Sleep Function and Synaptic Homeostasis: Linking Neurobiology and Mental Health

描述(由申请者提供)：本申请要求四年的资金，以建立一个康特中心，以发展协作神经科学研究。通过该中心，我们打算测试一个关于睡眠功能的全面、新颖的假说--突触内稳态假说。该假说指出，清醒时的可塑性过程会导致许多大脑回路中突触强度的净增加，从而导致新陈代谢消耗增加。在随后的睡眠中，大脑回路的加强会导致更大的慢波。反过来，睡眠慢波将突触强度重新正常化到基线水平，这在能量上是可持续的，对记忆和表现有利。因此，睡眠是我们为可塑性付出的代价，它的功能是对施加在神经元上的突触总重量进行动态平衡调节。这一假设解释了许多关于睡眠及其调节的事实，并做出了有趣的预测，这些预测与基础和临床神经科学都相关。我们建议通过威斯康星大学和华盛顿大学联合开展的四个紧密联系和互补的项目来检验这些预测。项目I(Pi Cirelli)采用分子/电生理学相结合的方法在动物模型中建立醒着时突触增强、睡眠慢波增加和由此产生的突触重整化之间的关系；项目II(Pi Toni)采用健康受试者的行为/高密度(HD)-EEG范式来确定学习是否在清醒和睡眠中都留下了局部EEC痕迹，并确定睡眠慢波是否需要重新正常化这种痕迹；项目III(Pi Raichle)使用相同的行为范式结合PET和fMRI来研究学习是否留下了被睡眠重整化的局部代谢痕迹；而项目IV(Pi Benca)在重度抑郁症患者中使用了相同的行为/HD-EEG范例，以评估保留的慢波稳态与睡眠剥夺治疗反应之间的预测关系。如果这一假说通过了这些联合测试，它将为我们为什么需要睡眠提供科学解释，范围从分子和细胞功能到系统神经生理学和神经成像。鉴于睡眠在每个生物体的生活中的核心作用，在每个年龄段，我们预计我们的计划的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.