Scientists have discovered nerve cells that control some symptoms of the disease

Summary

Feeling sick relates to the body and the brain. Scientists have now identified a group of neurons in mice that had absolute control over symptoms such as fever and behaviors such as seeking warmth.

During infection, inflammatory signals activate immune-sensitive neurons (genetically labeled in red) in the preoperative ventromedial medial area (VMPO) leading to induction of fever and other pathological behaviors. All cells were labeled with nuclear dye (blue). Credit: Courtesy of Dulac Lab/HHMI at Harvard University

Fever, chills, appetite that goes away – we can tell when we get sick. Many people attribute these symptoms of the disease to the immune system, which is fighting the infection. But there is another player involved when we feel sad under the weight of the weather.

“All of this is coordinated by the brain,” says neurobiologist Catherine Dulac, a researcher at the Howard Hughes Medical Institute at Harvard University. Now research from the Dulac team, published on June 8, 2022, in temper naturedemonstrates this broad response to an unspecified set of neurons in the brain.

It is not clear exactly how the brain acts as a gang leader for infection. Previous research identified receptors in the brain that are required for animals to develop fever. But the fever is only part of the story. One of the biggest mysteries is: Where lies the ultimate control over disease-related symptoms and behaviors?

Dulac, postdoctoral fellow Jessica A. Osterhout and colleagues injected mice with particles that mimic bacterial or viral infections to investigate this question. When the mice’s immune systems reacted to these inflammatory molecules, the researchers settled on neurons that jumped into action. The team monitored the gene expression of neurons by sequencing single-celled RNA and mapping the whereabouts of those neurons using a visualization technique called MERFISH, which was developed in the laboratory of HHMI researcher Xiaowei Zhuang at Harvard, who is collaborating on this work.

The researchers focused on an area of ​​the brain’s hypothalamus, the area that regulates most physiological functions. One group of neurons that responded to immune stimuli looked particularly promising. These cells, which the team dubbed LPS-activated VMPO (VMPOLPS) Neurons, sitting close to the blood/brain barrier where they can quickly pick up the winds of infection and connect with the circulatory system. “We thought this would be the ideal area,” Dulac says.

“More and more studies are showing that the connection between these two systems is very complex.”

Catherine Dulac, Research Scholar at Harvard University’s HHMI

Next, the team turned to VMPO . analysisLPS The role of neurons in regulating disease symptoms. In some mice, the scientists artificially activated these neurons thanks to a genetic strategy called TRAP2 developed by HHMI researcher Liqun Luo of Stanford University, also one of the collaborators on the work, and observed that the rodents’ body temperature rose while their appetite waned. When this happened, these mice moved to warmer parts of their enclosures — similar to the way people might huddle under a blanket when sick. In another group of mice, the team killed VMPOLPS nervous cells. When these mice were injected with bacterial or viral particles, they did not develop a fever or moved to warmer climates, suggesting that neurons were essential for those behaviors.

Scientists track how to use VMPOLPS Neurons in the hypothalamus are connected to twelve regions of the brain, including those related to stress, avoidance, appetite control, and thermoregulation. Using pulses of laser light, the scientists activated neural connectivity in a region known to regulate temperature and observed the mice’s body temperature rising. Similarly, when the association with an appetite-related region was turned on, the mice ate less food.

Together, experiments showed that VMPOLPS The population of neurons serves as the seat of disease symptoms. The disease response staff works with the triggers of the infection, and is required for certain symptoms to appear and to communicate directly with the areas of the brain that control how the disease develops. Because of VMPOLPS The proximity of neurons to the blood-brain barrier, scientists believe these cells help relay messages between the brain and the immune system.

At first, Dulac says, her team was more interested in detecting the fever. Eventually, “we realized there was a really interesting dialogue between non-neuronal cells and neurons,” she says. “The story has become way more complex.”

The researchers identified immune cells that make signaling molecules such as cytokines, chemokines, and prostaglandins. Some of these molecules affect the signals sent by VMPOLPS Neurons, indicating a pathway through which the brain and immune system communicate during illness. Based on their results, the team developed a model of how VMPOLPS Neurons act as a control center for disease symptoms.

“The authors show that this group of neurons can directly sense local immune signals and lead to changes in thermoregulation and appetite, raising the startling possibility that they are the cornerstones of a pathway linking the immune system with adaptive behavior,” said graduate students Maddy Jenkins and Elena. Grasheva, a neurophysiologist at Yale University, was not part of this work. “One of the major strengths of this study is that the authors look at this interaction at different levels from animal behavior to individual gene analysis,” they say.

There is still much to learn about how the brain responds to inflammation, from the acute kind investigated in this work, to chronic inflammation caused by aging, obesity, and degenerative diseases such as Alzheimer’s disease. “More and more studies are showing that the connection between these two systems is very complex,” Dulac says.

###

the quote

Jessica A. Oosterhout and others. “Preoptic neuron assembly controls fever and anorexia during illness.” temper nature. Published online June 8, 2022. doi: https://www.nature.com/articles/s41586-022-04793-z

.

Leave a Reply

Your email address will not be published.