers in the 1990s and appeared in English-language literature in 2004, but its functional role had been unclear. Cai’s team showed that PSTh neurons are necessary for CCK-induced suppression of feeding: when the PSTh neurons are silenced, CCK no longer reduces food intake; conversely, direct activation of PSTh neurons reduces eating. These experiments provide strong evidence that PSTh neurons contribute directly to the sensation of satiation driven by CCK.
Cai emphasized that satiation is almost certainly the product of coordinated activity across multiple brain regions rather than a single neural node. The PSTh is likely one important component within a broader network that registers fullness and signals termination of a meal.
Cai’s broader research aims to understand how emotion and feeding behaviors interact. “Eating and emotions are distinct behaviors, but they influence one another,” he said. “Some people eat more when stressed, others eat less. Emotional disturbances often accompany eating disorders and obesity. By revealing the neural mechanisms that link emotion and feeding, we hope to design more specific, effective treatments.”
About this neuroscience research news
Author: Press Office
Source: University of Arizona
Contact: Press Office – University of Arizona
Image: The image is in the public domain
Original Research: Closed access.
“Dissecting a disynaptic central amygdala-parasubthalamic nucleus neural circuit that mediates cholecystokinin-induced eating suppression” by Marina Rodriguez Sanchez et al. Molecular Metabolism
Abstract
Dissecting a disynaptic central amygdala-parasubthalamic nucleus neural circuit that mediates cholecystokinin-induced eating suppression
Objective
Cholecystokinin (CCK) is a gut-derived hormone that plays an important role in controlling eating and metabolism. Prior work has traced a multi-synapse pathway from the vagus nerve to the central nucleus of the amygdala (CEA) that mediates CCK’s appetite-suppressing effects. However, the downstream targets of the CEA remained unclear because the CEA contains a complex mixture of neuron types. This study aimed to identify the next stages of that circuit using a targeted experimental strategy.
Methods
Previous studies established that a distinct population of central amygdala neurons marked by protein kinase C-delta (PKC-δ) mediates CCK-induced anorexia by inhibiting other inhibitory neurons in the CEA. Building on that knowledge, the authors used the logic that neurons downstream of CEA PKC-δ+ cells should be disinhibited by PKC-δ activation and directly activated by CCK. The team applied optogenetically assisted electrophysiological circuit mapping and in vivo chemogenetic manipulation to determine the structure and function of the circuit.
Results
The investigators found that neurons in the parasubthalamic nucleus (PSTh) are activated both by CEA PKC-δ+ neuron activation and by peripheral administration of CCK. They showed that CEA PKC-δ+ neurons inhibit the CEA neurons that project to the PSTh, producing disynaptic disinhibition and activation of PSTh cells. Crucially, chemogenetic silencing of PSTh neurons diminished the feeding suppression normally induced by CCK, indicating that PSTh activity is necessary for that anorexigenic effect.
Conclusions
These results reveal a disynaptic central amygdala–parasubthalamic nucleus (CEA–PSTh) circuit that mediates CCK-induced eating suppression, providing a clearer neural mechanism for how CCK contributes to the termination of feeding. Identifying this circuit advances our understanding of the brain systems that signal satiety and may inform future therapeutic strategies that target feeding behavior with greater precision.