Summary: Researchers have mapped a specialized neural circuit that connects past experiences and environmental context to moment-to-moment control of appetite. Studying neurons in the dorsolateral septum (DLS), the team identified a relay that links the hippocampus—our memory hub—to the hypothalamus—the brain’s feeding center.
These DLS neurons signal via prodynorphin, a precursor to the opioid peptide dynorphin, to adjust eating behavior depending on where we are and what we have previously experienced there. When this circuit is disrupted, the brain can lose the ability to suppress or promote eating based on context, which may contribute to disordered eating behaviors such as binge eating and obesity.
Key Facts
- Contextual relay: A distinct population of DLS(Pdyn) neurons mediates communication from the dorsal hippocampus (context and memory) to the lateral hypothalamus (hunger regulation).
- Loss of contextual control: Disabling these neurons or removing the Pdyn gene prevents animals from linking positive feeding experiences to specific places, causing increased eating even in unfamiliar or inappropriate contexts.
- GLP-1 receptor link: These appetite-regulating neurons express GLP-1 receptors, suggesting that common GLP-1–based weight-loss medications may partly act by modulating this memory-feeding circuit.
Source: Mass General Brigham
How experience and place shape eating
Using mouse models, researchers affiliated with Mass General Brigham and the Broad Institute of MIT and Harvard characterized a neural pathway that translates contextual memory into feeding decisions. Their work highlights how experience-dependent signals guide whether and when animals choose to eat, and identifies molecular and cellular elements that could be targeted for treating eating disorders.
The full results are published in Neuron.
Senior author Amar Sahay, PhD, described the discovery as identifying “a neural circuit responsible for linking prior experiences with current aversions and preferences around food.” The findings point to potential new therapeutic strategies for disorders characterized by a loss of contextual control over eating, including some forms of binge eating.
Experiments showed that prodynorphin-expressing inhibitory neurons in the dorsolateral septum—denoted DLS(Pdyn)—receive dense input from the dorsal hippocampus and send inhibitory signals to GABAergic neurons in the lateral hypothalamic area (LHA). Those LHA circuits are well established as regulators of feeding behavior, and the DLS(Pdyn) cells act as a bridge that links contextual memory with hypothalamic feeding modules.
When researchers silenced DLS(Pdyn) neurons or deleted the Pdyn gene specifically in these cells, mice could no longer associate a positive feeding experience with a particular location. As a result, mice ate more even in unfamiliar settings, indicating that prodynorphin signaling and DLS activity normally restrain eating in contexts that should not trigger feeding.
Conversely, stimulating DLS(Pdyn) neurons suppressed feeding and promoted avoidance behaviors. This aligns with the known role of dynorphin and kappa opioid receptor signaling in producing dysphoria or anti-reward states that discourage consumption. The discovery that these neurons express GLP-1 receptors also suggests a mechanism by which GLP-1 agonists may reduce appetite—by engaging the same context-sensitive circuit that links memory to feeding decisions.
First author Travis Goode, PhD, emphasized that disruptions in dynorphin production or in the circuits that use this molecule might underlie certain eating disorders. Identifying these neurons and their molecular signals offers a focused target for future research into therapies that restore appropriate contextual control over eating.
Funding: This work was supported by a mix of public and private awards, including NIH grants, foundation fellowships, and institutional research awards acknowledged by the authors.
Key Questions Answered:
A: Yes. The study demonstrates that the brain uses contextual memories to tune hunger. When the DLS(Pdyn) circuit is impaired, animals fail to use past experience to suppress appetite, which can lead to overeating regardless of actual nutritional need.
Q: How might GLP-1 weight-loss drugs interact with this circuit?
A: The DLS(Pdyn) neurons express GLP-1 receptors, indicating that GLP-1–based medications may reduce appetite in part by influencing this hippocampus-to-hypothalamus relay that integrates memory and environmental cues.
Q: Could this discovery lead to treatments for binge eating?
A: Potentially. By pinpointing prodynorphin signaling and the specific DLS neurons that gate context-dependent feeding, the study offers new molecular and circuit-level targets that could be explored for therapies aimed at restoring contextual control in binge eating and related conditions.
Editorial Notes:
- This article was edited by an editor for clarity and context.
- The original journal article was reviewed in full by the reporting team.
- Additional explanatory context was added by staff to aid understanding.
About this memory, appetite, and neuroscience research news
Author: Brandon Chase
Source: Mass General Brigham
Contact: Brandon Chase – Mass General Brigham
Image: Image 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 et al., 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) can recruit hypothalamic feeding modules to calibrate eating across environments, but the specific cells and circuits that implement this integration have been unclear. Single-cell transcriptomics and transsynaptic tracing in the dorsolateral septum (DLS) identified an evolutionarily conserved subpopulation of prodynorphin (Pdyn)-expressing somatostatin-positive inhibitory neurons that receive dense input from the dorsal, but not ventral, hippocampus.
Circuit optogenetics, electrophysiology, and in vivo calcium imaging showed that DLS(Pdyn) neurons inhibit GABAergic neurons of the lateral hypothalamic area (LHA), display context-dependent responses to food rewards and aversive stimuli, and provide experience- and state-dependent calibration of feeding. Viral deletion of Pdyn in the DLS impaired context-dependent consumption of food rewards, implicating dynorphin and kappa opioid receptor signaling in these processes. Together, these findings illuminate how ancient LHA feeding circuits integrate dorsal hippocampal input via DLS(Pdyn) inhibitory neurons to link context with regulation of food intake.