PsyBrain 脑心前沿 / 睡眠与意识：顶刊文献解读专题 / A · 文献解读 / A020 · PNAS睡眠里的“合奏”：去甲肾上腺素、5-羟色胺与乙酰

A020 PNAS | 睡眠里的“合奏”：去甲肾上腺素、5-羟色胺与乙酰胆碱在NREM期竟然同步起伏

来源：公众号 PSY-Brain_Frontier ｜发布：2025-12-31 ｜原文链接

PsyBrain 脑心前沿 | 公众号 PSY-Brain_Frontier

一键关注，点亮星标 ⭐️

不错过每日前沿资讯

认知神经科学前沿文献分享

基本信息：

Title: Synchrony of neuromodulatory systems during NREM sleep

发表时间：2025.12.24

Journal:PNAS（Proceedings of the National Academy of Sciences of the United States of America）

影响因子：9.1

获取原文：

*添加小助手:*PSY-Brain-Frontier即可获取PDF版本
点击页面底部“阅读原文”即可跳转论文原网页

AI一句话锐评

把NREM睡眠从“低活动”改写为“多神经调质按节律同步协作的调控窗口”，这篇文章让“睡眠里的协调指挥”第一次在体内被清晰看见。

引言

我们对“睡着了的大脑”常有一种直觉：像把灯调暗，整体活动变弱就行。但现实更像精细的“状态切换系统”。经典观点认为，单胺类（monoamines）如去甲肾上腺素（norepinephrine, NE）与5-羟色胺（serotonin, 5-HT）在清醒最高、NREM睡眠降低、REM睡眠几乎沉默；而乙酰胆碱（acetylcholine, ACh）在清醒与REM较活跃、在NREM相对低。

可如果你有过夜里“明明没醒透却突然警觉一下”的体验，就会意识到：睡眠并非一条平滑曲线，而是夹杂着微觉醒（microarousal, MA）与短暂波动。近年来，借助遗传编码的神经递质荧光传感器（GRAB sensors），研究者发现NE、5-HT、ACh在NREM期并不是“低且稳”，而是以超慢频率（infraslow oscillation, ISO，约0.02–0.03 Hz）呈现节律性起伏，并与脑电（EEG）中纺锤波相关的σ频段功率（sigma power）起落耦合。

一个关键但一直缺乏体内直接证据的问题随之出现：这些神经调质系统在NREM期各自“自顾自振荡”，还是彼此协调、甚至相互依赖？如果它们真的同步，那就可能是大脑在睡眠中实现“既稳态维持、又随时可被唤醒”的一种机制，也可能解释睡眠对记忆等过程的精细调控为何需要跨脑区、跨系统的配合。本文正是围绕“多种神经调质在NREM期是否同步、同步是否推动觉醒、同步如何被系统间相互作用所塑造”展开。

实验设计与方法逻辑

作者在小鼠中同时植入EEG/EMG电极并进行双位点光纤光度法（2-site fiber photometry），在内侧前额叶（medial prefrontal cortex, mPFC）与海马（hippocampus）表达NE、5-HT、ACh的GRAB荧光传感器，记录自然睡眠-觉醒循环；用谱相干（spectral coherence）与互相关（cross-correlation）刻画ISO同步与时序，并以σ功率谷值对齐分析不同结局（持续NREM、MA、清醒、转REM）前的释放幅度与同步强度；再用药理学“静默”5-HT或NE系统检验依赖性，并用低频光遗传激活（optogenetics）在不引发状态转换的条件下测试系统间因果耦合。

核心发现

1）NREM期NE与5-HT高度同步（Figure 1）

在NREM睡眠中，去甲肾上腺素（NE）与5-羟色胺（5-HT）呈同频（ISO）起伏，且时间差接近0，显示两套系统并行协同，而非各自独立波动。

2）ACh也同步，但更早启动（Figure 2–3）

乙酰胆碱（ACh）与NE/5-HT同样在ISO频段同步，但ACh稳定领先约2–4秒，提示NREM期调质波动存在固定的先后序列。

3）同步越强越容易走向微觉醒/清醒（Figure 4）

当一次NREM-ISO循环最终进入微觉醒（MA）或清醒时，NE、5-HT、ACh的释放幅度与跨系统同步强度都更高，可预测NREM向觉醒方向的状态转换。

4）三系统相互依赖且可互相驱动（Figure 5–6）

药理静默NE或5-HT会连带削弱另外两者及ACh的NREM-ISO；在不引发醒来的低频光遗传刺激下，激活NE或5-HT神经元可诱发其他系统释放，支持跨系统耦合具有因果性。

Fig. 1. Synchronized release of NE and 5-HT during NREM sleep.

图10

Fig. 2. Synchronized release of ACh and 5-HT during NREM sleep.

图11

图12

Fig. 3. Synchronized release of NE and ACh during NREM sleep.

图13

Fig. 4. Synchronized release of multiple neuromodulators promotes arousal.

图14

Fig. 5. ISO during NREM sleep requires coordination among neuromodulatory systems.

图15

Fig. 6. Optogenetic activation of neuromodulatory systems.

图16

Abstract

Neuromodulatory systems play an essential role in regulating brain states and functions. The canonical view is that the release of monoamines including norepinephrine (NE) and serotonin (5-HT) is high during wakefulness and attenuated during sleep, particularly during rapid eye movement (REM) sleep, whereas the cholinergic system is active during both wakefulness and REM sleep and quiescent during non–REM (NREM) sleep. Recent studies have revealed a slow and rhythmic release pattern of neuromodulators during NREM sleep that drives infraslow oscillation (ISO) (0.02 to 0.03 Hz) in the brain. A key question is whether/how the release of different neuromodulators during sleep is coordinated. In this study, we combined 2-site fiber photometry with electroencephalogram/electromyography recording to monitor the release of NE, 5-HT, and acetylcholine in the cortex and hippocampus during sleep and wake cycles. We found that the ISO of these neuromodulators is synchronized during NREM sleep. The synchrony between neuromodulatory systems increases in the oscillatory cycles leading to arousal. Furthermore, pharmacological inhibition of either the 5-HT or NE system eliminates the oscillation of other neuromodulators during NREM sleep. Optogenetic activation of 5-HT or NE neurons during NREM sleep induces the release of other neuromodulators in the absence of sleep-to-wake transitions. These results suggest that the rhythmic neuromodulator releases are highly coordinated in the brain. The synchrony among multiple neuromodulatory systems across brain regions provides a powerful neural mechanism to orchestrate sleep architecture and sleep-related neural processes.

前沿交流 | 欢迎加入认知神经科学前沿交流群！

⭐️[解读链接]

图17