Maywood Elizabeth S, Chesham Johanna E, Winsky-Sommerer Raphaelle, Hastings Michael H
Division of Neurobiology, Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom
Division of Neurobiology, Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom.
J Neurosci. 2021 Oct 13;41(41):8562-8576. doi: 10.1523/JNEUROSCI.3141-20.2021. Epub 2021 Aug 26.
The timing and quality of sleep-wake cycles are regulated by interacting circadian and homeostatic mechanisms. Although the suprachiasmatic nucleus (SCN) is the principal clock, circadian clocks are active across the brain and the respective sleep-regulatory roles of SCN and local clocks are unclear. To determine the specific contribution(s) of the SCN, we used virally mediated genetic complementation, expressing Cryptochrome1 (Cry1) to establish circadian molecular competence in the suprachiasmatic hypothalamus of globally clockless, arrhythmic male -null mice. Under free-running conditions, the rest/activity behavior of -null controls expressing EGFP (SCN) was arrhythmic, whereas Cry1-complemented mice (SCN) had coherent circadian behavior, comparable to that of Cry1,2-competent wild types (WTs). In SCN mice, sleep-wakefulness, assessed by electroencephalography (EEG)/electromyography (EMG), lacked circadian organization. In SCN mice, however, it matched WTs, with consolidated vigilance states [wake, rapid eye movement sleep (REMS) and non-REMS (NREMS)] and rhythms in NREMS δ power and expression of REMS within total sleep (TS). Wakefulness in SCN mice was more fragmented than in WTs, with more wake-NREMS-wake transitions. This disruption was reversed in SCN mice. Following sleep deprivation (SD), all mice showed a homeostatic increase in NREMS δ power, although the SCN mice had reduced NREMS during the inactive (light) phase of recovery. In contrast, the dynamics of homeostatic responses in the SCN mice were comparable to WTs. Finally, SCN mice exhibited poor sleep-dependent memory but this was corrected in SCNmice. In clockless mice, circadian molecular competence focused solely on the SCN rescued the architecture and consolidation of sleep-wake and sleep-dependent memory, highlighting its dominant role in timing sleep. The circadian timing system regulates sleep-wake cycles. The hypothalamic suprachiasmatic nucleus (SCN) is the principal circadian clock, but the presence of multiple local brain and peripheral clocks mean the respective roles of SCN and other clocks in regulating sleep are unclear. We therefore used virally mediated genetic complementation to restore molecular circadian functions in the suprachiasmatic hypothalamus, focusing on the SCN, in otherwise genetically clockless, arrhythmic mice. This initiated circadian activity-rest cycles, and circadian sleep-wake cycles, circadian patterning to the intensity of non-rapid eye movement sleep (NREMS) and circadian control of REMS as a proportion of total sleep (TS). Consolidation of sleep-wake established normal dynamics of sleep homeostasis and enhanced sleep-dependent memory. Thus, the suprachiasmatic hypothalamus, alone, can direct circadian regulation of sleep-wake.
睡眠-觉醒周期的时间和质量由相互作用的昼夜节律和稳态机制调节。虽然视交叉上核（SCN）是主要时钟，但昼夜节律时钟在整个大脑中都有活性，SCN和局部时钟各自的睡眠调节作用尚不清楚。为了确定SCN的具体贡献，我们使用病毒介导的基因互补，表达隐花色素1（Cry1），以在全球无时钟、无节律的雄性无效小鼠的视交叉上下丘脑建立昼夜节律分子能力。在自由运行条件下，表达EGFP（SCN）的无效对照的休息/活动行为无节律，而Cry1互补小鼠（SCN）具有连贯的昼夜节律行为，与具有Cry1,2能力的野生型（WT）相当。在SCN小鼠中，通过脑电图（EEG）/肌电图（EMG）评估的睡眠-觉醒缺乏昼夜节律组织。然而，在SCN小鼠中，它与WT匹配，具有巩固的警觉状态[清醒、快速眼动睡眠（REMS）和非快速眼动睡眠（NREMS）]以及NREMSδ功率和总睡眠（TS）中REMS表达的节律。SCN小鼠的清醒比WT更碎片化，有更多的清醒-NREMS-清醒转换。这种破坏在SCN小鼠中得到了逆转。睡眠剥夺（SD）后，所有小鼠的NREMSδ功率均出现稳态增加，尽管SCN小鼠在恢复的非活动（光）期NREMS减少。相比之下，SCN小鼠中稳态反应的动力学与WT相当。最后，SCN小鼠表现出较差的睡眠依赖性记忆，但在SCN小鼠中得到了纠正。在无时钟小鼠中，仅聚焦于SCN的昼夜节律分子能力挽救了睡眠-觉醒和睡眠依赖性记忆的结构和巩固，突出了其在睡眠定时中的主导作用。昼夜节律定时系统调节睡眠-觉醒周期。下丘脑视交叉上核（SCN）是主要的昼夜节律时钟，但多个局部脑和外周时钟的存在意味着SCN和其他时钟在调节睡眠中的各自作用尚不清楚。因此，我们使用病毒介导的基因互补来恢复视交叉上下丘脑的分子昼夜节律功能，重点是SCN，在其他方面基因无时钟、无节律的小鼠中。这启动了昼夜活动-休息周期、昼夜睡眠-觉醒周期、非快速眼动睡眠（NREMS）强度的昼夜模式以及作为总睡眠（TS）比例的REMS的昼夜控制。睡眠-觉醒的巩固建立了睡眠稳态的正常动力学并增强了睡眠依赖性记忆。因此，单独的视交叉上下丘脑可以直接指导睡眠-觉醒的昼夜调节。
