Immune cells in the brain that act as scavengers to remove dying cells also play a potentially pivotal role in the regulation of behavior in both mice and humans, a research team has found. The newly identified function of the scavenger cells, known as microglia, to protect the brain from abnormal activation in health and disease has implications for treating behavioral abnormalities associated with neurodegenerative and inflammatory diseases in humans. The study was published  in Nature.

"When we think about brain function, we typically think about how neurons control our thoughts and behavior," says the senior author of the study. "But the brain also contains large amounts of non-neuronal cells, including microglia, and our study puts a fresh spotlight on these cells as partners of neurons in the regulation of neuronal activity and behavior. We found that microglia can sense and respond to neuronal activation and provide negative feedback on excessive neuronal activity. This novel microglia-mediated mechanism of neuromodulation could play an important role in protecting the brain from disease."

The researchers identified the biochemical circuit that supports neuron-microglia communication. When neurons are active, they release a molecule called adenosine triphosphate (ATP). Microglia can sense extracellular ATP, and the compound draws them toward the active neurons. As the next step, the microglia break ATP down to generate adenosine, which then acts on adenosine receptors on the surface of active neurons to suppress their activity and prevent excessive activation.

"In inflammatory conditions and neurodegenerative diseases like Alzheimer's, microglia become activated and lose their ability to sense ATP and to generate adenosine," says the first author of the study.

"This suggested to us that behavioral alterations associated with disease may be mediated, in part, by changes in microglial-neuron communication," adds the senior author.

The author describes the identification of the biochemical circuit that enables microglial control of neuronal responses as a potential "paradigm shift" in our understanding of how innate immune cells in the brain can contribute to behavior. This observation is particularly important given the fact that microglia, while residing in the brain, are uniquely equipped to also respond to signals generated in the peripheral body. Microglia can therefore act as an interface between peripheral body changes, like a viral infection, and the brain by communicating these signals to neurons to modulate behavioral responses.

By shedding valuable light on the interaction of neurons and microglia, the study carries a number of practical implications for further research. They range from novel approaches of neuromodulation of normal behaviors by targeting microglia, to potential treatment of behavioral abnormalities associated with neurodegenerative diseases.

"The future promise of our study also lies in the identification of novel signals like ATP that will allow microglia to modulate the function of highly diverse neurons, including neurons controlling sleep or metabolism," says the senior author. "We believe our work has the potential to add to our knowledge about the mechanisms of neuromodulation."

https://www.nature.com/articles/s41586-020-2777-8