美国加州大学伯克利分校霍华德休斯医学研究所丹扬团队，揭示小胶质细胞通过钙依赖性调节去甲肾上腺素的传递来调节睡眠。该项研究成果发表在2024年1月18日出版的《自然—神经科学》上。

他们在小鼠中发现，小胶质细胞可以通过G_i偶联GPCR、细胞内Ca²⁺信号传导和抑制去甲肾上腺素传递的机制来调节睡眠。小胶质细胞G_i信号的化学发生激活强烈促进睡眠，而Gi偶联P2Y12受体的药物阻断会减少睡眠。皮质双光子成像显示P2Y12-G_i激活升高了小胶质细胞内Ca²⁺，阻断这种Ca²⁺升高在很大程度上消除了G_i诱导的睡眠增加。小胶质细胞Ca²⁺水平也在自然的清醒到睡眠的转变中增加，部分原因是去甲肾上腺素水平降低。

此外，皮质生物传感器对去甲肾上腺素的成像显示，小胶质细胞P2Y12-G_i的激活显著降低了去甲肾上腺素水平，部分原因是腺苷浓度的增加。这些发现表明，小胶质细胞可以通过与去甲肾上腺素传递的相互作用来调节睡眠。

据悉，睡眠与免疫系统活动相互作用，但其与小胶质细胞(驻留在大脑中的免疫细胞)的具体关系仍然知之甚少。

附：英文原文

Title: Microglia regulate sleep through calcium-dependent modulation of norepinephrine transmission

Author: Ma, Chenyan, Li, Bing, Silverman, Daniel, Ding, Xinlu, Li, Anan, Xiao, Chi, Huang, Ganghua, Worden, Kurtresha, Muroy, Sandra, Chen, Wei, Xu, Zhengchao, Tso, Chak Foon, Huang, Yixuan, Zhang, Yufan, Luo, Qingming, Saijo, Kaoru, Dan, Yang

Issue&Volume: 2024-01-18

Abstract: 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 Gi-coupled GPCRs, intracellular Ca2+ signaling and suppression of norepinephrine transmission. Chemogenetic activation of microglia Gi signaling strongly promoted sleep, whereas pharmacological blockade of Gi-coupled P2Y12 receptors decreased sleep. Two-photon imaging in the cortex showed that P2Y12–Gi activation elevated microglia intracellular Ca2+, and blockade of this Ca2+ elevation largely abolished the Gi-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–Gi 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.

DOI: 10.1038/s41593-023-01548-5

Source: https://www.nature.com/articles/s41593-023-01548-5