Uncovering the Role of Microglia in Anxiety-Related Behaviors
Anxiety is a normal and often adaptive emotion that feels like unease, worry, and fear. However, when it becomes chronic and debilitating, it can develop into a serious disorder that affects an individual’s everyday life. Although anxiety-related conditions, including obsessive-compulsive spectrum disorder (OCSD), are prevalent, their roots remain unclear. In a recent study, University of Utah Health scientists revealed the importance of a minor cell type called microglia that control anxiety-related behaviors in laboratory mice. Traditionally, neurons, the predominant type of brain cells, were believed to control behavior.
Microglia function in the brain
Microglia are a type of immune cell located in the brain and account for only 10% of its cells. These cells have several roles, including defending the brain from inflammation, infectious agents, and damaged or abnormal cells. Moreover, they are thought to be the “garbage collector” of the brain that disposes of dying neurons and abnormally shaped proteins. However, recent discoveries revealed that microglia were also important in controlling behavior by communicating with specific neural circuits.
Microglia-mediated behavior control
The researchers showed that specific populations of microglia activated anxiety and OCSD behaviors in mice, while others dampened them. Additionally, microglia communicate with neurons to invoke behaviors. To find out more, the researchers used optogenetics, a technique that combines laser light and genetic engineering, to stimulate specific populations of microglia in the brain. The researchers discovered that they could activate anxiety-related behaviors with the flick of a switch, suggesting that behavior can be generated in two ways using neurons and microglia. Moreover, stimulating the microglia with the laser caused the neurons next to them to fire more strongly, suggesting the two types of cells communicate with each other to drive different behaviors.
Another control layer of microglia revealed
In a population of mice, a mutation in a gene called Hoxb8 caused mice to show signs of chronic anxiety and excessive grooming. Unexpectedly, the researchers identified microglia as the source of these behaviors. Further experiments revealed two control layers by two populations of microglia. The Hoxb8 microglia activate anxiety and OCSD behaviors, while ‘non-Hoxb8′ microglia dampen them. Stimulating the two populations of microglia at the same time prevented the onset of anxiety and OCSD-like behaviors, suggesting that the two populations of microglia act as a brake and an accelerator.
Importance of these mechanisms
The newly identified mechanisms of microglia could be important in maintaining behaviors within the healthy range under normal conditions. Under pathological conditions, these mechanisms could drive behaviors that become debilitating. The research is unique and has challenged the current dogma about the role of microglia in the brain. The findings suggest that defining these interactions in mice could lead to therapeutic targets to control excessive anxiety in patients.
Additional Piece
Anxiety-related disorders, including OCSD, affect millions of individuals worldwide. According to the World Health Organization, one in thirteen people worldwide suffer from anxiety disorders, with women being more prone to anxiety than men. The pandemic and its aftermath raised anxiety to new levels, leading to more individuals seeking help, including therapy and medication.
Existing treatments for anxiety disorders are diverse and include cognitive-behavioral therapy, medication, or a combination of both. However, these treatments cannot be effective for everyone, and some individuals may require alternative or additional therapies.
The recent study by University of Utah Health scientists provided insight into the mechanisms that microglia employed to control anxiety-related behaviors. The findings are significant because understanding how anxiety manifests in the brain can lead to better-targeted therapies.
Moreover, the study challenges the traditional view that only neurons control behavior in the brain. The research showed that microglia were part of the interaction and that they communicated with specific neurons and neural circuits to control behavior. The discovery that microglia play a role in anxiety creates new possibilities for therapies that attempt to target the mechanisms of anxiety disorders by either depressing or stimulating the function of microglia.
To further explore this, researchers are looking at whether sex differences exist in the controlling mechanisms of anxiety behaviors mediated by microglia. Additionally, researchers are exploring the connections between microglia and the gut microbiome, which has surprisingly been found to be an essential factor in mental health.
Conclusion
Understanding the role of microglia in controlling anxiety-related behaviors offers new avenues for possible therapeutic targets. Although the study was conducted on mice, the researchers’ findings offered unique insights into how the brain controls behavior and could be applicable in understanding anxiety disorders in humans. By continuing research into the underpinnings of anxiety and microglia, new treatments for anxiety disorders could be developed that offer hope to millions of individuals affected by anxiety worldwide.
