REM mechanisms in neocortical development

新皮质发育中的 REM 机制

• 批准号: 8296261
• 负责人: MARCOS G FRANK
• 金额: $ 55.42万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-16 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8296261
• 关键词: Abbreviations; Acute; Adult; Animals; Behavior; Behavioral; Binocular Vision; Brain; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium/calmodulin-dependent protein kinase; Cerebral cortex; Chemosensitization; Chronic; Detection; Development; Developmental Process; Electrophysiology (science); Enzymes; Experimental Designs; Extracellular Signal Regulated Kinases; Eye; Goals; Health; Hour; Human; Human Development; Infusion procedures; Investigation; Laboratories; Lead; Learning; Life; Long-Term Potentiation; Mammals; Measurement; Measures; Mediating; Methods; Modeling; Modification; Molecular; Monitor; N-Methyl-D-Aspartate Receptors; Neurons; Neurosciences; Ocular Dominance; Pathway interactions; Perinatal; Phosphotransferases; Play; Polysomnography; Process; Property; Protein Kinase; Proteins; REM Sleep; Recovery; Research; Role; Sensory; Series; Signal Pathway; Signal Transduction; Sleep; Sleep Deprivation; Sleep Fragmentations; Synapses; Synaptic plasticity; System; Techniques; Testing; Up-Regulation; Vision; Visual; Visual Cortex; Western Blotting; area striata; behavior measurement; calmodulin-dependent protein kinase II; critical period; experience; extracellular; improved; in vitro Model; in vivo; indexing; insight; mimicry; monocular deprivation; neocortical; optical imaging; rapid eye movement; research study; response; synaptogenesis; vigilance; vision development

DESCRIPTION (provided by applicant): Ocular dominance plasticity is a canonical form of synaptic plasticity in vivo triggered by changes in binocular vision. It has provided crucial insights into how cortical circuits develop and remodel in early life. We have shown that ocular dominance plasticity is consolidated via cellular mechanisms similar to those mediating long-term synaptic potentiation (LTP). Our goal is to more completely identify these mechanisms and the brain states in which they occur. To achieve this goal we will use our established methods of eliciting ocular dominance plasticity combined with behavioral state monitoring, inactivation of intracortical enzymes, optical imaging of intrinsic cortical signals, acute single-neuron electrophysiology in vivo, chronic tetrode recording of single-neurons in freely-behaving animals, and Western blot measurements of cortical proteins. These techniques are combined in a simple experimental design that allows us to determine how different brain states and intracellular signaling pathways promote long-lasting modifications of cortical circuitry. More specifically, we will test the following hypotheses a) rapid-eye-movement (REM) sleep is necessary for the consolidation of ocular dominance plasticity b) this is mediated by protein kinases (Ca2+/calmodulin- dependent protein kinase [CaMKII] and extracellular regulated kinase [ERK]) activated in REM sleep. We propose the following Specific Aims: 1. Determine the role of REM sleep in the consolidation of ocular dominance plasticity. In this Aim, we will examine the effects of different amounts of REM sleep on two different types of cortical plasticity that require strengthening of visual circuits. This will be accomplished by quantitatively measuring and manipulating vigilance states and binocular visual input to primary visual cortex in the freely-behaving animal. This is followed by three independent and objective measures of cortical plasticity in vivo (acute and chronic single-neuron electrophysiology and optical imaging of intrinsic cortical signals). 2. Determine the role of CaMKII and ERK in the consolidation of ocular dominance plasticity. In this Aim, we will examine the role of CaMKII and ERK signaling in the strengthening of cortical circuits that occurs during sleep. This will be achieved by a) measuring total and phosphorylated CaMKII and ERK proteins in the primary visual cortices of animals that are sacrificed after different amounts of visual experience and rapid- eye-movement sleep b) determining the effects of intracortical pan-CaMK, selective CaMKII and ERK inhibition on the consolidation of ocular dominance plasticity c) mimicry and occlusion experiments are then used to determine if the effects of REM sleep are mediated by CaMK, CaMKII or ERK kinase activity. The results of our investigations will provide new insights into how experience and endogenous brain activity guide cortical circuit development and plasticity. They will also provide new information about how normal and abnormal sleep impacts mammalian brain development. PUBLIC HEALTH RELEVANCE: The research in this proposal will provide important new insights into how rapid-eye-movement (REM) sleep promotes critical developmental processes in the cerebral cortex. This will improve our understanding of normal and pathological brain development and the function of sleep in early life.

描述（由申请人提供）：眼优势可塑性是由双眼视力变化触发的体内突触可塑性的一种规范形式。它为早期的皮质回路如何发展和改造提供了关键的见解。我们已经表明，通过类似于介导长期突触增强（LTP）的细胞机制，可以通过细胞机制巩固眼部优势可塑性。我们的目标是更彻底地确定这些机制及其发生的大脑状态。为了实现这一目标，我们将使用我们既定的方法来引起眼部优势可塑性，并结合行为状态监测，灭活性酶的灭活，内在皮质信号的光学成像，急性单神经物理生理学，体内急性单神经生理学，在体内的慢性四极管记录 - 行为动物和皮质蛋白的蛋白质印迹测量。这些技术结合在简单的实验设计中，该设计使我们能够确定不同的大脑状态和细胞内信号通路如何促进皮质回路的长期修饰。更具体地说，我们将测试以下假设a）巩固眼部优势可塑性b）这是由蛋白激酶（Ca2+/钙调蛋白 - 依赖性蛋白 - 依赖性蛋白激酶[CAMKII]和细胞外介导的，需要快速移动（REM）睡眠。调节的激酶[ERK]）在REM睡眠中激活。我们提出以下特定目的：1。确定REM睡眠在眼部优势可塑性巩固中的作用。在此目标中，我们将检查不同量的REM睡眠对两种不同类型的皮质可塑性的影响 这需要加强视觉电路。这将通过定量测量和操纵警惕性状态和双眼视觉输入到自由行为动物中的原代视皮。接下来是体内皮质可塑性的三种独立和客观测量（急性和慢性单神经元电生理学以及内在皮质信号的光学成像）。 2。确定Camkii和Erk在巩固眼部优势可塑性中的作用。在此目标中，我们将研究CAMKII和ERK信号传导在睡眠期间发生的皮质电路中的作用。这将通过a）测量在动物的主要视觉皮层中测量总和磷酸化的caMKII和ERK蛋白，这些蛋白在不同量的视觉体验和快速眼动睡眠b）确定心脏内pan-camk的影响，选择性均可实现。然后使用CAMKII和ERK抑制眼占主导地位可塑性的巩固c）模仿和遮挡实验，然后使用CAMK，CAMKII或ERK激酶活性介导REM睡眠的作用。我们的调查结果将为经验和内源性大脑活动如何指导皮质回路的发展和可塑性提供新的见解。他们还将提供有关睡眠正常和异常睡眠影响哺乳动物脑发育的新信息。 公共卫生相关性：该提案中的研究将提供重要的新见解，以了解快速移动（REM）睡眠如何促进大脑皮层中关键的发育过程。这将提高我们对正常和病理的大脑发育以及早期睡眠功能的理解。