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."
Authorship: In addition to Goode and Sahay, Mass General Brigham authors include Jason Bondoc Alipio, Cinzia Vicidomini, Devesh Pathak, Antoine Besnard, Michael D. Kritzer, Ain Chung, and Evan Macosko. Additional authors include Mollie X. Bernstein, Michael S. Totty, Delara Chizari, Nina Sachdev, Xin Duan. Stephanie C. Hicks, and Larry S. Zweifel.
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.
Paper cited: Goode, T et al. "A dorsal hippocampus-prodynorphinergic dorsolateral septum-to-lateral hypothalamus circuit mediates contextual gating of feeding" Neuron DOI: 10.1016/j.neuron.2026.01.025
