The urge to satisfy hunger is a primal one, but, as any dieter knows, choices about when and what to eat can be influenced by cues in the environment, not just how long it’s been since breakfast. The fact that food–associated visual cues in television commercials and on highway signs can contribute to overeating is well–documented. But how exactly do these external signals trigger cravings and influence behavior?

By developing a new approach to imaging and manipulating particular groups of neurons in the mouse brain, scientists at Harvard Medical School and Beth Israel Deaconess Medical Center have identified a pathway by which neurons that drive hunger influence distant neurons involved in the decision of whether or not to react to food–related cues. Their findings could open the door to targeted therapies that dampen food cue–evoked cravings in people with obesity.

The research was published online in the journal Nature.

“The main question we were asking is: how do evolutionarily ancient hunger–promoting neurons at the base of the brain, in the hypothalamus, influence ‘cognitive’ brain areas to help us find and eat calorie–rich foods in a complex and changing world?” said co–corresponding author Mark Andermann, HMS assistant professor of medicine and assistant professor in medicine at Beth Israel Deaconess.

“To put it simply, when you're hungry, the picture of a cheeseburger may be extremely appealing and effective in influencing your behavior,” explained lead author Yoav Livneh, a postdoctoral fellow in the Andermann lab. “But if your belly is full after eating a big meal, the same cheeseburger picture will be unappealing. We think that the pathway we discovered from hunger–promoting neurons to a region of the brain called the insular cortex plays an important role here.”

Brain imaging data in humans support the notion that the insular cortex is involved in deciding if a source of food is worth pursuing. Studies suggest that this process often goes awry in patients with obesity or other eating disorders that exhibit excessive cravings. Those findings indicate that specific changes in brain activity, including increased sensitivity to food cues, may underlie these disorders – rather than a lack of “willpower.”

In their study, Livneh, Andermann and co–corresponding author Bradford B. Lowell, professor of medicine at HMS and professor in medicine at Beth Israel Deaconess, and colleagues focused on the insular cortex, using a mouse model. Because the mouse insular cortex is located at the side of the brain in a hard–to–reach place, Andermann, Lowell, Livneh and colleagues pioneered the use of a tiny periscope that allowed them to see neurons in this previously unobservable part of the brain. The tool allowed the researchers to monitor and track individual neurons in awake mice as they responded to food cues in both sated and hungry physiological states.

Their experiments demonstrated that visual cues associated with food would specifically activate a certain group of neurons in the insular cortex of hungry mice, and that these neurons were necessary for mice to respond behaviorally to food cues. After mice had eaten until they were full, this brain response to food cues in the insular cortex was no longer present. While the mice were still sated, the researchers used genetic techniques to artificially create hunger by ‘turning on’ hunger–promoting neurons in the hypothalamus. These neurons express the gene for Agouti–related protein (AgRP) and were previously shown to restore simple feeding behaviors. By activating these AgRP neurons, Livneh and colleagues caused sated mice to once again react to visual stimuli and seek more food, and it also restored the pattern of food cue visual responses across neurons in insular cortex to that previously seen in hungry mice.