中脑导水管周围灰质外侧部调控快动眼睡眠的作用及机制

The mechanism of rapid eye movement (REM) sleep behavior disorder is unknown, so there are no effective clinical treatments. The discovery of key nuclei involved in REM sleep regulation has become an important scientific issue in the field of sleep research. We found that the expression of c-Fos in the lateral part of the periaqueductal gray (lPAG) was significantly increased after REM sleep rebound following REM sleep deprivation. Activation of glutamatergic neurons in the lPAG specifically increased the amount of REM sleep; on the contrary, inhibition of glutamatergic neurons in the lPAG decreased REM sleep. It was also suggested that the pivotal REM-on regions-sublaterodorsal tegmental nucleus (SLD) and medullary ventral gigantocellular reticular nucleus (Giv) have nerve fibers connections with lPAG. Therefore, we hypothesized that the glutamatergic neurons in the lPAG which projecting to SLD and Giv are involved in the regulation of REM sleep. To clarify the role of lPAG and its neural circuits in the regulation of REM sleep, we will use state-of-the-art sleep bioassay systems, Cre animals, specific nerve tracing technology, optogenetics, pharmacogenetics, selective neuronal damage and in vitro and in vivo electrophysiological technologies. The expected findings will provide theoretical basis for REM sleep regulation and provide theoretical basis and new ideas for REM sleep disturbances.

快动眼（REM）睡眠障碍因机制未明，临床缺乏有效对策。发现参与REM睡眠调控的关键核团，已成为睡眠研究领域重要科学问题。我们发现REM睡眠剥夺后的恢复期，中脑导水管周围灰质外侧部（lPAG）的c-Fos表达量显著增多；特异性激活lPAG区的谷氨酸能神经元，REM睡眠显著增高，反之亦然；lPAG和REM睡眠启动关键核团下外背侧被盖核（SLD）及延髓腹侧巨细胞网状核（Giv）均有神经纤维联系。由此我们提出假说：lPAG的谷氨酸能神经元是重要的REM睡眠调控中枢，通过与SLD及Giv的神经环路影响REM睡眠。本课题将利用睡眠觉醒解析平台、Cre动物、顺行和逆行神经纤维追踪、光遗传学和药物遗传学特异性操控神经元活性、选择性神经元损毁、离体和在体电生理等手段，阐明lPAG调节REM睡眠的作用及神经环路机制。预期结果将丰富和发展REM睡眠调节理论，并为发现REM睡眠障碍治疗新靶点提供理论依据和新思路。

快动眼（rapid eye movement, REM）睡眠障碍因机制未明，临床缺乏有效对策。发现参与REM睡眠调控的关键核团，已成为睡眠研究领域重要科学问题。我们发现REM睡眠剥夺及剥夺后的恢复期，中脑导水管周围灰质外侧部（lateral periaqueductal gray, LPAG）的谷氨酸能神经元c-Fos表达量显著增多；LPAG和REM睡眠启动及关闭（觉醒）调控的关键核团蓝斑（locus coeruleus, LC）、延髓腹侧巨细胞网状核（ventral gigantocellular reticular nucleus, Giv）及下外背侧被盖核（sublaterodorsal tegmental nucleus, SLD）均有神经纤维联系。由此我们提出假说：LPAG的谷氨酸能神经元是重要的睡眠觉醒调控中枢，通过不同的神经环路调控睡眠觉醒。本课题将利用睡眠觉醒解析平台、Cre动物、神经纤维追踪、光遗传学和药物遗传学特异性操控神经元活性、电生理等手段，阐明LPAG调节睡眠睡眠的作用及神经环路机制。研究结果显示：LPAG谷氨酸能神经元的钙信号活性在觉醒期最高，其次是REM睡眠期，而在非快眼动（non-REM，NREM）睡眠期最低。化学遗传及光遗传法特异性激活LPAG的谷氨酸能神经元可引起强烈的觉醒反应及不动行为，而抑制LPAG的谷氨酸能神经元则引起REM睡眠、觉醒量的降低及NREM睡眠的增加。特异性激活LPAG-LC及LPAG-GiV的神经环路可引起觉醒反应及不动行为，而LPAG投射到SLD的神经元则在REM睡眠反弹后激活。以上研究结果表明LPAG中的谷氨酸能神经元通过到LC和GiV的神经环路调控了觉醒，而通过到SLD的神经环路调控了REM睡眠。该研究对丰富和发展睡眠觉醒调节理论、认识觉醒及REM睡眠障碍的机制及治疗药物开发提供依据。