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Although there are many causes of infection, in most cases these symptoms always lead to similar symptoms such as fever, loss of appetite and fatigue. However, the exact way in which the nervous system alters body temperature and triggers these disease-related behaviors, in order to coordinate responses to infection, is still unknown. Researchers from Harvard University recently announced that they have succeeded in identifying the locations of specific neurons in mice that specifically cause fever and loss of appetite. This discovery, if confirmed in humans, could improve the treatment of chronic diseases.
During infection, the nervous system communicates with the immune system to understand how seriously the body is under attack, and then orchestrates a series of behavioral and physiological changes that manifest in the unpleasant symptoms of the disease. These adaptive changes aim to increase survival. For example, an increase in body temperature – a fever – makes it difficult for pathogens to survive.
These typical symptoms of disease are widespread throughout the animal kingdom, as they represent the body’s natural response to infection, and are essential to fight pathogens and enable recovery. Although one might assume that these symptoms appear as a side effect of the body’s immune reaction, they are actually mediated by the brain. But scientists do not yet know where and how this occurs in brain tissue.
Recently, researchers at Harvard University looked for the answer in mice. They discovered how preoperatively a small group of neurons near the base of the brain “read” signals from the body’s immune system and how these signals alter the activity of the neural circuit to trigger symptoms of illness, particularly fever and loss of appetite. Their study was published in the journal temper nature.
New neurons active in response to infection
Initially, researchers from the laboratories of Catherine Dulac and Xiaowei Zhuang were examining the “fever effect” in autistic patients, a phenomenon in which autism symptoms subside when a patient has symptoms of infection. The goal was to find the neurons that generate fever and determine their association with those involved in social behavior.
For this purpose, the team used mice as a study model. First, they caused a “mock” bacterial infection by injecting mice with a small amount of components of the bacterial membrane, called lipopolysaccharides (LPS). The following inflammatory response includes many pathological symptoms such as fever, loss of appetite, increased heat-seeking behavior, decreased mobility, and impaired social interactions. Next, they used sequencing and fluorescence imaging to determine which parts of the brain were most active during injury.
Then postdoctoral researcher Jessica Osterhout found that a specific area of the hypothalamus, called the ventral medial preoperative area (VMPO), was significantly 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, not previously described, are located in the hypothalamus, which controls key homeostatic functions that keep the body in a healthy, balanced state.
As a result, the team used a combination of powerful and precise methods, chemical genetics and optogenetics, to control and study connectivity between different populations of neurons. Using these tools, the researchers were able to activate or deactivate specific neurons in the brains of mice and determine their functions.
Sure enough, the researchers found that they could raise the mice’s body temperature, increase heat-seeking behavior, and reduce appetite. The neurons, which are described in the study, operate in 12 brain regions, some of which are known for their ability to control thirst, pain and social interactions. This suggests that other pathological behaviors may be influenced by the activity of neurons in this region.
Certain nervous behavior brings hope
During the experiments, the scientists also observed intense activity and activation in this group of neurons when immune system molecules fire increased signals. This indicates that the brain and immune system communicate with each other via paracrine signaling in the pre-medullary region and the blood-brain septum. Paracrine signaling is the production of a cell-specific signal to cause changes in neighboring cells.
Oosterhout said in a statement: As a neuroscientist, we often think of neurons that activate other neurons and not that these other paracrine or secretion-type approaches are really necessary. I changed my way of thinking about the problem “.
Furthermore, in these neurons, researchers have discovered 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 come into contact with the blood and the peripheral immune system are activated, and these non-neuronal cells secrete cytokines and chemokines which in turn activate the set of neurons that we found.e “.
The hope is that one day scientists will be able to exploit these findings in humans, and reverse the process when it becomes a health threat. Fever, for example, is usually a healthy reaction that helps eliminate the pathogen. But when it rises too high, it puts the body at risk. Likewise, loss of appetite or decreased thirst may be beneficial initially, but persistent nutrient or hydration deficiency may impede recovery from infection.
Jessica Osterhout concludes: “ If we know how it works, maybe we can help patients who have a hard time dealing with these kinds of symptoms, like chemotherapy patients or cancer patients, for example, who have very poor appetite. “.
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