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Updated: Jul 5, 2025

Optogenetic Manipulation of Neural Circuits During Monitoring Sleep/wakefulness States in Mice
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Microglia regulate sleep through calcium-dependent modulation of norepinephrine transmission

Chenyan Ma1, Bing Li1, Daniel Silverman1

  • 1Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA, USA.

Nature Neuroscience
|January 18, 2024
PubMed

Insights

Microglia, the brain's immune cells, regulate sleep by influencing norepinephrine transmission. Activating specific microglial pathways promotes sleep, while blocking them reduces it, revealing a novel sleep regulation mechanism.

Area of Science:

  • Neuroimmunology
  • Sleep Science
  • Cellular Neuroscience

Background:

  • The reciprocal relationship between sleep and the immune system is established, yet the specific role of microglia in sleep regulation is unclear.
  • Microglia, the central nervous system's resident immune cells, are increasingly recognized for their roles beyond immunity, including neuronal function and plasticity.

Purpose of the Study:

  • To investigate the role of microglia in regulating sleep-wake cycles.
  • To elucidate the molecular mechanisms by which microglia influence sleep, focusing on G-protein coupled receptors (GPCRs) and neurotransmission.

Main Methods:

  • Utilized chemogenetics and pharmacological interventions in mice to manipulate microglial Gi signaling and P2Y12 receptors.
  • Employed two-photon imaging in the cortex to monitor intracellular calcium (Ca2+) dynamics in microglia and norepinephrine levels.
  • Measured changes in sleep duration and architecture in response to microglial manipulation.

Main Results:

  • Chemogenetic activation of microglial Gi signaling significantly increased sleep duration.
  • Pharmacological blockade of the Gi-coupled P2Y12 receptor in microglia decreased sleep.
  • Microglial Gi activation elevated intracellular Ca2+ and reduced cortical norepinephrine levels, partly via increased adenosine.

Conclusions:

  • Microglia actively regulate sleep through a signaling pathway involving Gi-coupled GPCRs, intracellular Ca2+, and suppression of norepinephrine transmission.
  • These findings reveal a novel neuro-immune interaction where microglia modulate sleep by influencing norepinephrine and adenosine signaling in the brain.

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