Brain nerve cells
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Studies by researchers at the Icahn School of Medicine at Mount Sinai, have shown how resident macrophage 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 potentially in humans. The newly identified function of these microglia, in protecting the brain from abnormal activation could have implications for treating behavioral abnormalities associated with neurodegenerative and inflammatory diseases in humans.

“When we think about brain function, we typically think about how neurons control our thoughts and behavior,” said Anne Schaefer, MD, PhD, Professor of Neuroscience, and Psychiatry, at the Icahn School of Medicine at Mount Sinai, and senior author of the team’s published study in Nature. “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. Schaefer and colleagues describe their findings in a report titled, “Negative feedback control of neuronal activity by microglia.”

Human and animal behaviour relies on the coordinated activity of excitatory and inhibitory neurons, which together define distinct neuronal circuits and associated behaviours., the authors noted. But while the regulation of neuronal activity in the brain has long been viewed as “an exclusive prerogative of neurons”, recent findings have suggested that the brain’s immune cells – the microglia – might also be involved in this process. “Microglia, the brain’s resident macrophages, help to regulate brain function by removing dying neurons, pruning non-functional synapses, and producing ligands that support neuronal survival.

Through their newly reported studies the Mount Sinai researchers found that microglia are also “critical modulators” of neuronal activity and associated behavioral responses in mice. “We found that, similar to inhibitory neurons, microglia sense neuronal activation and suppress excessive neuronal activity,” they wrote. Their experiments identified the biochemical circuit that support neuron-microglia communication. Active neurons release adenosine triphosphate (ATP). The microglia can then sense extracellular ATP, which draws them toward the active neurons. The microglia then break ATP down to generate adenosine, which acts on adenosine receptors on the surface of active neurons to suppress their activity and prevent excessive activation. “Microglial sensing of ATP, the ensuing microglia-dependent production of adenosine, and the adenosine-mediated suppression of neuronal responses via the adenosine receptor A1R are essential for the regulation of neuronal activity and animal behavior,” the authors reported. The effects were also specific to certain regions of the brain, they noted. “Suppression of neuronal activation by microglia occurs in a highly region-specific fashion and depends on the ability of microglia to sense and catabolize extracellular ATP, which is released upon neuronal activation by neurons and astrocytes.”

“In inflammatory conditions and neurodegenerative diseases like Alzheimer’s, microglia become activated and lose their ability to sense ATP and to generate adenosine,” noted 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,” added Schaefer, who is also Co-Director of the Center for Glial Biology at The Friedman Brain Institute at the Icahn School of Medicine. Schaefer describes the team’s 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. “We found that microglia can sense and respond to neuronal activation and provide negative feedback on excessive neuronal activity,” she said. “This novel microglia-mediated mechanism of neuromodulation could play an important role in protecting the brain from disease.” The authors further concluded, “Our findings suggest that this microglia-driven negative feedback mechanism operates similarly to inhibitory neurons and is essential for protecting the brain from excessive activation in health and disease.”

The findings are particularly significant, Schaefer added, given the fact that microglia, while residing in the brain, are also uniquely equipped to also respond to signals generated peripherally. Microglia could therefore act as an interface between peripheral body changes – such as 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 has practical implications for further research. Future studies may focus on novel approaches to the neuromodulation of normal behaviors by targeting microglia, or on the potential treatment of behavioral abnormalities associated with neurodegenerative diseases. “Microglia-driven neurosuppression is likely to have a key role in constraining excessive neuronal activation that cannot be sufficiently suppressed by inhibitory neurons alone,” the team commented. “This potent mechanism may also allow microglia to relay changes in the state of the local or peripheral environment to neurons and thereby to direct specific behavioral responses.”

Added Schaefer, “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. We believe our work has the potential to add to our knowledge about the mechanisms of neuromodulation.”

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