Neurons trigger the frantic search for food – 04/02/2024 – Science

For the first time, researchers have identified a set of nerve cells, located deep in the brain, directly related to the manifestation of compulsive food-seeking behavior. The discovery, published in the journal Nature Communications, was made by a group from the University of California at Los Angeles (UCLA), in the United States, and the Federal University of ABC (UFABC), in São Bernardo do Campo (SP).

This is a population of neurons hidden in a region called the periaqueductal gray matter, which is at the base of the brain, in the opposite direction to the prefrontal cortex. Also known as VGAT cells (vesicular GABA transporter), they use the neurotransmitter Gaba (gamma-aminobutyric acid), which plays an important role in regulating neuronal activity. They are present in several areas of the brain and spinal cord, contributing to the modulation of mood, sleep, anxiety and the response to stress, among other functions.

“However, the relationship between VGAT cells in the periaqueductal gray region and food was not known”, describes researcher Avishek Adhikari, from the Department of Psychology at the University of UCLA. At the UCLA Neuroscience Laboratory, under the leadership of Adhikari, studies are carried out to understand how the brain coordinates the constellation of changes related to emotional behaviors, with a focus on fear and anxiety.

The discovery was accidental. “We were investigating neurons in the periaqueductal gray matter with an interest in anxiety, not food”, reveals the main author of the work, Brazilian neuroscientist Fernando Reis, from UCLA. The researchers’ initial hypothesis was that the activation of VGAT cells should inhibit fear and panic reactions. “When we activated them in mice, we saw that not only did this not happen, but there was an unrestrained search for food”, says Reis, who decided to deepen the study by carrying out more tests. The investigation was supported by Fapesp through three projects.

The new battery of experiments brought surprising revelations. Even in completely sated animals, without any hunger, the activation of these cells triggered a frantic search for food and made them eat more than would be normal. The opposite also happened. Animals purposely left very hungry ate less when VGAT neurons were inhibited.

During the tests, the scientists observed that the mice seemed to enjoy the stimulation they received. “They spent more time on the side of the box where they received stimuli to activate the periaqueductal VGAT cells. We believe that the uncontrolled search for food produces positive, pleasant and pleasurable sensations of reward”, observes Reis.

The mice were also willing to overcome obstacles to reach food. “They climbed a small wire grate that gave low-voltage shocks to reach pieces of nuts. It’s not desirable, but the impetus to get to the food was greater than the discomfort,” reports Adhikari.

Light stimuli

The neuronal circuit stimulated by the researchers corresponds to around 10% to 12% of the nerve cells contained in the periaqueductal gray substance. The technology chosen to selectively activate them was optogenetics. “The problem that optogenetics tries to solve is how to manipulate the activity of a subset of cells in a specific area of ​​the brain”, explains Adhikari, who did his postdoctoral work at the laboratory at Stanford University, in the United States, where this technique was developed. developed.

Optogenetics makes neurons sensitive to light so that they can be stimulated or inhibited. To do this, researchers inject target neurons with a genetically modified virus, which carries a light-sensitive protein obtained from a single-celled algae. “After infection with the modified virus, the selected population of neurons receives this photosensitive protein and also instructions to start manufacturing it”, explains researcher Alexandre Kihara, from UFABC, one of the 5 Brazilians who are part of the team of researchers who discovered the relationship between this subgroup of VGAT cells and food.

The mice also received a fiber optic implant to conduct blue light to properly infected cells. “Captured by photosensitive proteins, the light stimulus is converted into electrical activity. In this way, we can make the cells more or less active according to the wavelength of the light emitted”, describes Juliane Ikebara, who was a doctoral fellow at UFABC and is co-author of the work.

Under blue light, the mice brutally changed their behavior. “We saw well-fed, sated animals dart after an insect to devour it,” says Adikhari.

Mapping the areas affected by the increased release of the neurotransmitter Gaba revealed an impact on deep regions of the brain, such as the so-called zona incerta. “We saw an increase in neural activity in this area when the animal is approaching food”, explains the researcher.

The most important question is whether periaqueductal VGAT cells in humans also induce food consumption. Previous experiments indicate that the function of the periaqueductal area is similar in humans and rats. In both species, injecting electrical current into this area causes acute symptoms of fear, panic and analgesia.

“Our findings cannot be directly tested in humans at this time, but future studies could show whether activation of these periaqueductal VGAT cells in monkeys induces food seeking, which would suggest that something similar happens in humans,” says Adhikari.

New studies initiated by the group investigate the predilection of animals whose neurons were stimulated by foods rich in proteins and sugars, among other aspects. “The mice didn’t want vegetables. They preferred sausage, sugar, cheese and chocolate,” says Adhikari.

For researchers, the discovery that stimulation or inhibition of this specific area of ​​the brain causes behaviors similar to those seen in anorexia or binge eating could lead to the exploration of new approaches to controlling eating disorders.