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Although there are many causes of infection, in the majority of cases these always trigger similar symptoms such as fever, loss of appetite and fatigue. Yet exactly how the nervous system alters body temperature and triggers these disease-related behaviors, in order to coordinate responses to infection, has so far remained unknown. Recently, researchers from Harvard University declared having succeeded in locating, in mice, certain neuronal cells inducing in particular fever and loss of appetite. This discovery, if confirmed in humans, could improve the treatment of chronic diseases.
During an infection, the nervous system communicates with the immune system to understand how badly the body is under attack, then orchestrates a series of behavioral and physiological alterations that manifest in the unpleasant symptoms of the disease. These adaptive changes aim to increase survival. For example, increased body temperature — fever — makes it harder for pathogens to survive.
These typical symptoms of illness are widely shared across the animal kingdom, as they represent the body’s natural response to infection, essential for fighting off pathogens and enabling recovery. Although one might assume that these symptoms arise as a side effect of the body’s immune reaction, they are indeed mediated by the brain. But scientists didn’t know until now where or how it happens in brain tissue.
Recently, researchers at Harvard University looked for the answer in mice. They discovered how a small group of preoptic neurons near the base of the brain “read” signals from the body’s immune system and how these signals alter neural circuit activity to trigger symptoms of disease, especially fever and loss of appetite. Their study is published in the journal Nature.
New neurons, players in the response to infection
Initially, researchers from the labs of Catherine Dulac and Xiaowei Zhuang were examining the ‘fever effect’ in autistic patients, a phenomenon in which autism symptoms subside when a patient experiences symptoms of infection. . The aim was to find the neurons that generate fever and identify their link with those involved in social behavior.
For this purpose, the team used mice as a study model. First, they induced a “fake” bacterial infection by injecting the mice with a small amount of bacterial membrane components, called lipopolysaccharides (LPS). The inflammatory response that follows includes several disease symptoms such as fever, loss of appetite, increased heat-seeking behavior, decreased movement, and impaired social interactions. Next, they used sequencing and fluorescence imaging to determine which parts of the brain were most active during infection.
Postdoctoral researcher Jessica Osterhout then found that a specific area of the hypothalamus, called the ventral medial preoptic area (VMPO), was highly activated compared to controls. This area is close to the blood-brain barrier, which helps blood flow to the brain while providing a barrier against pathogens.
Specifically, these neurons, which have not been previously described, are found in the hypothalamus, which controls key homeostatic functions that keep the body in a healthy and balanced state.
As a result, the team used a set of powerful and precise methods, chemogenetics and optogenetics, to control and study the connectivity between the different neuronal populations. Using these tools, the researchers were able to activate or inhibit specific neurons in the brains of mice and determine their functions.
Sure enough, researchers found that they could raise body temperature in mice, increase heat-seeking behavior, and decrease appetite. The neurons, described in the study, project to 12 brain areas, some of which are known to control thirst, pain sensation and social interactions. This suggests that other sickness behaviors may be affected by the activity of neurons in this region.
A specific neural behavior, bringing hope
During the experiments, the scientists also noticed intense activity and activation in this population of neurons when immune system molecules gave off increased signals. This suggests that the brain and the immune system communicate with each other via paracrine signaling at the ventral medial preoptic area and the blood-brain barrier. Paracrine signaling is the production of a specific signal by cells to trigger changes in neighboring cells.
Osterhout said in a statement: As a neuroscientist, we often think of neurons activating other neurons and not that these other paracrine-type or secretion-type methods are really essential. It changed my way of thinking about the problem “.
Moreover, the researchers discovered in these neurons receptors capable of detecting molecular signals from the immune system, an ability that most neurons do not have. Professor Dulac explains: What happens is that the blood-brain barrier cells that are in contact with the blood and with the peripheral immune system become activated, and these non-neuronal cells secrete cytokines and chemokines which in turn activate the population of neurons we founde “.
The hope is that scientists can one day exploit these findings in humans, reversing the process when it becomes a health threat. A fever, for example, is usually a healthy reaction that helps eliminate a pathogen. But when it rises too high, it endangers the organism. Similarly, loss of appetite or reduced thirst may initially be beneficial, but sustained lack of nutrients or hydration may compromise recovery from infection.
Jessica Osterhout concludes: “ If we know how it works, maybe we can help patients who have difficulty with these kinds of symptoms, like chemo patients or cancer patients, for example, who have a very poor appetite. “.