Sleep and wakefulness are controlled by a wide range of neuronal populations in the mammalian brain. Activation of adenosine A2A receptor (A2AR)-expressing neurons in the nucleus accumbens (NAc) core promotes slow-wave sleep (SWS). The neuronal mechanism by which activation of NAc A2AR neurons induces SWS, however, is unknown. We hypothesized that the ability of NAc activation to induce sleep is mediated by the classic somnogen adenosine, which can be formed by various processes in all types of cells. Here, to investigate whether astrocytes are involved in the ability of the NAc to regulate SWS, we ablated glial fibrillary acidic protein (GFAP)-positive cells in the NAc core of mice by virus-mediated expression of diphtheria toxin (DT) receptors and intraperitoneal administration of DT. Analysis of electroencephalogram and electromyogram recordings of DT-treated wild-type mice revealed that SWS was remarkably increased at 1 week after DT treatment, whereas sleep-wake behavior was unchanged in DT-treated A2AR knockout mice. Cell ablation was associated with an increased number of GFAP-positive cells and activation of microglia in the NAc. In-vivo microdialysis revealed significantly increased levels of extracellular adenosine in the NAc at 1 week after DT treatment. Our findings suggest that elevated adenosine levels in the NAc core promote SWS by acting on A2ARs and provide the first evidence that adenosine is an endogenous candidate for activating NAc A2AR neurons that have the ability to induce SWS.

中文翻译：

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小鼠伏隔核核心星形胶质细胞和神经元消融后，细胞外腺苷和慢波睡眠增加。

睡眠和清醒受到哺乳动物大脑中各种神经元种群的控制。伏伏核（NAc）核心中表达腺苷A2A受体（A2AR）的神经元的激活促进了慢波睡眠（SWS）。但是，NAc A2AR神经元激活诱导SWS的神经元机制尚不清楚。我们假设，NAc激活诱导睡眠的能力是由经典的smnogen腺苷介导的，它可以通过各种类型的细胞中的各种过程形成。在这里，为了研究星形胶质细胞是否参与NAc调节SWS的能力，我们通过病毒介导的白喉毒素（DT）受体和腹膜内表达消融了小鼠NAc核心中的胶质纤维酸性蛋白（GFAP）阳性细胞DT的管理。对经DT处理的野生型小鼠的脑电图和肌电图记录的分析表明，在DT处理后1周，SWS显着增加，而在DT处理的A2AR基因敲除小鼠中，睡眠觉醒行为没有改变。细胞消融与NAc中GFAP阳性细胞数量增加和小胶质细胞活化有关。体内微透析显示，DT治疗后1周，NAc中的细胞外腺苷水平显着增加。我们的发现表明，NAc核心中升高的腺苷水平通过作用于A2ARs促进了SWS，并提供了第一个证据，即腺苷是激活具有诱导SWS能力的NAc A2AR神经元的内源性候选物。而在DT处理的A2AR基因敲除小鼠中，觉醒行为没有改变。细胞消融与NAc中GFAP阳性细胞数量增加和小胶质细胞活化有关。体内微透析显示，DT治疗后1周，NAc中的细胞外腺苷水平显着增加。我们的发现表明，NAc核心中升高的腺苷水平通过作用于A2ARs促进了SWS，并提供了第一个证据，即腺苷是激活具有诱导SWS能力的NAc A2AR神经元的内源性候选物。而在DT处理的A2AR基因敲除小鼠中，觉醒行为没有改变。细胞消融与NAc中GFAP阳性细胞数量增加和小胶质细胞活化有关。体内微透析显示，DT治疗后1周，NAc中的细胞外腺苷水平显着增加。我们的发现表明，NAc核心中升高的腺苷水平通过作用于A2ARs促进了SWS，并提供了第一个证据，即腺苷是激活具有诱导SWS能力的NAc A2AR神经元的内源性候选物。