Sleep is a fundamental process that supports various physiological functions and contributes to overall brain health. Lack of sleep or poor sleep quality has been associated with chronic health issues such as high blood pressure, stroke, obesity, and mental health conditions like depression and heart disease.
Moreover, sleep disturbances have been linked to neurodegenerative diseases, which coincide with microglia dysfunction. Microglia are immune cells found in the brain’s central nervous system, and their connection to sleep regulation has yet to be extensively explored.
A recent study conducted by researchers at the University of California, Berkeley, in collaboration with Huazhong University of Science and Technology and other Chinese institutes, aimed to investigate the potential role of microglia in regulating sleep. Published in Nature Neuroscience, the study suggests that microglia modulate sleep through the transmission of the neurotransmitter norepinephrine, which influences arousal, attention, and stress responses.
Chenyan Ma, Bing Li, and their colleagues reported in their paper, “We show in mice that microglia can regulate sleep through a mechanism involving Gi-coupled GPCRs, intracellular Ca2+ signaling, and suppression of norepinephrine transmission.”
To explore the role of microglia in sleep regulation, the researchers conducted a series of experiments on mice. They utilized chemogenetic techniques to manipulate and image microglia signaling in the brain, specifically activating or blocking P2Y12, a Gi-protein-coupled ATP/ADP receptor crucial to microglia function.
During the experiments, the researchers observed the neural mechanisms following the experimental activation or blocking of P2Y12-Gi signaling and monitored the mice’s sleeping behavior. This provided new insights into how microglia potentially regulate sleep in mice and possibly in humans and other mammals.
The researchers noted, “Chemogenetic activation of microglia Gi signaling strongly promoted sleep, whereas pharmacological blockade of Gi-coupled P2Y12 receptors decreased sleep.”
By employing two-photon imaging in the cortex, the team also found that P2Y12-Gi activation increased microglia intracellular Ca2+ levels. Furthermore, inhibiting this Ca2+ elevation largely eliminated the sleep increase induced by Gi signaling. The researchers discovered that the microglia Ca2+ levels increased during natural transitions from wakefulness to sleep, partially due to decreased norepinephrine levels. Additionally, imaging of norepinephrine with a biosensor in the cortex indicated that microglia P2Y12-Gi activation significantly reduced norepinephrine levels, partly by increasing adenosine concentration.
Overall, the findings indicate that microglia play a crucial role in sleep regulation through reciprocal interactions with norepinephrine transmission. This research sets the stage for further investigations into the role of microglia in sleep regulation, with a particular focus on norepinephrine transmission.
Given the association between microglia dysfunction, sleep disturbances, and neurodegenerative diseases like Alzheimer’s, this study may expand our understanding of these conditions, potentially leading to the development of novel therapeutic strategies in the future.
