Manipulating a newly discovered neural circuit can either reduce appetite or lead to significant overeating.
We engage our jaws for a variety of activities such as speaking, singing, laughing, and chewing, each of which depends on the intricate coordination of muscles controlled by brain neurons.
Recent research from Rockefeller University, led by Christin Kosse and Jeffrey M. Friedman, has revealed that the neural circuit responsible for the jaw movements crucial for survival—eating—may be simpler than previously thought. They discovered a three-neuron circuit that connects a hormone signaling hunger to the jaw movements involved in chewing. This circuit includes a group of neurons in a specific area of the hypothalamus known to cause obesity when damaged.
Interestingly, when these BDNF neurons are inhibited, animals tend to eat excessively and even perform chewing motions without any food or sensory cues that usually signal hunger. Conversely, activating these neurons leads to decreased food consumption and stops the chewing motions, effectively acting as an appetite suppressant.
The straightforward structure of this circuit implies that the drive to eat could resemble a reflex more than previous theories suggested, potentially offering new insights into how the feeding process is initiated.
“It’s fascinating to discover that these neurons are so closely linked to motor control,” said study’s lead author Christin Kosse, a research associate in the lab. “We didn’t anticipate that restricting jaw movement could work as a form of appetite control.”
More than just the sensation of hunger?
The urge to eat arises not only from hunger but is also influenced by various factors such as pleasure, social interactions, rituals, and habits. Sensory elements like smell, taste, and emotions can also determine our eating behavior. In humans, the conscious decision to eat less or more can play a significant role as well. Understanding obesity proves complex due to the intricate combination of diet, environment, and genetics. Genetic mutations, including those affecting leptin (an appetite-suppressant hormone) and BDNF, can lead to extreme overeating and significant obesity, indicating that these elements typically help control appetite.
When Friedman’s research team began their investigation, they aimed to locate the BDNF neurons that manage overeating—a challenge that has stumped scientists for years due to the widespread presence of BDNF neurons in the brain, which also regulate neuron development and survival.
The study focused specifically on the ventromedial hypothalamus (VMH), a deep-brain area associated with glucose regulation and appetite. Prior research has shown that damage to the VMH can lead to overeating and obesity, similar to the effects of mutated BDNF proteins, suggesting that the VMH might play a regulatory role in eating behavior.
They hoped that by documenting how BDNF affects eating behavior, they could uncover the neural circuitry responsible for converting sensory inputs into jaw movements. They found that BDNF neurons in the VMH—unlike those in other brain areas—activate when animals become obese, implying that they are stimulated to suppress food intake as weight is gained. Thus, a lack of these neurons or mutations in BDNF can result in obesity.
Chewing without food
Researchers conducted a series of experiments using optogenetics to either activate or deactivate the BDNF neurons in the VMH of mice. When these neurons were activated, the mice completely refrained from eating, despite being hungry. Silencing these neurons led to the opposite outcome; the mice consumed an astonishing 1200% more food than usual over a short time frame.
“Initially, we theorized that BDNF neurons might encode emotional responses related to hunger or the pleasure of eating,” Kosse explains. “However, further experiments showed that activating these neurons reduced food intake regardless of whether the mice were presented with standard chow or high-calorie foods, like a chocolate mousse cake for mice.”
Because hunger isn’t the only reason we eat, they also offered highly palatable food to already satiated mice. The mice consumed the treats until the BDNF neurons were inhibited, at which point they immediately stopped eating.
“This initially confused us because earlier studies indicated that the desire to eat for pleasure differs from the hunger drive, which attempts to alleviate the unpleasant sensation associated with hunger,” Kosse points out. “We showed that activating BDNF neurons can suppress both motivations to eat.”
Equally remarkable was that inhibiting BDNF neurons prompted the mice to engage in chewing motions directed at any nearby objects, even in the absence of food. This chewing compulsion was so strong that the mice nibbled on various items around them, including a water feeder, wooden blocks, and even wires monitoring their neural activity.
The neural circuit
So how does this motor-control switch relate to the body’s hunger and eating desires?
By mapping the connections of the BDNF neurons, the researchers discovered that these neurons serve as a critical component of a three-part neural circuit linking hormonal signals that regulate appetite to the motions required for eating.
At one end of the circuit are specialized neurons in the arcuate nucleus (Arc) of the hypothalamus that detect hunger signals, including leptin, which fat cells release. A high leptin level indicates energy availability, whereas low levels signal the need to eat. Mice without leptin become obese. The Arc neurons then send signals to the VMH, where they activate the BDNF neurons, which subsequently project to the brainstem center known as Me5 to control jaw muscle movements.
“Previous studies have demonstrated that mice with Me5 neurons destroyed during development do not eat solid food, leading to starvation,” Kosse states. “Thus, manipulating the BDNF neurons that connect to this area leads to jaw movements.”
This also clarifies why VMH damage is linked to obesity, according to Friedman. “Our findings indicate that the obesity seen in such cases arises from the loss of BDNF neurons, unifying known mutations that cause obesity into a coherent circuit structure.”
The research presents a deeper understanding of the link between sensation and behavior. “The structure of the feeding circuit is surprisingly similar to that of a reflex,” Friedman remarks. “This is unexpected because eating is a complex behavior influenced by many factors, whereas a reflex consists of a specific stimulus and a consistent response. Our findings suggest the boundary between behavior and reflex may not be as clear-cut as previously thought. We believe neurons in this circuit are influenced by other brain neurons that regulate appetite signals.”
This idea aligns with neurophysiologist Charles Sherrington’s early 20th century work, which illustrated how a reflex like coughing could be moderated by conscious desires, such as wanting to suppress it in a crowded theatre.
Kosse adds, “Given that eating is essential for survival, this food-regulating circuit may have ancient roots, potentially serving as a foundation for more complex processing that evolved in the brain.”
Looking ahead, the researchers are interested in exploring the Me5 brainstem area, hypothesizing that the jaw’s motor controls might serve as a model for understanding other behaviors, including compulsive actions linked to stress, such as chewing on a pencil or one’s hair.
“By investigating these premotor neurons in Me5, we may uncover whether other neuron groups project into this area, influencing distinct natural behaviors, just like BDNF neurons affect eating,” she concludes. “Are there stress-sensitive neurons that also connect here?”
