PDF(Pubmed)
Abstract：
Dorsal raphe (DR) 5-HT neurons regulate sleep-wake transitions. Previous studies demonstrated that single-unit activity of DR 5-HT neurons is high during wakefulness, decreases during non-rapid eye movement (NREM) sleep, and ceases during rapid eye movement (REM) sleep. However, characteristics of the population-level activity of DR 5-HT neurons, which influence the entire brain, are largely unknown. Here, we measured population activities of 5-HT neurons in the male and female mouse DR across the sleep-wake cycle by ratiometric fiber photometry. We found a slow oscillatory activity of compound intracellular Ca2+ signals during NREM sleep. The trough of the concave 5-HT activity increased across sleep progression, but 5-HT activity always returned to that seen during the wake period. When the trough reached a minimum and remained there, REM sleep was initiated. We also found a unique coupling of the oscillatory 5-HT activity and wideband EEG power fluctuation. Furthermore, optogenetic activation of 5-HT neurons during NREM sleep triggered a high EMG power and induced wakefulness, demonstrating a causal role of 5-HT neuron activation. Optogenetic inhibition induced REM sleep or sustained NREM, with an EEG power increase and EEG fluctuation, and pharmacological silencing of 5-HT activity using a selective serotonin reuptake inhibitor led to sustained NREM, with an EEG power decrease and EEG fluctuation. These inhibitory manipulations supported the association between oscillatory 5-HT activity and EEG fluctuation. We propose that NREM sleep is not a monotonous state, but rather it contains dynamic changes that coincide with the oscillatory population-level activity of DR 5-HT neurons.SIGNIFICANCE STATEMENT Previous studies have demonstrated single-cell 5-HT neuronal activity across sleep-wake conditions. However, population-level activities of these neurons are not well understood. We monitored DR 5-HT population activity using a fiber photometry system in mice and found that activity was highest during wakefulness and lowest during REM sleep. Surprisingly, during non-REM sleep, the 5-HT population activity decreased with an oscillatory pattern, coinciding with EEG fluctuations. EEG fluctuations persisted when DR 5-HT neuron activity was silenced by either optogenetic or pharmacological interventions during non-REM sleep, suggesting an association between the two. Although oscillatory DR 5-HT neuron activity did not generate EEG fluctuations, it provides evidence that non-REM sleep exhibits at least binary states.
摘要：
背侧中交（DR）5-HT神经元调节睡眠-觉醒过渡。先前的研究表明，在觉醒过程中，DR5-HT神经元的单单位活动较高，在非快速眼动（NREM）睡眠期间减少，并在快速眼动（REM）睡眠期间停止。然而,DR5-HT神经元的群体水平活动特征，影响整个大脑，基本上是未知的。这里,我们通过比例纤维光度法测量了雄性和雌性小鼠DR在整个睡眠-觉醒周期中5-HT神经元的种群活动。我们发现NREM睡眠过程中复合细胞内Ca2信号的振荡活动缓慢。凹形5-HT活动的低谷在睡眠过程中增加，但是5-HT活动总是恢复到唤醒期间的水平。当低谷达到最小值并保持在那里时，开始快速眼动睡眠。我们还发现了振荡5-HT活动和宽带EEG功率波动的独特耦合。此外，在NREM睡眠期间5-HT神经元的光遗传学激活触发了高EMG功率和诱导的觉醒，证明了5-HT神经元激活的因果作用。光遗传学抑制诱导的REM睡眠或持续的NREM，随着EEG功率的增加和EEG的波动，和使用选择性5-羟色胺再摄取抑制剂的5-HT活性的药理学沉默导致持续的NREM，EEG功率降低和EEG波动。这些抑制操作支持振荡5-HT活性与EEG波动之间的关联。我们认为NREM睡眠不是单调的状态，而是包含与DR5-HT神经元的振荡种群水平活动一致的动态变化。重要声明先前的研究已经证明在睡眠-觉醒条件下单细胞5-HT神经元活动。然而,这些神经元的群体水平活动还没有得到很好的理解。我们使用纤维测光系统在小鼠中监测了背侧中缝（DR）5-HT种群的活动，发现在清醒时活动最高，在快速眼动（REM）睡眠时活动最低。令人惊讶的是,在非REM睡眠期间，5-HT种群活动以振荡模式下降，与脑电图波动相吻合。在非REM睡眠期间，当光遗传学或药物干预使DR5-HT神经元活动沉默时，EEG波动持续存在。暗示两者之间的联系。尽管振荡DR5-HT神经元活动没有产生EEG波动，它提供了非REM睡眠至少表现出二元状态的证据。
