If you struggle to stick to a diet, researchers at HHMI’s Janelia Research Campus say the culprit may be hunger-sensitive brain cells called AGRP neurons. New experiments show these cells produce aversive feelings that compel animals — including people — to seek food, helping explain why snacking can feel irresistible.
Hunger often feels unpleasant, and that negative sensation can undermine dieting efforts. Scott Sternson, a group leader at Janelia, explains that AGRP neurons impose an internal cost for ignoring physiological needs. In modern environments where food is abundant, that signal can seem like an annoyance. From an evolutionary perspective, however, the push to act makes sense: when food or water is scarce, seeking it can be risky and requires motivation.
Rather than directly forcing an animal to eat, AGRP neurons act as a motivational system that teaches animals to respond to sensory cues that predict food. Sternson’s team also found a distinct set of neurons that produce unpleasant thirst signals. Their findings, published in Nature on April 27, 2015, indicate these need-sensitive neurons transmit a negative-valence teaching signal: animals learn to associate environmental cues with relief from the aversive state produced by those cells.
Multiple types of neurons coordinate feeding behavior, and hunger influences virtually every cell in the body. Yet until this work, the neuronal basis for the aversive quality of hunger was not fully reconciled with prior observations. Earlier studies often focused on neurons that promote eating by enhancing the positive aspects of food — for example, by increasing the hedonic response to taste. That left open the question of whether a separate, negative signal motivates animals to end the hunger state.
AGRP neurons reside in the hypothalamus, a brain region that regulates energy balance. Researchers had already established that AGRP cells become active when the body needs energy and that their activation correlates with feeding. What was missing was an explanation of how AGRP activity generates a behavioral drive. To explore this, the team combined targeted neural manipulations with behavioral assays in mice.
In a key set of experiments, postdoctoral researcher Nicholas Betley and graduate student Zhen Fang Huang Cao offered well-fed mice two flavored, non-nutritive gels — strawberry and orange. The mice sampled both flavors normally. The researchers then artificially activated AGRP neurons while the animals consumed one of the flavors. When tested later, mice avoided the flavor that had been paired with AGRP activation, indicating that AGRP activity carried negative valence and conditioned avoidance.
In a complementary test, the team switched AGRP neurons off while hungry mice consumed a particular flavor. The animals developed a preference for the flavor paired with AGRP inhibition, suggesting they were motivated to seek states that silence the aversive signal. Additional experiments showed the mice learned to prefer locations where AGRP activity had been silenced and to avoid places associated with AGRP activation.
Using a miniature mobile microscope, postdoctoral researcher Shengjin Xu recorded AGRP neuron activity in hungry mice. As expected, AGRP cells were active while animals sought food. Crucially, the neurons shut down not only when the mice began eating but also as soon as the animals saw food or even a cue that predicted food. Activity remained low during consumption. This rapid reduction in AGRP signaling in response to food cues fits the idea that AGRP neurons provide an aversive teaching signal: relief from that signal reinforces behaviors and cues that predict food availability.
The researchers extended the approach to thirst-sensitive neurons in the subfornical organ (SFO). Like AGRP neurons, SFO neurons produced aversive signals: animals avoided places where SFO neurons had been active and sought places where the cells had been silenced. Despite their shared motivational quality, the two systems are specific in their goals: AGRP neurons drive feeding while SFO neurons drive drinking. Independent work has also implicated SFO circuits in regulating thirst, supporting the broader conclusion that need-sensing neurons use negative-valence signals to teach animals which cues and locations predict relief.
Looking ahead, the team plans to compare AGRP and SFO circuits in more detail and to explore ways to modulate AGRP function. A better understanding of how these neurons generate aversive signals could eventually inform strategies to reduce unwanted overeating and improve dieting success, although translational applications will require extensive additional research.
Source: Jim Keeley — HHMI
Image Source: Public domain
Video Source: Video credited to Scott Sternson, HHMI, Janelia Farm (originally presented at Kavli Frontiers of Science)
Original Research: “Neurons for hunger and thirst transmit a negative-valence teaching signal” by J. Nicholas Betley, Shengjin Xu, Zhen Fang Huang Cao, Rong Gong, Christopher J. Magnus, Yang Yu and Scott M. Sternson. Nature. Published online April 27, 2015. doi:10.1038/nature14416
Abstract
Neurons for hunger and thirst transmit a negative-valence teaching signal
Homeostasis maintains essential physiological variables within a healthy range, and deviations from that balance trigger behavior critical for survival. The motivational processes that drive behavior in response to physiological need states remain incompletely understood. Using cell-type-specific manipulations in mice, the authors examined two neuron populations that regulate energy and fluid homeostasis. They found that starvation-sensitive AGRP neurons show properties consistent with a negative-valence teaching signal: mice avoid AGRP activation, indicating it is aversive, and inhibition of AGRP neurons conditions preferences for flavors and places. Deep-brain calcium imaging revealed that AGRP neuron activity rapidly declines in response to food-related cues. Complementary experiments showed that activation of thirst-promoting SFO neurons also conditions avoidance. Together, these findings indicate that need-sensing neurons teach animals to prefer environmental cues associated with nutrient or water ingestion by reducing a negative-valence signal during homeostatic restoration.
“Neurons for hunger and thirst transmit a negative-valence teaching signal” by J. Nicholas Betley, Shengjin Xu, Zhen Fang Huang Cao, Rong Gong, Christopher J. Magnus, Yang Yu and Scott M. Sternson. Nature. Published online April 27, 2015. doi:10.1038/nature14416