Hunger, the hollow ache nestled deep in your belly, arises as a reminder to keep your body fully stocked with energy. Science has had clues for some time how the mechanisms of hunger work, via various hormones, but until recently, the processes leading up to that motivational signal — the “black box” of hunger, as it’s often called — have remained a mystery.

Scientists have known for years that two hormones, ghrelin and leptin, play key roles in making your brain feel either hungry or full. When researchers inject each hormone into rats’ brains, the animals either begin to crave food or reject it, even if their current state should suggest the opposite. But these studies fail to capture, claim researchers of a new study, how hunger is actually manifested. Why, for instance, do we crave certain foods after a meal, such as ice cream over broccoli, even though we’re apparently full? Moreover, which parts of the brain handle which duties? Solving these mysteries could hold insights into overeating and hunger’s role in obesity.

"Psychologists have explained how cues from the environment and from the body interact, demonstrating that food and stimuli linked with food [such as a McDonald's sign] are rewarding and therefore promote hunger," explained Beth Israel Deaconess Medical Center (BIDMC) neuroendocrinologist Dr. Bradford Lowell in a statement. They know, for instance, that fasting increases hunger’s cognitive link with the reward centers of the brain — that much is clear. But what lies inside the neural circuitry itself is still hazy.

So Lowell and his colleagues targeted specific pathways in mice’s brain to better understand the inner-workings of hunger. In their prior research, the team has used two techniques to peer into the brain — rabies circuit mapping and channelrhodopsin-assisted circuit mapping, both of which allow scientists to analyze brain activity on a neuron-by-neuron basis. "By making use of these new technologies, we are able to follow the synapses, follow the axons, and see how it all works,” Lowell said.

For the present study, the team relied solely on rabies circuit mapping. It’s a technique that involves infecting a single neuron with a modified version of the rabies virus. In this case, they targeted the Agouti-peptide (AgRP) expressing neurons — a patch of neurons in the brain’s hypothalamus that prior studies have found to activate in the presence of a caloric deficit. Mice whose AgRP neurons are stimulated (either naturally or artificially) will seek out food, even if they weren’t hungry before, as if they hadn’t eaten for weeks.

"We wanted to know, of all the millions of neurons in a mouse brain, which provided input to the AgRP neurons," Lowell said. "And the shocking result was that there were only two sites in the brain that were involved — the dorsal medial hypothalamus and the paraventricular nucleus, with the input from the paraventricular neurons shown to be extremely strong."

These two regions led researchers to believe that another subset of neurons, which released the hormones thyrotropin-releasing hormone (TRH) and pituitary adenylate cylcase-activating polypeptide (PACAP), were responsible for either turning the AgRP neurons on or off. This surprised the team, because when they selectively stimulated certain parts, mice that had normally been hungry now showed no motivation to eat, while the sated mice appeared ravenous.

"This has led us to the discovery of a novel, previously unknown means of activating AgRP neurons and producing hunger," explained Lowell. "Surprisingly, these hunger-inducing neurons were found in a region of the brain which has long been thought to have the opposite effect — causing satiety.” While the team’s results seem perhaps just as tangled as the neuronal pathways they study, the upshot is that now scientists have a better understanding of which routes hunger takes in the brain.

Being armed with this knowledge doesn’t just facilitate studies on mice; it opens up the possibility to learn why people with eating disorders, either overeating or starvation, come to embody their particular hunger levels. Scientists like Lowell can look at the neural pathways and see where the speed bumps lie, what’s causing the traffic.

“We are getting closer and closer to completing our wiring diagram, and the nearer we come to understanding how it all works,” Lowell concluded, “the better our chances of being able to treat obesity and eating disorders, the consequences of abnormal hunger."

Source: Krashes M, Shah B, Madara J. An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger. Nature. 2014.