Do single neurons need to sleep and why?

 描述(申请人提供)：睡眠是无处不在的，普遍的，不可抗拒的，严格控制的，它的丧失损害了表现和认知。睡眠被认为为大脑执行基本的恢复功能，越来越多的证据表明，睡眠最终可能反映出局部对稳态的需求，这种需求是由醒来的细胞后果触发的，主要与与学习相关的突触可塑性的成本有关。这一证据与睡眠和觉醒可以在单个神经元水平上发生、调节和执行其功能的假设相一致。最近，在自由活动的大鼠身上使用多阵列记录，我们获得了直接证据，表明睡眠可以在一组皮质神经元内局部发生，而大脑的其余部分仍保持清醒，并且这种“局部睡眠”随着清醒时间的延长而增加。如果是这样的话，局部睡眠是否发生在不同的物种中，潜在的机制是什么？它们与在系统层面管理睡眠的规则相似吗？它们是否反映了细胞对修复的需求，这些需求是由觉醒中学习引起的可塑性变化的渐进式积累(神经元“疲劳”)还是仅仅由剧烈活动(“疲劳”)触发的？此外，是否有细胞/超微结构迹象表明脑细胞觉醒可塑性的成本，反之，睡眠已经发生并恢复了内稳态？最后，清醒时发生的局部睡眠是否会导致表现障碍，这可以解释睡眠受限的人和一些神经精神障碍中观察到的表现/认知缺陷？这些都是令人着迷和长期存在的问题，通过利用几项允许单细胞分析和因果操作的技术突破，最终有可能直接解决这些问题，这些技术突破包括多阵列记录、高密度(HD)脑电、活体钙成像、热/光/药物遗传学和连续块面扫描电子显微镜(SBF-SEM)。该提案包括三个高度一体化和互为补充的项目，利用苍蝇(项目I)、老鼠(项目II)和人类(项目III)解决三个相关问题：局部睡眠发生在不同的物种中吗？它是由与触发睡眠的机制相似的机制触发的，还是仅仅由疲劳引起的？2.觉醒可塑性的细胞/超微结构特征是什么，反过来，睡眠的恢复功能又是什么？3.在清醒的大脑中，局部睡眠的行为/认知后果是什么？

 DESCRIPTION (provided by applicant): Sleep is pervasive, universal, irresistible, tightly regulated, and its loss impairs performance and cognition. Sleep is thought to perform essential restorative functions for the brain, and increasing evidence suggests that sleep may ultimately reflect a local need for homeostasis that is triggered by the cellular consequences of wake, primarily related to the costs of synaptic plasticity associated with learning. This evidence is consistent with the hypothesis that sleep and wake may occur, be regulated, and perform their functions at the level of individual neurons. Recently, using multi-array recordings in freely moving rats, we obtained direct evidence that sleep can occur locally within a group of cortical neurons, while the rest of the brain remains awake, and that such "local sleep" increases with the duration of wake. If so, does local sleep occur in different species, and what are the underlying mechanisms? Are they similar to those governing the regulation of sleep at the systems level? And do they reflect cellular needs for restoration triggered by the progressive accumulation of plastic changes due to learning in wake (neuronal "tiredness") or merely by intense activity ("fatigue")? Moreover, are there cellular/ultrastructural signatures of the cost o wake plasticity for brain cells and, conversely, that sleep has occurred and restored homeostasis? Finally, does the occurrence of local sleep during wake lead to performance impairments, which could explain the performance/cognitive deficits observed in sleep-restricted humans and in some neuropsychiatric disorders? These are fascinating and long-standing questions, and it is finally becoming possible to address them directly by taking advantage of several technological breakthroughs that permit single cell analysis and causal manipulations, including multi-array recordings, high-density (hd) EEG, in vivo calcium imaging, thermo/opto/pharmacogenetics, and serial block- face scanning electron microscopy (SBF-SEM). This proposal includes three highly integrated and complementary projects employing flies (Project I), mice (Project II), and humans (Project III) to address three related questions: . Does local sleep occur in different species, and is it triggered by mechanisms similar to those that trigger sleep proper, or merely by fatigue? 2. What are the cellular/ultrastructural signature of wake plasticity and, conversely, of the restorative functions of sleep? 3. What are the behavioral/cognitive consequences of local sleep in an awake brain?