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 from Mount Sinai 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 September 30, 2020 in Nature.
"When we think about brain function, we typically think about how neurons control our thoughts and behavior," says Anne Schaefer, MD, PhD, Professor of Neuroscience, and Psychiatry, at the Icahn School of Medicine at Mount Sinai, and 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."
Mount Sinai 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 Ana Badimon, PhD, a former student in the Schaefer Lab and 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 Dr. Schaefer, who is also Co-Director of the Center for Glial Biology at The Friedman Brain Institute at the Icahn School of Medicine.
Dr. Schaefer 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, she adds, 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 Dr. Schaefer. "We believe our work has the potential to add to our knowledge about the mechanisms of neuromodulation."
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Other partners in the Mount Sinai-led study include California Institute of Technology, the Nagoya University Graduate School of Medicine in Japan, Kobe University Graduate School of Medicine in Japan, University of Minnesota, and Harvard Medical School.
The research described in this press release is funded in part by the National Institutes of Health, The Brain and Behavior Research Foundation, The Whitehall Foundation, and The Edward Mallinckrodt Jr. Foundation.
The National Institute on Aging, part of the National Institutes of Health, recently awarded the Icahn School of Medicine at Mount Sinai a $2.99 million grant (number RF1AG068558) that will enable Dr. Schaefer and colleagues to investigate the epigenetic mechanisms of systems microglia activation during aging and its contributions to neurodegenerative diseases.
About the Mount Sinai Health System
The Mount Sinai Health System is New York City's largest academic medical system, encompassing eight hospitals, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai is a national and international source of unrivaled education, translational research and discovery, and collaborative clinical leadership ensuring that we deliver the highest quality care--from prevention to treatment of the most serious and complex human diseases. The Health System includes more than 7,200 physicians and features a robust and continually expanding network of multispecialty services, including more than 400 ambulatory practice locations throughout the five boroughs of New York City, Westchester, and Long Island. The Mount Sinai Hospital is ranked No. 14 on U.S. News & World Report's "Honor Roll" of the Top 20 Best Hospitals in the country and the Icahn School of Medicine as one of the Top 20 Best Medical Schools in country. Mount Sinai Health System hospitals are consistently ranked regionally by specialty by U.S. News & World Report.
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Journal
Nature