Who among us has never finished a hearty meal, only to go looking for something else to eat, most often something particularly delicious, like a second slice of cake or another scoop of ice cream? This seemingly impulsive behavior, associated with the activation of pleasure circuits in the brain, may be caused by a small group of cells in the brainstem, one of the most primitive structures in the central nervous system, located near the base of the brain in vertebrates since hundreds of millions of years ago. The peculiar function of these neurons, which trigger a desire to eat even if a person is not hungry, was described in an article published in the journal Nature Communications in March by a team led by Brazilian neuroscientist Avishek Adhikari, a researcher at the University of California, Los Angeles (UCLA).
Adhikari, of Indian descent, became interested in neuroscience while studying chemistry at the University of São Paulo (USP). During his master’s and PhD, which he studied in the USA, he specialized in characterizing how different areas of the brain trigger feelings of fear and anxiety. His research group at UCLA is studying a region of the central nervous system called the periaqueductal gray (PAG). The PAG, located in the brain stem, is like a powerful alarm. When fully activated, it triggers an intense panic response.
In experiments on mice, Brazilian neuroscientist Fernando Reis, a member of Adhikari’s lab, was attempting to identify the function of a specific handful of PAG cells — the VGAT neurons, which release the neurotransmitter gamma-aminobutyric acid (GABA) — when he discovered something surprising. Instead of influencing the fear response like other PAG cells, the VGAT neurons caused rodents to begin a frantic search for food — especially high-calorie foods. “We didn’t expect this,” says Adhikari.
To examine the function of these cells, the researchers used a technique called optogenetics. They injected the PAGs of the rodents with a virus containing a gene that produces a light-sensitive protein, then used different colored lasers to stimulate or inhibit the action of VGAT neurons while the animals were exposed to different objects or foods.
Initial tests indicated that the VGAT neurons naturally became more active when mice were looking for food than after they began eating it, a sign that they might be involved in the desire to eat. Reis then performed a battery of experiments in which he placed the rodents in a box, sometimes with a new object (a ping-pong ball or a block of wood) and sometimes with a cricket or a nut.
When the VGAT neurons were activated by light, the animals quickly began exploring the environment and the unfamiliar object — nibbling on the ball or block, for example. When the box contained a cricket, which is common prey for rodents, the mice swiftly captured the insects and consumed them, even though they were already well fed. When presented with a nut, which has more calories than a cricket, the rodents were even quicker to eat. The mice also ate more nuts, as well as other foods they like, such as chocolate and cheese, and fewer vegetables.
When the rodents were placed near a ball and a nut at the same time but were unable to reach either of them, they spent most of their time in the corner of the box near the nut, indicating that activation of the neurons motivated them to search for food. With their VGAT neurons activated, the animals, which were always well fed, were only able to reach the food by walking over a surface that emitted a low electrical charge — enough to cause slight discomfort, but not pain. Usually, mice that were not hungry would avoid this aversive stimulus.
While observing the rodents, Reis and his colleagues also found evidence that VGAT neuron activation was associated with a pleasant and pleasurable state. “After a few repetitions of activating these cells every time the test animal stood on a certain side of the box, it began to remain on that side for longer. When we added a button that could be pressed to activate the cells, the rodent started pressing it more often,” says Adhikari. “If these cells triggered unpleasant sensations, such as hunger, they would not repeat the behavior.”
The tests also showed that activation of these neurons is needed to stimulate the search for food. When the research team used a green laser to inhibit VGAT neurons, the rodents stopped looking for food, even if they were hungry.
Because the periaqueductal gray and VGAT neurons also exist in humans, the scientists hypothesize that they may be linked to eating disorders. “The results suggest that lower activation of this circuit than normal could lead to anorexia. Excessive activation could cause binge eating,” says Reis. If the same effect does occur in humans, the neuroscientist argues, it could be possible to find a way to modify how these neurons function in order to help treat eating disorders.
“Activation of this circuit could also be used to compensate for the loss of appetite resulting from cancer treatment, for example,” says Alexandre Kihara, a neuroscientist from the Federal University of ABC and coauthor of the study.
Immunologist Licio Velloso of the University of Campinas (UNICAMP), who did not participate in the study, sees great potential in the finding that this circuit influences the way rodents look for food and which types of food they seek out. But for now, he says, the findings from the animal model should not be extrapolated to humans. “In people, these cells might make connections with other circuits involved in nutrition,” he explains. “In addition, gamma-aminobutyric acid is an important neurotransmitter in almost all regions of the central nervous system. A therapy that influences its levels could have major side effects.” One theoretical solution proposed by Velloso would be to identify compounds that act exclusively on these neurons and then evaluate how they affect the search for food.
Projects
1. Degeneration and development of the nervous system: The role of epigenetic processes (nº 19/17892-8); Grant Mechanism Regular Research Grant; Principal Investigator Alexandre Hiroaki Kihara (UFABC); Investment R$289,304.54.
2. Characterization of the interneuron population and in vivo cortical and hippocampal electrophysiological activity of adult rats subjected to neonatal anoxia (nº 16/17329-3); Grant Mechanism Doctoral Fellowship; Supervisor Alexandre Hiroaki Kihara (UFABC); Beneficiary Juliane Midori Ikebara; Investment R$335,898.05.
Scientific article
REIS, F. M. C. V. et al. Control of feeding by a bottom-up midbrain- subthalamic pathway. Nature Communications. mar. 7, 2024.
