The cost of plasticity: from cells to systems

描述（由申请人提供）：突触可塑性是神经系统的基本特征，是神经发育、适应和学习的基础。越来越多的证据表明，突触可塑性机制的缺陷涉及许多精神疾病的病理生理学，从精神分裂症到情绪障碍。因此，NIMH将脑可塑性的研究“在细胞、突触、回路和行为层面”确立为他的战略研究重点之一，最终目标是“确定这些过程的神经生物学基础”。“这项提案将研究人类和三种动物模型（苍蝇、小鼠、大鼠），以测试突触可塑性在一定程度上是适应性的这一新颖而具有挑衅性的想法，但超过这一点，或在脆弱的个体中，它可能会变得适应不良。突触可塑性的“代价”通常不被考虑，但在精神疾病的病理生理学中可能是至关重要的，并将在超微结构，细胞，电路和行为水平上进行评估。我们之前由NIMH资助的工作已经确定，唤醒可塑性的总体结果是突触强度的净增加，这是由睡眠重新正常化的。但是，当可塑性“过度”时会发生什么，例如，因为它超出了生理范围而没有干预睡眠？基于在动物和人类中获得的初步结果，我们假设延长的可塑性可能导致对神经元活动（OFF期，性能缺陷）和细胞功能/完整性（细胞应激，超微结构异常）的负面影响。目的1将使用大鼠来测试可塑性依赖性突触过载是否导致神经元OFF期的发生、清醒期间局部EEG减慢和性能受损。它还将确定这些影响在多大程度上是可塑性的区域特异性后果，而不是长时间清醒的一般影响。目标2将使用高密度（hd）脑电图在人类中询问是否在脑电图θ波的局部增加，这发生在清醒期间作为特定脑回路中的扩展可塑性的结果，导致局部性能缺陷，局部增加的睡眠需求，和依赖睡眠的功能恢复。目标3将使用苍蝇和小鼠来测试通过延长觉醒来延长可塑性是否会导致细胞应激和亚细胞损伤，以及在睡眠限制条件下长期这样做是否会导致持久的细胞损伤和认知缺陷。可塑性在每个生物体的生命中起着核心作用，但其对神经结构和功能的影响可能是巨大的，特别是在脆弱的发育时期，如青春期，或在脆弱的人群中，如精神病患者。在细胞和系统水平上证明可塑性的代价将对预防和治疗精神障碍有明确的实际意义。

DESCRIPTION (provided by applicant): Synaptic plasticity is a fundamental feature of the nervous system that underlies neural development, adaptation and learning. There is growing evidence that deficits in the mechanisms of synaptic plasticity are involved in the pathophysiology of many psychiatric disorders, from schizophrenia to mood disorders. For this reason, NIMH has established as one of his strategic research priorities the study of brain plasticity "at the cellular, synaptic, circuit, and behavioral level," with the final goal of "determining the neurobiological bases of these processes." This proposal will study humans and three animal models (flies, mice, rats) to test the novel and provocative idea that synaptic plasticity is adaptive up to a point, but beyond that point, or in vulnerable individuals, it can become maladaptive. The "cost" of synaptic plasticity is not often considered but may be crucial in the pathophysiology of psychiatric disorders, and will be assessed at the ultrastructural, cellular, circuit, and behavioral level. Our previous NIMH-funded work has established that the overall result of wake plasticity is a net increase in synaptic strength, which is renormalized by sleep. But what happens when plasticity is "excessive," for instance because it is extended beyond the physiological range without intervening sleep? Based on preliminary results obtained in both animals and humans, we hypothesize that extended plasticity can lead to negative consequences on neuronal activity (OFF periods, performance deficits) and on cellular function/integrity (cellular stress, ultrastructural abnormalities). Aim 1 will use rats to test whether plasticity-dependent synaptic overload leads to the occurrence of neuronal OFF periods, local EEG slowing during wake, and performance impairment. It will also establish to what extent these effects are a region- specific consequence of plasticity, rather than a general effect of prolonged wake. Aim 2 will use high density (hd) EEG in humans to ask whether the local increase in EEG theta waves, which occurs during wake as a result of extended plasticity in specific brain circuits, leads to local performance deficits, locally increased sleep need, and o sleep-dependent restoration of function. Aim 3 will use flies and mice to test whether extending plasticity by prolonging wakefulness leads to cellular stress and subcellular damage, and whether doing so chronically under sleep restriction conditions leads to lasting cellular damage and cognitive deficits. Plasticity plays a central role in the life of every organism, but its coston neural structure and function may be substantial especially at vulnerable developmental times, such as adolescence, or in vulnerable populations, such as psychiatric patients. Demonstrating the cost of plasticity at the cellular and systems level will have clear practical implications forthe prevention and treatment of mental disorders.