Identification and analyses of molecules and neural circuits regulating REM sleep

哺乳动物睡眠由快速眼动睡眠(REM)和非快速眼动睡眠(NREM)组成。快速眼动睡眠特别容易受到各种外部因素或疾病的影响。尽管有几个基因与快速眼动睡眠有关，但这些基因的产物与大脑中调节快速眼动睡眠的关键区域之间的关系仍然知之甚少。此外，环境因素引起的REM睡眠变化的分子机制尚不清楚。在这里，我把重点放在Cpne7上，这是一个在背侧亚核(SLD)高度表达的基因，SLD是啮齿类动物产生快速眼动睡眠的关键脑区。Cpne7，Copine-7的产物在大脑中的功能尚不清楚。因此，我创造了一个Cpne7-Cre敲入鼠系，它允许我们检查Cpne7缺失的影响，并从基因上标记和操纵表达Cpne7的细胞。结果，我发现Cpne7-KO小鼠的基线睡眠没有改变。然而，Cpne7-KO小鼠在更换笼子或浸水和束缚应激后的REM睡眠时间更长，这两种情况都会显著减少REM睡眠，这表明Copine-7在某些条件下参与了REM睡眠的调节。此外，SLD中表达Cpne7的神经元的化学激活减少了REM睡眠的数量，表明这些神经元负向调节REM睡眠。总体而言，这些结果表明SLD中表达Copine-7和Cpne7的神经元是控制REM睡眠的调节系统的候选分子或神经元组件。

Mammalian sleep is composed of rapid-eye-movement (REM) sleep and non-REM (NREM) sleep. REM sleep is particularly susceptible to various external factors or diseases. Although several genes are associated with REM sleep, the relationship between the products of these genes and the brain areas critical for regulating REM sleep remains poorly understood. Moreover, the molecular mechanisms underlying changes in REM sleep caused by environmental factors are unclear. Here, I focused on Cpne7, as a gene that is highly expressed in the sublateral dorsal nucleus (SLD), a brain area critical for generating REM sleep in rodents. The function of the product of Cpne7, copine-7 in the brain was unknown. Therefore, I generated a Cpne7-Cre knock-in mouse line that allows us to examine the effect of deleting Cpne7 and to genetically label and manipulate cells that express Cpne7. As a results, I found the baseline sleep was not changed in Cpne7-KO mice. However, the amount of REM sleep was more in Cpne7-KO mice following cage change or water immersion and restraint stress, both of which are conditions that acutely reduce REM sleep, suggesting copine-7 is involved in the regulation of REM sleep under certain conditions. Moreover, chemogenetic activation of Cpne7-expression neurons in the SLD reduced the amount of REM sleep, suggesting these neurons negatively regulate REM sleep. Collectively, these results suggest copine-7 and Cpne7-expressing neurons in the SLD as candidate molecular or neuronal components of the regulatory system that controls REM sleep.