Local sleep homeostasis and single cell rest

局部睡眠稳态和单细胞休息

• 批准号: MR/S01134X/1
• 负责人: Vladyslav Vyazovskiy
• 金额: $ 120.42万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS01134X%2F1
• 关键词: Local; sleep; homeostasis; single; cell

Sleep and wake are strictly regulated processes. The need for sleep ("sleep pressure") increases gradually during the periods that we are awake, as reflected by us feeling tired. However, this sleep need dissipates when we sleep, reaching the lowest levels just before we wake up fresh and rested. It has therefore been proposed that sleep is necessary for various restorative processes, which include metabolic recovery and renormalisation of brain functions. Suppressed immune function, reduced mood, and increased risk of obesity and cardiovascular disease are only a few of many detrimental effects resulting from chronic sleep deprivation or disrupted and mistimed sleep. Most direct evidence for the immediate consequences of sleep deprivation comes from psychological experiments. Impairments range from the slowing of responsiveness, reduced attention and increased variability in task performance, to the reduction of higher order brain functions such as executive functions, memory or emotional control. This indicates that the brain is among the first targets that are impacted by sleep deprivation. However, despite this extensive knowledge of the importance of sleep, much controversy remains about the biological mechanisms that convey the numerous benefits of sleep to the brain and body.The predominant idea that sleep plays a "restorative" role fits well with our subjective experience. However, the question remains: what precisely needs to be restored after a period of wakefulness and how do restorative changes occurring at the level of individual cells benefit from a global shut down occurring during sleep? We have recently advanced a new hypothesis that the biological function of sleep is to allow for vital "repair and maintenance" of the neurons in our brains. We have also proposed that these repair functions can only occur if the rest periods of individual neurons are aligned precisely at a time scale of seconds or less. The reasoning for this is that we have billions of neurons in our brain, and each of them is connected with thousands of other neurons, all of whom are constantly talking to one another. Therefore, it appears that our neurons cannot rest and repair themselves independently, but must shut down at the same time so that they do not disturb one another and allow each individual cell to obtain the rest it needs. The flip side of this is that when areas of our brain are unable to "fall asleep", they remain in a state of "local wakefulness" that leads to us experiencing a bad night's sleep. Indeed, there are intriguing parallels between the repair processes in brain cells after waking and those observed in muscle cells after exercise. However, whilst you can rest your muscles while being awake, to rest the brain during waking is much more difficult. If neurons attempt to obtain rest while we are awake, it is not only much less efficient but also has serious negative effects on our performance. Similar phenomena can be found outside of biology. The London Underground system, for example, can only function properly during the day because it has extensive maintenance every night, during which all trains stop running between the interconnected stations. We suggest that sleep allows a similar period of maintenance for the brain. In our project we will combine expertise in cutting edge techniques, including electrophysiology, molecular-genetics and pharmacology, and will perform research at several distinct scales - from single cells, to local networks of cells, to the behaviour of the organism. Our project will thus make a major advance in the field of sleep neuroscience and the knowledge obtained will benefit numerous clinical applications that are concerned with the prevention and treatment of sleep disturbances, including improving the management of sleep in shift workers and the prognosis of patients suffering from neurodegenerative disorders, such as Alzheimer's disease.

