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

基本信息

批准号：
7650157
负责人：
Chiara Cirelli
金额：
$ 20.8万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7650157
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

项目摘要

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.

睡眠脑电图中的慢波活动（SWA; 0.5-4.0 Hz）是睡眠需求的标志随着先前清醒的持续时间和睡眠期间的指数降低。生物学然而，负责SWA增加的过程是先前清醒的函数，仍然未知。根据最近的假设 - 睡眠功能的突触稳态假设 - 塑料过程在清醒期间发生会导致许多皮质回路的突触强度净增加。作为结果，当皮质神经元在睡眠期间低频开始振荡时，它们变得强烈同步，导致高振幅的缓慢波，从而增加SWA。这些慢波，在转弯，负责重新归一化突触强度，并对能量产生有益的影响代谢和性能。最近的工作表明，与假设一致，清醒是与参与突触增强的基因的诱导相关，例如ARC，BDNF，P-CREB和 NGFI-A，而睡眠与参与突触抑郁的基因表达较高有关，例如钙调神经和NSF。在这些结果的基础上，该项目将检查突触增强/抑郁与自由行为中SWA的本地现场潜在记录并联老鼠。 AIM 1将在清醒和睡眠中量化突触AMPA受体数量和磷酸化状态为了确认前者与突触增强和后者有关的预测沮丧。 AIM 2将测试以相同数量的清醒状态睡眠SWA会更高的预测，如果通过增加的探索活动来诱导突触增强的标记在较高水平。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预测，与突触增强相关的局部分子变化与大鼠对侧运动皮层中SWA稳态的局部增加。因此，该项目将提供整个建议的分子 /电生理基础。