A research team that included six BBRF grantees has published results of experiments that identify a brain circuit and specific cell types whose actions link our past experiences with how much we eat.

“These findings may shed light on therapeutics to treat disordered eating, including binge eating disorder, which arises in part from loss of contextual control or calibration of eating,” said Amar Sahay, Ph.D., senior author of the team’s paper, which appeared in the journal Neuron. Dr. Sahay, of Mass General Brigham, Harvard Medical School, and the Broad Institute of MIT and Harvard, is a 2017 BBRF Independent Investigator and 2008 and 2006 BBRF Young Investigator.

As noted by the National Eating Disorders Association, disordered eating “refers to a spectrum of problematic eating behaviors and distorted attitudes about food, weight, shape, and appearance.” The behaviors can include various forms of dieting, skipping meals, fasting, restricting food intake, excessive use of diuretics, laxatives, and weight loss medications, as well as compensatory behaviors such as purging and excessive exercising seen in people diagnosed with eating disorders such as bulimia nervosa and anorexia nervosa.

The new research, conducted in mice, traces how neurons in the brain translate contextual information into appetite control, via circuitry that the investigators say is quite ancient in evolutionary terms. This stands to reason, since both appetite and the regulation of eating are so central not just to basic survival but also to an organism’s ability to maintain a state of health. Disordered eating and eating disorders are the result of processes, still incompletely understood, in which evolved mechanisms become dysfunctional.

Appetite and eating involve highly complex interlinked processes at the level of circuits, cells, and molecules. The new research specifically focuses on how the brain links environments with appetite for and responses to food. This linkage can be thought of as the way the individual, in the healthy state, controls appetite, and in an unhealthy state, can lose control over eating—as is seen in eating disorders.

The hippocampus is a key brain area involved in the encoding of contextual information and goals, including about food. Mice, like humans and other mammals, have two hippocampi, one on each side of the brain. These structures have dorsal and ventral regions, with the dorsal hippocampus (DHPC) especially devoted to processing spatial and contextual information.

In addition to the hippocampus, the hypothalamus is another brain area important in the new research: it is implicated in regulating internal states as well as learning-dependent processes that contribute to food-seeking and eating. The team notes emerging evidence suggesting that neural networks connecting the DHPC and hypothalamus play a role in disordered eating.

A third brain area with an important role in the new research is called the lateral septum (LS), which is composed of a great variety of cell types that form networks of inhibitory neurons that receive large inputs from the cortex and subcortical areas, as well as the hippocampus. Of particular interest to the team was the dorsolateral subregion of the LS (DLS): it receives dense inputs from the DHPC, and among the targets of its networks is the hypothalamus, including its lateral subregion (LHA), which may incorporate contextual information for its role in feeding.

The central finding in the new research concerns a cell type that is predominant in the DLS, called Sst-expressing neurons. These are inhibitory neurons that are distinguished by their expression of a potent neuropeptide called somatostatin, or Sst. A small subpopulation within the Sst-expressing neurons in the DLS co-express a peptide called prodynorphin, (Pdyn) a precursor of dynorphin, a naturally occurring opioid.

These prodynorphin-expressing Sst neurons are specifically found in the dorsal part of the lateral septum, where they receive inputs from the dorsal (but not ventral) hippocampus. And, they form connections with inhibitory neurons in the lateral hypothalamus.

By experimentally measuring and manipulating activity of prodynorphin-expressing neurons, the team was able to show that such neurons in the dorsolateral septum critically relay experience-related information between the hippocampus and hypothalamus—again, the brain areas, respectively, that store memories of contexts and control feeding.

Tellingly, when these “relay” cells were either silenced or had prodynorphin deleted (using genetic techniques), mice became unable to associate a prior favorable feeding experience with a location. Moreover, such mice were found to have changes in appetite, even when they were in locations not previously associated with food. This suggests the circuit’s activity is shaped by experience, previously learned contexts, and signaling by the prodynorphin-expressing relay cells.

Other experiments showed that simulation of these prodynorphin-expressing neurons suppressed feeding in the mice, and promoted food avoidance. This is consistent with the role of dynorphin, the naturally occurring opioid made from prodynorphin, in regulating reward signals. In this regard, it is noteworthy that these same prodynorphin-expressing neurons in the dorsolateral septum involved in contextual linkage with appetite also express the receptor for GLP1, the hormone that regulates blood sugar. So-called GLP1 drugs like Wegovy and Ozempic stimulate GLP1 receptors, with the effect of reducing appetite and promoting a sensation of fullness. The circuit described in the new research may be involved in the complex mechanism of action of GLP1 drugs.

Travis Goode, Ph.D., the first author of the new paper and a 2020 BBRF Young Investigator whose grant directly supported this research, commented that “dysfunction in dynorphin production, or in the circuits that use it, may contribute to disordered eating.” By shedding light on circuit dysfunctions that may underlie abnormal contextual feeding, Dr. Goode says the new findings could “point toward new brain targets for eating-related issues.”

The research team also included: Michael Totty, Ph.D., 2025 BBRF Young Investigator; Cinzia Vicidomini, Ph.D., 2017 BBRF Young Investigator; Antoine Besnard, Ph.D., 2021 and 2014 BBRF Young Investigator; and Larry S. Zweifel, Ph.D., 2016 BBRF Independent Investigator.