Summary: Researchers have identified a specialized neural circuit that links past experiences and environmental context to current appetite control. By studying brain cells in the dorsolateral septum, the team discovered a “relay station” that connects the hippocampus (memory center) to the hypothalamus (feeding center).
These neurons use a chemical signal called prodynorphin to calibrate eating habits based on where we are and what we’ve experienced there previously. The discovery reveals that when this circuit malfunctions, the brain loses its ability to regulate food intake based on context, potentially driving disordered eating behaviors like binge eating or obesity.
Key Facts
- The Contextual Relay: The brain uses a specific circuit—DLS(Pdyn) neurons—to communicate between the memory-storing hippocampus and the hunger-regulating hypothalamus.
- Loss of Appetite Control: Silencing these specific cells prevents the brain from associating favorable feeding experiences with specific locations, leading to increased appetite even in unfamiliar or inappropriate settings.
- GLP-1 Connection: These appetite-regulating neurons express receptors for GLP-1, suggesting that popular weight-loss medications may achieve their effects partly by influencing this newly discovered memory-feeding circuit.
Source: Mass General Brigham
Our past experiences shape how much we eat and where and what we choose to eat.
Using preclinical models, researchers from Mass General Brigham and the Broad Institute of MIT and Harvard have identified brain cells that translate contextual information into appetite control.
The findings suggest that dysfunction in this brain circuit could be a factor in disordered eating and obesity, meaning that these neurons could be a new target for treatment.
Results are published in Neuron.
“We identified a neural circuit that is responsible for linking our prior experiences with current aversions and preferences when it comes to dining choices,” said senior author Amar Sahay, PhD, of the Department of Psychiatry at Mass General Brigham. Sahay is also a Broad associate member.
“These findings may shed light on therapeutics to treat disordered eating in humans such as binge eating that arises in part from loss of contextual control or calibration of eating.”
Using mouse models, the researchers showed that Prodynorphin secreting neurons in the dorsolateral septum, DLS(Pdyn), relay information between the hippocampus and hypothalamus, the brain regions that store memories of contexts and control feeding, respectively.
Importantly, silencing these cells or deleting the Pdyn gene in these cells prevented mice from associating a prior favorable feeding experience with a location and increased mice’s appetite even in a non-familiar location, suggesting that the circuit’s activity is shaped by experience, previously learned contexts, and prodynorphin signaling.
The researchers also found that stimulation of DLS(Pdyn) neurons suppressed feeding and promoted avoidance consistent with the role of dynorphin—an endogenous opioid made from prodynorphin that mediates dysphoria or anti-reward signaling—as a chemical signal. Because DLS(Pdyn) neurons also express the receptor for GLP1, this discovery suggests that widely used GLP1 drugs may work in part through this circuit.
“Dysfunction in dynorphin production or in the neural circuits that use it may contribute to disordered eating,” said first author Travis Goode, PhD, a Research Fellow in the Sahay lab in the Department of Psychiatry. “Our findings may point toward new brain targets for eating-related issues.”
Funding: Goode is a recipient of Brain & Behavior Research Foundation Young Investigator Award, a Harvard Brain Initiative Travel Grant, and a NIH K99/R00 Pathway to Independence Award (K99MH132768).
Bernstein is a recipient of a NIH Predoctoral Individual National Research Service Award (F31DA058381). Duan acknowledges support from NIH R01EY030138, R01NS123912, and U01NS136405. Macosko acknowledges support from NIH 1U19MH1148.
Zweifel acknowledges support from the University of Washington Center of Excellence in Opioid Addiction Research/Molecular Genetics Research Core (P30DA048736).
Sahay acknowledges support from the Simons Collaboration on Plasticity and the Aging Brain, NIH R01MH111729, NIH R01MH131652, NIH R01MH111729-04S1, NIH R01AG076612, NIH R01AG076612-S1 diversity supplement, the James and Audrey Foster MGH Research Scholar Award, and the Department of Psychiatry at MGH.
Key Questions Answered:
A: Yes. This research shows that our brains rely on contextual memories to “calibrate” hunger. When the DLS(Pdyn) circuit is disrupted, the brain fails to use past experiences to suppress appetite, which can lead to overeating regardless of actual nutritional needs.
A: The study found that these specific appetite-controlling neurons contain GLP-1 receptors. This suggests that these medications don’t just affect the stomach or metabolism; they likely work by “plugging into” this brain circuit to help regulate hunger through memory and environmental cues.
A: Absolutely. By identifying prodynorphin as the chemical signal that promotes “anti-reward” or food avoidance, scientists now have a specific target to develop therapies that restore contextual control for those struggling with binge eating or obesity.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this memory, appetite, and neuroscience research news
Author: Brandon Chase
Source: Mass General Brigham
Contact: Brandon Chase – Mass General Brigham
Image: The image is credited to Neuroscience News
Original Research: Open access.
“A dorsal hippocampus-prodynorphinergic dorsolateral septum-to-lateral hypothalamus circuit mediates contextual gating of feeding” by Travis D. Goode, Mollie X. Bernstein, Michael S. Totty, Jason Bondoc Alipio, Cinzia Vicidomini, Devesh Pathak, Antoine Besnard, Delara Chizari, Nina Sachdev, Michael D. Kritzer, Ain Chung, Xin Duan, Evan Macosko, Stephanie C. Hicks, Larry S. Zweifel, Amar Sahay. Neuron
DOI:10.1016/j.neuron.2026.01.025
Abstract
A dorsal hippocampus-prodynorphinergic dorsolateral septum-to-lateral hypothalamus circuit mediates contextual gating of feeding
Contextual encoding in the dorsal hippocampus (DHPC) may recruit hypothalamic feeding modules to calibrate eating across environments, but the mechanistic instantiation of cells and circuits that undergird these processes is limited.
Single-cell transcriptomics and transsynaptic tracing of the dorsolateral septum (DLS) identified an evolutionarily conserved prodynorphin (Pdyn)-expressing subpopulation of somatostatin (Sst)-expressing inhibitory neurons that receives dense dorsal, but not ventral, hippocampal inputs.
Circuit optogenetics, electrophysiology, and in vivo calcium imaging demonstrated that DLS(Pdyn) neurons inhibit GABAergic neurons of the lateral hypothalamic area (LHA), exhibit context-dependent neural responses to food rewards and aversive stimuli, and confer contextual and internal state-dependent calibration of feeding.
Viral deletion of Pdyn in the DLS impaired context-dependent food reward consumption, suggesting a role for dynorphin/kappa opioid receptor signaling in these processes.
Together, our findings highlight how ancient LHA feeding circuits integrate DHPC input through DLS(Pdyn) inhibitory neurons to link context with regulation of food consumption.
