Research in engineered mice by scientists at Beth Israel Deaconess Medical Center (BIDMC) has revealed new insights into the complex interplay among neurons that govern hunger, behavior and learning, which could ultimately help to shed light on what happens in some eating disorders.

“Our discovery provides the answer to this important question of how we learn to seek and consume food and how hunger enhances the learning of tasks oriented towards acquiring food,” said research lead Bradford B. Lowell, MD, PhD, of the Division of Endocrinology at BIDMC, who is also a professor of medicine at Harvard Medical School. “With additional work, our discovery could ultimately shed light into what goes wrong in disorders of hunger such as obesity and anorexia nervosa.”

Lowell and colleagues report on their findings in Nature, in a paper titled, “Food cue regulation of AgRP hunger neurons guides learning.”

The BIDMC team has been at the forefront of research to identify the small population of agouti-related peptide (AgRP)-expressing neurons that are found in the hypothalamus. These neurons are activated by fasting, which causes the sensation of hunger, as “… an aversive state that motivates the seeking and consumption of food,” the authors explained. “Eating returns AGRP neuron activity towards baseline on three distinct timescales: rapidly and transiently following sensory detection of food cues, slowly and longer-lasting in response to nutrients in the gut, and even more slowly and permanently with restoration of energy balance.” However, the team continued, precisely how the AGRP cells and the unpleasant feeling of hunger they cause actually motivate an animal to find food and eat hasn’t been understood.

To try and answer this longstanding question, the BIDMC team turned to their engineered mouse model to investigate AgRP neuronal activity. The mouse model—on which more than 100 scientific papers have been published—allows researchers to switch AgRP neurons on and off, determine what activates or inactivates them, and map their connections to other regions of the brain.

“Using this model, we and others discovered some time ago that these neurons are turned on by fasting, causing hunger, and that artificially turning them on in a recently fed mouse that otherwise would not eat, causes huge amounts of food to be eaten, as if the mouse had not eaten in days,” commented first author Janet Berrios, PhD, a postdoctoral fellow at BIDMC. In fact, just the presence of food or a cue linked to the presence of food will instantaneously inhibit the neuron’s activity, easing the unpleasant hunger sensation. If food isn’t eaten in a short period of time, however, neuronal activity rebounds, restoring hunger to its previous levels.

For their newly reported study the team trained the engineered mice to recognize a food cue by associating a light with access to food, just as a dog can be trained to associate the sound of a cupboard opening with getting a biscuit. The team was then able to observe how various levels of hunger and the presence of the food cues affected the AgRP neurons.

As they expected, they observed that fasting activated the AgRP neurons, and food cues in the environment work—via a network of neurons elsewhere in the brain—to inhibit AgRP activity. But remarkably, when the team blocked off this network, it caused the mice to have great difficulty learning a task in which sensory cues related to food were used to guide acquisition of food. “Interference with this circuit impairs food cue inhibition of AGRP neurons and, notably, greatly impairs learning of a sensory cue-initiated food-acquisition task,” the team noted. “This is specific for food, as learning of an identical water-acquisition task is unaffected.”

From this, the researchers suggest that fasting or deprivation known to activate the AgRP neurons and the feeling of hunger causes an unpleasant, or aversive, feeling. When food cues in the environment inhibit AgRP activity, it also tamps down the aversive feeling, which in turn serves as a reward powerful enough to enhance learning.

“Calorific deficiency activates AGRP neurons … and this causes the aversive feeling of hunger,” they wrote. Environmental cues that are instructive for food acquisition then engage a particular neuronal circuit that transiently reduces the AGRP neuronal activity. “As AGRP neurons have been proposed to transmit a negative-valence teaching signal, these ‘appetitive’ falls in aversive AGRP neuron activity, over time, increase the incentive salience of food cues, thereby facilitating the learning of food acquisitions tasks,” the team proposed.

“It’s as if these rewarding, sensory cue-linked drops in unpleasant AgRP neuron activity push the mouse towards environmental cues and tasks associated with obtaining food,” said Lowell, who noted that thirst likely works the same way, although through a different specialized set of neurons. “An obvious implication of this idea is that it explains why dieting is so difficult—dieters are perpetually stuck with this aversive feeling. So, in short, it appears that we eat and drink because we’ve learned that this reduces the activity of these deprivation neurons, and hence the linked bad feelings.”