Microglia regulate sleep through calcium-dependent modulation of norepinephrine transmission

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

Conclusions:

• Microglia actively regulate sleep through a signaling pathway involving G_i-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.