Here''s what happens when you get an infection: The nervous system communicates with the immune system to determine if the body is under attack, and then orchestrates a series of behavioral and physiological changes that manifest as sickness''s unpleasant symptoms. For neuroscientists, longstanding questions have been: How and where does this happen in the brain?
Researchers from Harvard''s Catherine Dulac and Xiaowei Zhuang''s labs searched for a clue in mice''s brains.
In an a study published in Nature, researchers and their collaborators describe discovering a small group of neurons near the brain''s base that may induce symptoms of sickness, including fever and appetite loss.
The neurons, which haven''t been described previously, are found in the hypothalamus, which controls key homeostatic functions that keep the body in a healthy state. Researchers found receptors in the neurons that are capable of collecting molecular signals from the immune system, an capability that most neurons have.
According to Jessica Osterhout, a postdoctoral researcher at the Dulac Lab and the research''s lead author, it was vital for us to establish this broad principle so that the brain may even discern these immune states. This was previously difficult to understand.
The research found that the key area of the hypothalamus is right next to the permeable blood-brain barrier, which helps circulate blood to the brain.
What''s happening is that the cells of the blood-brain barrier that are in contact with the blood and with the peripheral immune system are activated, and these non-neuronal cells secrete cytokines and chemokines that, in turn, activate the number of neurons we discovered, according to Dulac, Lee and Ezpeleta Professor of Arts and Sciences and Higgins Professor of Molecular and Cellular Biology.
Scientists are able to one day deliver the research to humans, reversing the process if it becomes a health danger.
A fever, for instance, is usually a good reaction that helps eliminate a pathogen. However, when it gets too high, it becomes dangerous. Similarly, loss of appetite or reduced thirst may, at first, be beneficial. However, a sustained lack of nutrients or hydration may start to impede recovery.
If we know how it works, then we may be able to assist patients who have difficulty with these kinds of symptoms, such as chemo patients or cancer patients, who have a very low appetite, but there isn''t really anything we can do for them, according to Osterhout.
The project was started as a project to investigate the fever effect in autism patients, a phenomenon in which autism symptoms fade as a patient experiences infection symptoms. Initially, the goal was to identify the neurons that produce fever and link them to social activities.
Osterhout uncovered many types of neurons that are activated when an animal is sick. She identified about 1,000 neurons in the hypothalamus'' ventral medial preoptic region because of their proximity to the blood-brain barrier.
Osterhout injected mice with pro-inflammatory medications that mimic bacterial or viral infection. Using a wide range of approaches, chemical therapy and optogenetics, to monitor and investigate the connectivity among the different neuronal populations. Through these techniques, researchers were able to activate or silence the neurons in command in mice and pin down their function.
These researchers found that they could increase body temperature in mice, improve warmth-seeking behavior, and decrease appetite. The neurons described in the study have extended to twelve brain areas, some of which are known to control thirst, pain sensation, and social interactions. This suggests that other sickness behaviors might be affected by the neuron activity in the area.
During the experiments, scientists noticed increased activity and activation in this cell of neurons when molecules from the immune system gave off increased signals. This suggests that the brain and the immune system were communicating with each other through paracrine signals at the ventral medial preoptic area and the blood-brain barrier right next to it. Paracrine signals are when cells produce a signal to trigger changes in nearby cells.
Osterhout said the process improved her understanding of how neurons function.
We often think of neurons activating other neurons, not that these other paracrine-type or secretion-type methods are absolutely necessary, according to a neuroscientist. It altered how I was deciphering the problem.
