Sleep interacts reciprocally with immune system activity, but its specific relationship with microglia—the resident immune cells in the brain—remains poorly understood. Here, we show in mice that microglia can regulate sleep through a mechanism involving G_i-coupled GPCRs, intracellular Ca²⁺ signaling and suppression of norepinephrine transmission. Chemogenetic activation of microglia G_i signaling strongly promoted sleep, whereas pharmacological blockade of G_i-coupled P2Y12 receptors decreased sleep. Two-photon imaging in the cortex showed that P2Y12–G_i activation elevated microglia intracellular Ca²⁺, and blockade of this Ca²⁺ elevation largely abolished the G_i-induced sleep increase. Microglia Ca²⁺ level also increased at natural wake-to-sleep transitions, caused partly by reduced norepinephrine levels. Furthermore, imaging of norepinephrine with its biosensor in the cortex showed that microglia P2Y12–G_i activation significantly reduced norepinephrine levels, partly by increasing the adenosine concentration. These findings indicate that microglia can regulate sleep through reciprocal interactions with norepinephrine transmission.

睡眠与免疫系统活动相互作用，但其与小胶质细胞（大脑中常驻的免疫细胞）的具体关系仍然知之甚少。_{在这里，我们在小鼠中证明，小胶质细胞可以通过涉及 G i}偶联 GPCR、细胞内 Ca ²⁺信号传导和去甲肾上腺素传输抑制的机制来调节睡眠。_{小胶质细胞 G i}信号传导的化学遗传学激活强烈促进睡眠，而 G _i偶联 P2Y12 受体的药理学阻断则减少睡眠。皮质中的双光子成像显示，P2Y12–G _i激活升高了小胶质细胞细胞内的 Ca ²⁺，而阻断这种 Ca ²⁺升高很大程度上消除了 G _i诱导的睡眠增加。小胶质细胞 Ca ²⁺水平在自然觉醒到睡眠过渡时也增加，部分原因是去甲肾上腺素水平降低。此外，用皮质中的生物传感器对去甲肾上腺素进行成像表明，小胶质细胞 P2Y12-G _i激活显着降低了去甲肾上腺素水平，部分原因是增加了腺苷浓度。这些发现表明小胶质细胞可以通过与去甲肾上腺素传输的相互作用来调节睡眠。