Studies in mice by a Baylor College of Medicine-led team have identified a previously unknown neural circuit that is activated by food odors and stops the animals from eating, to the point that they starve to death. The researchers say further studies will be needed to determine whether the same circuit, which connects the basal forebrain to the lateral hypothalamus, may also be involved in regulating nicotine-related appetite suppression, or driving food aversion behaviors that can be characteristic of eating disorders.

“We think this work has potential implications that reach beyond feeding behaviors and mouse physiology,” said Benjamin Arenkiel, PhD, associate professor of neuroscience and molecular and human genetics and a McNair Scholar at Baylor. “This circuit is highly involved with how our brain perceives the outside world and brings this information to the hypothalamus, thus connecting with aspects of physiology like feeding, which relates to eating disorders that are associated with many neuropsychiatric conditions.” Arenkiel is also a member of the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital.

Arenkiel and colleagues reported their findings in eLife, in a paper titled, “Sensory perception drives food avoidance through excitatory basal forebrain circuits.”

Appetite is driven by the body’s nutritional state, environmental cues, mood, and reward pathways, the authors explained. Sensory perception of food can increase appetite or, in the case of rotting or spoiled food, reduce appetite and food aversion. “The integration of sensory information to either drive or diminish appetite involves a complex combination of both innate and learned behaviors,” they noted.

In humans and rodents, smell, or olfaction, plays a key sensory perceptive role in feeding. Individuals who can’t smell show abnormal food perception and appetite changes. Food smell also affects feeding and metabolism in mice. The hypothalamus plays a critical role in feeding behavior and appetite, but how multisensory information, and in particular olfactory perception of food, is relayed to relevant neurons in the hypothalamus isn’t understood.

Researchers in Arenkeil’s lab used a combination of techniques, including in vivo microendoscopy-imaging, to identify a subset of neurons in the basal forebrain (BF) that express vGlut2 (vGlut2BFneurons), and which were specifically activated by food odors. “That was very interesting because we know that the sense of smell can drive appetite,” noted Jay M.Patel, a student in the Arenkeil lab and lead author of the team’s published paper. “For instance, after smelling dessert, you may want to eat it even though you just had a big meal. Or conversely, after smelling a spoiled dish you won’t eat it, even if you are very hungry.”

When the scientists then used genetic and viral techniques to activate vGlut2+ neurons in the basal forebrain of experimental mice, they found that the animals’ feeding behavior changed. They stopped eating, and within a couple of weeks starved to death. Weight loss was evident within four or five days. “Experimental animals rapidly lost 30% of their initial body weight as food intake ceased, eventually leading to starvation and death within 9–12 days after viral injection,” the authors wrote. A battery of tests confirmed that the weight loss wasn’t due to any metabolic dysfunction. There were no changes to pituitary or circulating thyroid hormones, or to levels of glucose or insulin, and leptin levels were no different between the experimental and control groups, so leptin signaling wasn’t involved in the weight loss or reduced food intake. Rather, the animals lost weight because vGlut2BFneuron stimulation effectively instructed them to stop eating. “They did not eat even when they were hungry, which we found remarkable because animals are compelled to eat to survive,” Patel said.

The finding that activation of food-responsive vGlut2BFneurons switched off feeding and led to starvation was “intriguing”, given that food odors are commonly considered to be positive stimuli, the researchers pointed out. Further experiments showed that the vGlut2+ basal forebrain neurons were more strongly responsive to naturally aversive odors than they were to food or control stimuli, which triggered food avoidance behavior in mice. “It seemed that the animals were afraid of food,” Patel continued “Even though they were hungry, they avoided locations where food was placed.”

By labeling neurons the team showed that the basal forebrain vGlut2+ excitatory neurons sent out projections to the lateral hypothalamus (LH), creating a direct, functional link between the BF and this area of the hypothalamus, which is a known feeding control center. Using optogenetic techniques the researchers then demonstrated that activating the vGlut2BFneuron projections in the lateral hypothalamus of experimental animals had the same effect as activating the vGlut2BFneurons, triggering reduced food intake and food avoidance, even after a period of fasting.

Optogenetic stimulation of either the vGlut2BFneurons or their LH projections also triggered avoidance of food odors. “We also found that a subset of these excitatory neurons responded to food-related odors, and an even larger portion of them responded to odors associated with aversive and/or spoiled food odorants,” the authors wrote. “Collectively, these data suggest that the induced hypophagia elicited by targeted activation of vGlut2BFneurons or their projections to LH, may be attributed to a circuit-specific food avoidance.”

“We have identified a brain circuit driven by vGlut2+ neurons in the basal forebrain that suppresses appetite when it’s active and stimulates feeding behavior when it’s inactive,” Patel said. “We also determined that this circuit, which is formed by just a couple of thousand neurons involved in perceiving the outside world, connects with and overrides feeding behaviors regulated by the hypothalamus.”

The researchers suggest that their data further add to growing evidence that the basal forebrain acts as a key integrator of multiple sensory stimuli. “Notably, these findings reveal a previously unknown circuit that links cholinergic signaling in the basal forebrain to feeding behavior, appetite suppression, and food avoidance,” they concluded. “In the future, it will be important to uncover potential functions of this circuit in behaviors associated with nicotine-mediated appetite suppression, addiction, and/or learned food aversion associated with eating disorders.”