睡眠和清醒是严格控制的过程。睡眠的需要（“睡眠压力”）在我们醒着的时候逐渐增加，这反映在我们感到疲倦。然而，这种睡眠需求在我们睡觉时消散，在我们醒来之前达到最低水平。因此，有人提出，睡眠是各种恢复过程所必需的，包括代谢恢复和大脑功能的重新正常化。免疫功能受抑制、情绪低落、肥胖和心血管疾病风险增加，这些只是长期睡眠不足或睡眠中断和时间不当造成的许多有害影响中的一小部分。睡眠剥夺的直接后果的最直接证据来自心理学实验。损伤的范围从反应速度减慢，注意力降低和任务表现的可变性增加，到高级大脑功能的减少，如执行功能，记忆或情绪控制。这表明大脑是受睡眠剥夺影响的第一个目标。然而，尽管人们对睡眠的重要性有了广泛的了解，但关于睡眠对大脑和身体的诸多益处的生物学机制仍存在许多争议。睡眠起着“恢复”作用的主导思想与我们的主观经验非常吻合。然而，问题仍然存在：在一段时间的清醒之后，究竟需要恢复什么？在睡眠期间发生的全面关闭如何使个体细胞水平上发生的恢复性变化受益？我们最近提出了一个新的假设，即睡眠的生物学功能是对我们大脑中的神经元进行至关重要的“修复和维护”。我们还提出，只有当单个神经元的休息时间在秒或更短的时间尺度上精确对齐时，这些修复功能才能发生，其理由是我们的大脑中有数十亿个神经元，每个神经元都与数千个其他神经元相连，所有这些神经元都在不断地相互交流。因此，我们的神经元似乎不能独立地休息和自我修复，而必须同时关闭，这样它们才不会相互干扰，让每个细胞都能获得所需的休息。另一方面，当我们的大脑区域无法“入睡”时，它们仍然处于“局部觉醒”状态，导致我们经历了一个糟糕的夜晚睡眠。事实上，清醒后脑细胞的修复过程与运动后肌肉细胞的修复过程之间存在有趣的相似之处。然而，虽然你可以在清醒时休息你的肌肉，但在清醒时休息大脑要困难得多。如果神经元试图在我们醒着的时候获得休息，不仅效率会低得多，而且还会对我们的表现产生严重的负面影响。类似的现象在生物学之外也可以找到。例如，伦敦地铁系统只能在白天正常运行，因为它每天晚上都要进行大量的维护，在此期间，所有列车都停止在相互连接的车站之间运行。我们认为，睡眠可以让大脑有一个类似的维持期。在我们的项目中，我们将联合收割机的尖端技术，包括电生理学，分子遗传学和药理学的专业知识，并将在几个不同的规模进行研究-从单细胞，到局部细胞网络，到生物体的行为。因此，我们的项目将在睡眠神经科学领域取得重大进展，所获得的知识将有利于与预防和治疗睡眠障碍有关的许多临床应用，包括改善轮班工人的睡眠管理和患有神经退行性疾病的患者的预后，如阿尔茨海默病。

项目成果

Somnotate: A probabilistic sleep stage classifier for studying vigilance state transitions.

• DOI: 10.1371/journal.pcbi.1011793
• 发表时间: 2024-01
• 期刊: PLoS computational biology
• 影响因子: 4.3
• 作者: Brodersen PJN;Alfonsa H;Krone LB;Blanco-Duque C;Fisk AS;Flaherty SJ;Guillaumin MCC;Huang YG;Kahn MC;McKillop LE;Milinski L;Taylor L;Thomas CW;Yamagata T;Foster RG;Vyazovskiy VV;Akerman CJ
• 通讯作者: Akerman CJ

Human lesions and animal studies link the claustrum to perception, salience, sleep and pain.

• DOI: 10.1093/brain/awac114
• 发表时间: 2022-06-03
• 期刊: Brain : a journal of neurology

Intracellular chloride regulation mediates local sleep pressure in the cortex.

• DOI: 10.1038/s41593-022-01214-2
• 发表时间: 2023-01
• 期刊: Nature neuroscience
• 影响因子: 25
• 作者: Alfonsa H;Burman RJ;Brodersen PJN;Newey SE;Mahfooz K;Yamagata T;Panayi MC;Bannerman DM;Vyazovskiy VV;Akerman CJ
• 通讯作者: Akerman CJ

Intraneuronal chloride levels encode tiredness in cortex

神经元内氯化物水平编码皮质的疲劳

• DOI: 10.1101/2021.05.14.444189
• 发表时间: 2021
• 作者: Alfonsa H