PNAS | 睡眠里的“合奏”：去甲腎上腺素、5-羥色胺與乙酰膽堿在NREM期竟然同步起伏

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基本信息：

Title:Synchrony of neuromodulatory systems during NREM sleep

發(fā)表時(shí)間：2025.12.24

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

影響因子：9.1

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AI一句話銳評(píng)

把NREM睡眠從“低活動(dòng)”改寫(xiě)為“多神經(jīng)調(diào)質(zhì)按節(jié)律同步協(xié)作的調(diào)控窗口”，這篇文章讓“睡眠里的協(xié)調(diào)指揮”第一次在體內(nèi)被清晰看見(jiàn)。

引言

我們對(duì)“睡著了的大腦”常有一種直覺(jué)：像把燈調(diào)暗，整體活動(dòng)變?nèi)蹙托小５F(xiàn)實(shí)更像精細(xì)的“狀態(tài)切換系統(tǒng)”。經(jīng)典觀點(diǎn)認(rèn)為，單胺類（monoamines）如去甲腎上腺素（norepinephrine, NE）與5-羥色胺（serotonin, 5-HT）在清醒最高、NREM睡眠降低、REM睡眠幾乎沉默；而乙酰膽堿（acetylcholine, ACh）在清醒與REM較活躍、在NREM相對(duì)低。

可如果你有過(guò)夜里“明明沒(méi)醒透卻突然警覺(jué)一下”的體驗(yàn)，就會(huì)意識(shí)到：睡眠并非一條平滑曲線，而是夾雜著微覺(jué)醒（microarousal, MA）與短暫波動(dòng)。近年來(lái)，借助遺傳編碼的神經(jīng)遞質(zhì)熒光傳感器（GRAB sensors），研究者發(fā)現(xiàn)NE、5-HT、ACh在NREM期并不是“低且穩(wěn)”，而是以超慢頻率（infraslow oscillation, ISO，約0.02–0.03 Hz）呈現(xiàn)節(jié)律性起伏，并與腦電（EEG）中紡錘波相關(guān)的σ頻段功率（sigma power）起落耦合。

一個(gè)關(guān)鍵但一直缺乏體內(nèi)直接證據(jù)的問(wèn)題隨之出現(xiàn)：這些神經(jīng)調(diào)質(zhì)系統(tǒng)在NREM期各自“自顧自振蕩”，還是彼此協(xié)調(diào)、甚至相互依賴？如果它們真的同步，那就可能是大腦在睡眠中實(shí)現(xiàn)“既穩(wěn)態(tài)維持、又隨時(shí)可被喚醒”的一種機(jī)制，也可能解釋睡眠對(duì)記憶等過(guò)程的精細(xì)調(diào)控為何需要跨腦區(qū)、跨系統(tǒng)的配合。本文正是圍繞“多種神經(jīng)調(diào)質(zhì)在NREM期是否同步、同步是否推動(dòng)覺(jué)醒、同步如何被系統(tǒng)間相互作用所塑造”展開(kāi)。

實(shí)驗(yàn)設(shè)計(jì)與方法邏輯

作者在小鼠中同時(shí)植入EEG/EMG電極并進(jìn)行雙位點(diǎn)光纖光度法（2-site fiber photometry），在內(nèi)側(cè)前額葉（medial prefrontal cortex, mPFC）與海馬（hippocampus）表達(dá)NE、5-HT、ACh的GRAB熒光傳感器，記錄自然睡眠-覺(jué)醒循環(huán)；用譜相干（spectral coherence）與互相關(guān)（cross-correlation）刻畫(huà)ISO同步與時(shí)序，并以σ功率谷值對(duì)齊分析不同結(jié)局（持續(xù)NREM、MA、清醒、轉(zhuǎn)REM）前的釋放幅度與同步強(qiáng)度；再用藥理學(xué)“靜默”5-HT或NE系統(tǒng)檢驗(yàn)依賴性，并用低頻光遺傳激活（optogenetics）在不引發(fā)狀態(tài)轉(zhuǎn)換的條件下測(cè)試系統(tǒng)間因果耦合。

核心發(fā)現(xiàn)

1）NREM期NE與5-HT高度同步（Figure 1）

在NREM睡眠中，去甲腎上腺素（NE）與5-羥色胺（5-HT）呈同頻（ISO）起伏，且時(shí)間差接近0，顯示兩套系統(tǒng)并行協(xié)同，而非各自獨(dú)立波動(dòng)。

2）ACh也同步，但更早啟動(dòng)（Figure 2–3）

乙酰膽堿（ACh）與NE/5-HT同樣在ISO頻段同步，但ACh穩(wěn)定領(lǐng)先約2–4秒，提示NREM期調(diào)質(zhì)波動(dòng)存在固定的先后序列。

3）同步越強(qiáng)越容易走向微覺(jué)醒/清醒（Figure 4）

當(dāng)一次NREM-ISO循環(huán)最終進(jìn)入微覺(jué)醒（MA）或清醒時(shí)，NE、5-HT、ACh的釋放幅度與跨系統(tǒng)同步強(qiáng)度都更高，可預(yù)測(cè)NREM向覺(jué)醒方向的狀態(tài)轉(zhuǎn)換。

4）三系統(tǒng)相互依賴且可互相驅(qū)動(dòng)（Figure 5–6）

藥理靜默NE或5-HT會(huì)連帶削弱另外兩者及ACh的NREM-ISO；在不引發(fā)醒來(lái)的低頻光遺傳刺激下，激活NE或5-HT神經(jīng)元可誘發(fā)其他系統(tǒng)釋放，支持跨系統(tǒng)耦合具有因果性。

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

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

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

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

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

Fig. 6. Optogenetic activation of neuromodulatory systems.

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.

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分享人：BQ

審核：PsyBrain 腦心前沿編輯部