There is a group of just 5 thousand neurons at the base of the brain, in a region called the hypothalamus, which does not merely control hunger and satiation. Specialized in the production of two chemical communicators in the brain (the neuropeptide Y, known as NPY and the agouti-related peptide AgRP), these neurons also affect the brain’s reward mechanisms, which coordinate pleasurable sensations. The dual role of these cells was observed by a group of Brazilian and American researchers and was described in June in Nature Neuroscience. “It was the first time that the influence of these cells on other functions of the central nervous system was recorded,” the physician Marcelo Dietrich commented. He is a researcher from the Federal University of Rio Grande do Sul (UFRGS) and the article’s first author.
Dietrich had suspected for some time that the neurons that produce NPY and AgRP might have connections with other brain areas because of the side effects of appetite inhibiting drugs. Compounds such as sibutramine, which has been withdrawn from the market in several countries and is sold in Brazil subject to prescription, reduce hunger by inducing an effect similar to the deactivation of these neurons. However, they also cause a number of changes in the organism, such as a better mood (sibutramine was originally developed as an antidepressant), but entail a higher risk of cardiovascular problems. “We imagined that the neurons that produce NPY and AgRP might not be isolated or tied only to hunger,” Dietrich told us. “We thought that they might also have some role in more sophisticated cognitive functions and we decided to see if they were involved in reward mechanisms,” says the researcher, who is currently spending a period at the laboratory of Tamas Horvath at Yale University in the United States.
To test the possible connections of these neurons with those in other brain regions, Dietrich carried out a number of experiments on rodents genetically modified to have less activity in their appetite neurons. “The cells weren’t eliminated, but their functioning was deficient, thus minimizing the feeling of hunger,” he explained.
The expected outcome was that other mechanisms connected with the group of neurons should also become less active. However, this did not occur. At first, the mice were released in an acrylic box in which a small plastic cylinder had been placed, in order to evaluate their behavior. As rodents are curious and like to become acquainted with any novelty in their environment, the degree of exploration also works as a gauge of the activation of the reward mechanisms. The researchers had imagined that the animals would show little interest in the new object, as their hunger neurons were not working properly, but what they observed was the opposite. As soon as they entered the box, the animals walked frenetically to and fro, exploring the novelties and gathering information about this hitherto unknown environment. This was the first indication that the reward mechanisms were responding significantly.
In the second stage, the researcher repeated the tests, applying a cocaine injection to the animals. This drug is known to activate the neurological reward paths. The larger the dose, the more the mice moved about their environment. Finally, Dietrich established a procedure in which cocaine was injected for five days; this was followed by four days of abstinence and then the drug was applied again. “The brain develops a sort of memory for the effects of cocaine; it created dependency and the rodents responded even more strongly at the end of the tests,” the researcher recalled.
Dietrich then improved the test further, to find out if inhibiting the activity of the neurons that produce NPY and AgRP increased the search for pleasurable situations. This time he put the animals in a box that on one side gave access to another box containing water with cocaine and, on the other side, was linked to a third box containing pure water. First he put the animals in the middle box and allowed them to explore the other two. The animals visited the two boxes roughly the same number of times. Then Dietrich closed the access to the pure water box and only allowed the animals to visit the box with cocaine water. In the next stage, he did the opposite: blocked access to the cocaine box, only allowing visits to the pure water box. And finally, he allowed access to the two boxes again. This time, however, the visits to the cocaine environment were twice as frequent as the visits to the pure water box. This confirmed the search for pleasure.
A matter of age
“We observed that the neurons that produce NPY and AgRP are connected to the neurons that produce dopamine, the pleasure neurotransmitters,” explains Dietrich. “However, this relation is the reverse: when the appetite neurons are inhibited, the dopamine producers become more active, strengthening the functioning of the reward mechanisms,” he explained.
However, there was still a question. The tests had been conducted with adult, genetically modified mice that had been born without the protein that activates the hunger neurons and the researchers had observed that the older the animal, the weaker the effect.
To evaluate the influence of age, it was necessary to change the strategy. The scientists switched off the hunger neurons in animals of different ages (with 5, 10, 15 and 20 days, and adults) and repeated the tests. The results confirmed that the deactivation of the hunger neurons in the younger animals intensified the action of the reward mechanism.
Dietrich believes that this provides evidence that it is in the first week of the rodents` life that these cells establish links to those from other brain areas. In humans, this stage of brain development corresponds to the last three months of pregnancy. “Modifying the functioning of these neurons at the start of development might have consequences that only appear much later in life, increasing susceptibility to drug addiction,” suspects the researcher, who started to investigate the function of the hypothalamus during his doctorate at URFGS, under the guidance of Diogo Onofre de Souza.
Dietrich now plans to understand the influence of feeding newborns on the pleasure search mechanism. “We want to understand how the cells that regulate appetite react when mothers, instead of breastfeeding, give the child mushy food and other foodstuffs in lieu of mother’s milk,” he told us. “Ideally, one day, we want to be able to suggest the nutrients and the number of calories that are recommended for these connections to form properly.”
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