Oscillatory population-level activity of dorsal raphe serotonergic neurons sculpts sleep structure
Oscillatory population-level activity of dorsal raphe serotonergic neurons sculpts sleep structure
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中缝背侧血清素能神经元的群体水平振荡活动塑造睡眠结构
DOI：
10.1101/2021.11.19.469231
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Tanaka Kenji F.
中科院分区：
文献类型：
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作者：
Kato Tomonobu;Mitsukura Yasue;Yoshida Keitaro;Mimura Masaru;Takata Norio;Tanaka Kenji F.
中缝背核（DR）5-HT神经元参与调节睡眠-觉醒转换。先前的研究表明，DR 5-HT神经元的单单位活动在清醒期间较高，在非快速眼动（NREM）睡眠期间降低，并且在快速眼动（REM）睡眠期间停止。然而，DR 5-HT神经元的群体水平活动的特征，它可以影响整个大脑，在很大程度上是未知的。本研究采用比率纤维光度法测定了雄性和雌性小鼠DR中5-HT神经元在睡眠-觉醒周期中的群体活动。我们发现在NREM睡眠期间复合细胞内Ca 2+信号的缓慢振荡活动。凹型5-HT活性的谷值沿着增加，但5-HT活性水平总是恢复到清醒时的水平。当波谷达到最低水平并保持在那里时，REM睡眠开始。我们还发现了一个独特的耦合振荡5-HT活动和脑电功率波动，这表明脑电波动是一个代理的5-HT活动。在NREM睡眠期间，5-HT神经元的光遗传激活触发了高EMG功率并诱导觉醒。光遗传抑制可诱导REM睡眠或持续NREM，并伴有脑电功率增加和脑电波动。这些操作证明了DR 5-HT神经元在塑造睡眠-觉醒结构中的因果作用。我们还观察到人类男性在NREM睡眠期间的EEG波动，暗示人类存在5- HT振荡活动。我们提出，NREM睡眠不是一个单调的状态，但它是动态调节的振荡群体活动的DR 5- HT neurons.Significant statementPrevious研究已经证明了单细胞5-HT神经元活动的睡眠-觉醒条件，然而，这些神经元的群体水平的活动在很大程度上是未知的。我们监测中缝背核（DR）5-HT群体活动，使用纤维光度测定系统在小鼠中，并证明活动是最高的清醒期间，和最低的快速眼动（REM）睡眠。令人惊讶的是，在非REM（NREM）睡眠期间，5-HT群体活动以振荡模式下降，与EEG波动一致。我们通过光遗传学检查了这些5-HT神经元活动的因果作用，发现DR 5-HT神经元通过影响EEG和EMG模式来塑造睡眠-觉醒条件。我们在人类睡眠脑电图研究中发现了类似的脑电图波动，表明在不同物种的NREM期间存在振荡的5-HT神经元活动。
Dorsal raphe (DR) 5-HT neurons are involved in regulating 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 can influence the entire brain, are largely unknown. Here we measured population activities of 5-HT neurons in male and female mouse DR across the sleep-wake cycle by a ratiometric fiber photometry system. We found a slow oscillatory activity of compound intracellular Ca2+signals during NREM sleep. The trough of concave 5-HT activity increased along with sleep progression, but the 5-HT activity level always returned to that seen in wake periods. When the trough reached the minimum level and remained there, REM sleep initiated. We also found a unique coupling of the oscillatory 5-HT activity and EEG power fluctuation, suggesting that EEG fluctuation is a proxy for 5-HT activity. Optogenetic activation of 5-HT neurons during NREM sleep triggered a high EMG power and induced wakefulness. Optogenetic inhibition induced REM sleep or sustained NREM with an EEG power increase and EEG fluctuation. These manipulations demonstrated a causal role of DR 5-HT neurons in sculpting sleep-wake structure. We also observed EEG fluctuations in human males during NREM sleep, implicating the existence of 5- HT oscillatory activity in humans. We propose that NREM sleep is not a monotonous state, but that it is dynamically regulated by the oscillatory population activity of DR 5- HT neurons.Significant statementPrevious studies have demonstrated single-cell 5-HT neuronal activity across sleep- wake conditions; however, population-level activities of these neurons are largely unknown. We monitored dorsal raphe (DR) 5-HT population activity using a fiber photometry system in mice and demonstrated that activity was highest during wakefulness, and lowest during rapid eye movement (REM) sleep. Surprisingly, during non-REM (NREM) sleep, the 5-HT population activity decreased with an oscillatory pattern, coinciding with EEG fluctuations. We examined the causal role of these 5-HT neuron activities by optogenetics and found that DR 5-HT neurons sculpted sleep-wake conditions by influencing EEG and EMG patterns. We found similar EEG fluctuations in a human sleep EEG study, suggesting the presence of oscillatory 5-HT neuron activity during NREM across species.