Brain Plasticity and Local Sleep Homeostasis: A Molecular Perspective

大脑可塑性和局部睡眠稳态：分子视角

• 批准号: 7346830
• 负责人: Chiara Cirelli
• 金额: $ 26.7万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-27 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7346830
• 关键词: AMPA Receptors; Adult; Area; BDNF gene; Behavioral; Behavioral Paradigm; Biological Markers; Biological Process; Brain; Brain region; Brain-Derived Neurotrophic Factor; Calcineurin; Calcium/calmodulin-dependent protein kinase; Cellular Membrane; Cerebral cortex; Chemosensitization; Chromosome Pairing; Circadian Rhythms; Condition; Contralateral; Data; Electrodes; Electroencephalogram; Endocytosis; Energy Metabolism; Environment; Event-Related Potentials; Excitatory Synapse; Exploratory Behavior; Exposure to; F-Actin; Forelimb; Frequencies; Gene Expression; Genes; GluR2 subunit AMPA receptor; Glutamates; Hand; Homeostasis; Hour; Human; Individual; Injection of therapeutic agent; Learning; Link; Localized; Long-Term Depression; Long-Term Potentiation; Measurement; Measures; Mediating; Memory; Mental Depression; Molecular; Motor; Motor Cortex; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NR1 gene; Neurons; Numbers; Occipital lobe; Parietal; Performance; Phosphorylation; Plastics; Preparation; Process; Protein Dephosphorylation; Proteins; Protocols documentation; Rattus; Relative (related person); Side; Site; Sleep; Sleep Deprivation; Slow-Wave Sleep; Surface; Synapses; Testing; Time; Toxin; Training; Wakefulness; Work; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; amino 3 hydroxy 5 methylisoxazole 4 propionate; awake; brain electrical activity; calmodulin-dependent protein kinase II; gene induction; human NR1 protein; in vivo; motor learning; receptor; research study; response; synaptic depression

Slow wave activity (SWA; 0.5-4.0 Hz) in the sleep electroencephalogram is a marker of sleep need, increasing with the duration of prior wakefulness and decreasing exponentially during sleep. The biological process responsible for the increase of SWA as a function of prior wakefulness, however, remains unknown. According to a recent hypothesis - the synaptic homeostasis hypothesis of sleep function - plastic processes occurring during wakefulness result in a net increase in synaptic strength in many cortical circuits. As a consequence, when cortical neurons begin oscillating at low frequencies during sleep, they become strongly synchronized, leading to slow waves of high amplitude and thereby to increased SWA. These slow waves, in turn, are responsible for the renormalization of synaptic strength and have beneficial effects on energy metabolism and performance. Recent work has shown that, consistent with the hypothesis, wakefulness is associated with the induction of genes involved in synaptic potentiation, such as Arc, BDNF, P-CREB, and NGFI-A, while sleep is associated with higher expression of genes involved in synaptic depression, such as calcineurin and NSF. Building upon these results, this Project will examine specific molecular markers of synaptic potentiation/depression in parallel with local field potential recordings of SWA in freely behaving rats. Aim 1 will quantify synaptic AMPA receptor number and phosphorylation state in wakefulness and sleep to confirm the prediction that the former is associated with synaptic potentiation and the latter with synaptic depression. Aim 2 will test the prediction that sleep SWA will be higher, for the same amount of wakefulness, if markers of synaptic potentiation are induced at higher levels through increased exploratory activity. Aim 3 will employ a forelimb motor learning task inspired by the human learning task used in Projects II, III, and IV to test the prediction that local molecular changes associated with synaptic potentiation are associated with a local increase in SWA homeostasis in rat contralateral motor cortex. Thus, this Project will provide the molecular / electrophysiological underpinning for the entire proposal.

睡眠脑电中的慢波活动(SWA；0.5-4.0赫兹)是睡眠需要的标志， 随着先前清醒时间的延长而增加，并在睡眠期间呈指数下降。生物学的 然而，作为先前觉醒的函数，导致SWA增加的过程仍然未知。 根据最近的一项假说--睡眠功能的突触动态平衡假说--可塑性过程 在清醒时发生，会导致许多皮质回路中突触强度的净增加。作为一名 结果，当皮层神经元在睡眠期间开始以低频率振荡时，它们变得强烈 同步的，导致高幅度的慢波，从而增加SWA。这些慢波，在 转而，负责突触强度的重整化，并对能量有有益的影响 新陈代谢和表现。最近的研究表明，与这一假设一致，清醒状态 与参与突触增强的基因的诱导有关，如Arc、BDNF、P-CREB和 NGFI-A，而睡眠与突触抑制相关基因的高表达有关，如 钙调神经磷酸酶和NSF。在这些结果的基础上，本项目将研究特定的分子标记 自由行为中突触增强/抑制与局域场电位记录的平行关系 老鼠。目标1将量化清醒和睡眠中突触AMPA受体的数量和磷酸化状态 以证实前者与突触增强有关而后者与突触有关的预测 抑郁症。目标2将测试睡眠SWA会更高的预测，在相同的清醒时间下， 如果突触增强的标志物是通过增加探索性活动在更高水平上诱导的。目标3 将采用受项目II、III和IV中使用的人类学习任务启发的前肢运动学习任务 为了测试与突触增强相关的局部分子变化与 大鼠对侧运动皮质局部SWA动态平衡增加。因此，该项目将提供 整个提案的分子/电生理基础。