Researchers discover the same set of neurons responsible for fever and drowsiness

Study led by a Brazilian at the University of HarvardWe UNITED STATESdiscovered a population of neurons capable of controlling both fever and torpor, a state in which physiological and metabolic functions are extremely reduced. Published in the magazine NatureThe work, supported by FAPESP, could give rise to new treatments for various clinical pathologies, such as strokes, and even help make long space trips possible.

“This population of neurons, located in the region of the hypothalamus called the medial preoptic nucleus, can be identified by the expression of the EP3-type prostaglandin E2 receptor. When these neurons are inhibited, they produce fever; when activated, they induce what we call torpor, a state characterized by a profound and prolonged drop in body temperature and metabolism.”explain Natalia Machadoassistant professor at Harvard Medical School and researcher at the Beth Israel Deaconess Medical Center. The Brazilian was responsible for coordinating the study, in collaboration with Professor Clifford Saper.

Outcome and next steps

Researchers explain that certain species, such as mice, reach a state of torpor when subjected to hunger and cold simultaneously. Humans do not achieve torpor naturally, but the authors believe that the identified group of neurons would also be conserved in us during evolution. The right stimulus could activate or inhibit them, causing fever or drowsiness. During torpor, mice reduce their metabolism by 80%.

“Our idea now is to identify a circulating molecule responsible for these responses and which can be transformed, in the future, into drugs, thus opening the way to new medical treatments in humans,” » Natalia adds.

The work also counts, among the authors, Luis Henrique Angenendt da Costawho made postdoctoral at the Faculty of Dentistry of Ribeirão Preto of the University of São Paulo (FORP-USP) and completed an internship in Machado’s laboratory with bag of FAPESP.

Torpor induction

“Inducing a reduction in body temperature and metabolism can be a very interesting strategy for the treatment of stroke, for example by making the affected tissues tolerate the lack of oxygen for longer, thus increasing the time needed to carry out a medical intervention”illustrates Costa.

Currently, there are ways to achieve therapeutic hypothermia. However, the temperature drops very little and serious side effects can still occur, such as heart instability and intense tremors. Indeed, the body tries at all costs to return to its normal temperature range. The activation of the population of neurons described by the group causes a decrease in body temperature without there being any counter-response from the body. This avoids the unwanted effects of hypothermia. “It’s as if we had set the animals’ thermostat to a lower range, about 10°C below body temperature before torpor induction,” Machado said.

Other hypotheses

In an extreme hypothesis, reducing metabolism could even help during long space trips. Some examples are those planned for Mars by the American (Nasa) and European (ESA) space agencies. With the body in a state of torpor, the demand for energy and therefore food would be lower, which could be essential to support the journey of around a thousand days between the outward journey and the return trip and also reduce the stock of food needed for the journey. “It would not be as drastic a decline in metabolic function as in mice, but something close to the hibernation that bears do in winter,” illustrates the researcher.

Fever induction

In the case of fever induction, as increasing body temperature is a strategy to combat invaders such as viruses and bacteria, the development of new therapies that facilitate their production may also have a positive impact on individuals who present an inadequate response, as observed in the elderly.

To ensure that this specific family of neurons could induce both fever and torpor, the researchers used a set of methods in genetically modified mice that allowed them to specifically manipulate neurons that express EP3-like prostaglandin E2 receptors in the preoptic region, located in the hypothalamus of the brain.

Techniques used

Using the chemogenetic technique, these neurons were infected with an adenovirus which promotes the expression of a mutated receptor in these cells, allowing them to be subsequently activated using a specific drug. The neurons were also manipulated using optogenetics, in which an optical fiber implanted in the region of the brain studied emits light at a specific wavelength that activates these cells. Using techniques measuring neuronal activity in real time, the researchers also observed that calcium is the main intracellular signal involved in the fever and torpor responses of these neurons.

Eventually, the researchers removed these neurons, which prevented the animals from getting fevers and falling into torpor. These data show the importance of these cells in the regulatory mechanisms that lead to both increases and decreases in body temperature in mice.

The role of this family of neurons having been determined, researchers now wish to find a non-invasive way to induce the effects of torpor, since the techniques used in the experiments could not be reproduced in humans. For example, the possibility that a circulating hormone or peptide carries out signaling would be a fundamental avenue for developing new treatments.

*Source: André Julião | FAPESP Agency