Sleep Function and Synaptic Homeostasis: Linking Neurobiology and Mental Health

描述（由申请人提供）：本申请要求四年的资金，以建立一个康特中心，以发展合作神经科学研究。通过该中心，我们打算测试一个全面的，关于睡眠功能的新假说-突触稳态假说。该假说指出，清醒期间的可塑性过程导致许多大脑回路中突触强度的净增加，从而导致代谢消耗增加。强化的大脑回路会在随后的睡眠中产生更大的慢波。反过来，睡眠慢波将突触强度重新正常化到能量可持续且有益于记忆和表现的基线水平。因此，睡眠是我们为可塑性付出的代价，它的功能是对影响神经元的总突触重量进行稳态调节。这一假说解释了关于睡眠及其调节的许多事实，并做出了与基础和临床神经科学相关的有趣预测。我们建议通过四个紧密联系和互补的项目来测试这样的预测，这些项目将在威斯康星州大学和华盛顿大学联合进行。项目我（PI Cirelli）在动物模型中采用组合的分子/电生理学方法来建立清醒期间突触增强、睡眠慢波增加和所产生的突触重整之间的关系;项目二（PI Tononi）在健康人类受试者中采用行为/高密度（hd）-EEG范例来确定学习是否在清醒和睡眠中留下局部EEC痕迹，并确定是否睡眠慢波是必要的重新正常化这个痕迹;项目III（PI Raichle）采用相同的行为范式，结合PET和fMRI来研究学习是否会留下被睡眠重新正常化的局部代谢痕迹;项目四（PI Benca）采用相同的行为/ HD-重性抑郁症患者的脑电图模式，以评估保留的慢波稳态和睡眠剥夺治疗反应之间的预测关系。如果这一假设通过了这些综合测试，它将为我们为什么需要睡眠提供一个科学的解释，从分子和细胞功能到系统神经生理学和神经成像。鉴于睡眠在每个年龄段的每个生物体的生活中的核心作用，我们希望我们的项目结果将对人类健康和疾病的许多方面产生重大影响。

DESCRIPTION (Provided by applicant): This application requests four years of funding to establish a Conte Center to Develop Collaborative Neuroscience Research. Through the Center, we intend to test a comprehensive, novel hypothesis about the function of sleep - the synaptic homeostasis hypothesis. The hypothesis states that plastic processes during wakefulness result in a net increase in synaptic strength in many brain circuits, leading to increased metabolic consumption. Strengthened brain circuits then lead to larger slow waves during subsequent sleep. In turn, sleep slow waves renormalize synaptic strength to a baseline level that is energetically sustainable and beneficial for memory and performance. Sleep is therefore the price we pay for plasticity, and its function is the homeostatic regulation of the total synaptic weight impinging on neurons. The hypothesis accounts for many facts about sleep and its regulation and makes intriguing predictions that are relevant for both basic and clinical neuroscience. We propose to test such predictions through four tightly linked and complementary projects, to be carried out jointly at the University of Wisconsin and at Washington University. Project I (PI Cirelli) employs a combined molecular / electrophysiological approach in an animal model to establish a relationship between synaptic potentiation during waking, an increase in sleep slow waves, and the resulting synaptic renormalization; Project II (PI Tononi) employs behavioral / high-density (hd)-EEG paradigms in healthy human subjects to determine whether learning leaves a local EEC trace in both wakefulness and sleep, and to determine whether sleep slow waves are necessary to renormalize this trace; Project III (PI Raichle) employs the same behavioral paradigms in conjunction with PET and fMRI to investigate whether learning leaves a local metabolic trace that is renormalized by sleep; and Project IV (PI Benca) employs the same behavioral / hd-EEG paradigms in patients with major depression to evaluate a predicted relationship between preserved slow wave homeostasis and therapeutic response to sleep deprivation. If the hypothesis survives these combined tests, it will provide a scientific explanation of why we need to sleep that ranges all the way from molecular and cellular function to systems neurophysiology and neuroimaging. Given the central role of sleep in the life of every organism, at every age, we expect that the results of our program will have major implications for many aspects of human health and disease.