Summary
A recent study by University of Utah Health scientists revealed the importance of a minor cell type called microglia, which control anxiety-related behaviors in laboratory mice. Microglia activate anxiety and OCSD behaviors, with specific populations activating while other populations dampen them. Microglia communicate with neurons to invoke behaviors, and stimulating specific populations of microglia with optogenetics activates anxiety-related behaviors. The study challenges the traditional view that only neurons control behavior in the brain and creates new possibilities for therapeutic targets for anxiety disorders. It also raises new questions about the role of microglia in gut microbiome connections in mental health.
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The pandemic and its aftermath have raised anxiety to new levels. But the roots of anxiety-related conditions, including obsessive-compulsive spectrum disorder (OCSD), remain unclear. In a new study, University of Utah Health scientists have uncovered information about the importance of a minor cell type in the brain, microglia, in controlling anxiety-related behaviors in laboratory mice. Traditionally, neurons, the predominant type of brain cell, are believed to control behavior.
The researchers showed that, like the buttons on a game controller, specific populations of microglia activate anxiety and OCSD behaviors, while others dampen them. Additionally, microglia communicate with neurons to invoke behaviors. The findings, published in Molecular Psychiatryit could eventually lead to new approaches for targeted therapies.
“A small amount of anxiety is good,” says Nobel laureate Mario Capecchi, Ph.D., distinguished professor of human genetics at the University of Utah Spencer Fox Eccles School of Medicine and lead author of the study. “Anxiety motivates us, stimulates us and gives us that extra push that says, ‘I can.’ But a large dose of anxiety overwhelms us. We become mentally paralyzed, our hearts beat faster, we sweat and confusion settles in our minds.”
The newly identified mechanisms could be important in maintaining behaviors within the healthy range under normal conditions. Under pathological conditions, the mechanisms could drive behaviors that become debilitating, Capecchi says.
“This work is unique and has challenged current dogma about the role of microglia function in the brain,” says Naveen Nagajaran, Ph.D, a U of U Health geneticist and neuroscientist and lead author of the study.
Microglia manipulation
Mice with OCSD-like behaviors cannot resist grooming. They lick their bodies so much that their fur falls out and welts appear. Previously, Capecchi’s team discovered that a mutation in a gene called Hoxb8 caused mice to show signs of chronic anxiety and excessive grooming. Unexpectedly, they identified that the source of these behaviors was a type of immune cell called microglia. Representing only 10% of the cells in the brain, microglia were thought to be the “garbage collector” of the brain that disposed of dying neurons, the most common brain cell, and abnormally shaped proteins. Their discoveries were also among the first to reveal that Hoxb8 microglia were important in controlling behavior by communicating with specific neural circuits.
But how the microglia accomplished these tasks remained a mystery. To find out more, Nagajaran turned to optogenetics, a technique that combines laser light and genetic engineering. As if he were playing a video game, he used the laser to stimulate specific populations of microglia in the brain.
To the astonishment of the researchers, they were able to activate anxiety-related behaviors with the flick of a switch. When they used the laser to stimulate a subpopulation, Hoxb8 microglia, the mice became more anxious. When the laser activated Hoxb8 microglia in other parts of the brain, the mice groomed themselves. Targeting Hoxb8 microglia elsewhere had multiple effects: The mice’s anxiety increased, they preened and froze, an indicator of fear. Every time the scientists turned off the laser, the behaviors stopped.
“It was a big surprise for us,” says Nagarajan. “It is conventionally thought that only neurons can generate behaviors. The current findings shed light on a second way that the brain generates behaviors using microglia.” In fact, stimulating the microglia with the laser caused the neurons next to them to fire more strongly, suggesting that the two types of cells communicate with each other to drive different behaviors.
Further experiments revealed another control layer by a population of microglia that do not express Hoxb8. Stimulating “non-Hoxb8” and Hoxb8 microglia at the same time prevented the onset of anxiety and OCSD-like behaviors. These results suggested that the two populations of microglia act as a brake and an accelerator. They balance each other under normal conditions and induce a disease state when the signals are unbalanced.
Research shows that microglia location and type are two characteristics that appear to be important in adjusting anxiety and OCSD behaviors. From there, the microglia communicate with specific neurons and neural circuits that ultimately control behavior, Capecchi says. “We want to learn more about the bidirectional communications between neurons and microglia,” she says. “We want to know what is responsible for that.” Defining these interactions in mice could lead to therapeutic targets to control excessive anxiety in patients.
https://www.sciencedaily.com/releases/2023/06/230605181304.htm
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