REM mechanisms in neocortical development

新皮质发育中的 REM 机制

• 批准号: 8460005
• 负责人: MARCOS G FRANK
• 金额: $ 42.38万
• 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/8460005
• 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.

描述(申请人提供)：眼优势可塑性是体内突触可塑性的典型形式，由双眼视觉的变化触发。它为大脑皮层回路在早期生命中如何发展和重塑提供了至关重要的见解。我们已经证明，眼睛优势可塑性是通过细胞机制巩固的，类似于那些介导长时程突触增强(LTP)的机制。我们的目标是更全面地确定这些机制以及它们发生时的大脑状态。为了实现这一目标，我们将使用我们已建立的方法，结合行为状态监测、皮质内酶的失活、固有皮质信号的光学成像、体内急性单神经元电生理学、自由行为动物中单个神经元的慢性四极管记录以及皮质蛋白的蛋白质印迹测量，来诱导眼睛优势可塑性。这些技术结合在一个简单的实验设计中，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电路的长期修改。更具体地说，我们将测试以下假设a)快速眼动(REM)睡眠对于巩固眼优势可塑性是必要的b)这是由REM睡眠中激活的蛋白激酶(钙/钙调蛋白依赖的蛋白激酶[CaMKII]和细胞外调节的激酶[ERK])介导的。我们提出了以下具体目标：1.确定快速眼动睡眠在巩固眼优势可塑性中的作用。在这个目标中，我们将研究不同的快速眼动睡眠对两种不同类型的皮质可塑性的影响。 这需要加强视觉回路。这将通过定量测量和操纵警觉状态和双眼视觉输入到行为自由的动物的初级视觉皮质来实现。紧随其后的是三种独立和客观的活体皮质可塑性测量(急性和慢性单个神经元电生理学和内在皮质信号的光学成像)。2.确定CaMKII和ERK在眼优势可塑性巩固中的作用。在这一目标中，我们将研究CaMKII和ERK信号在睡眠过程中加强皮质回路中的作用。这将通过a)测量动物初级视皮层中总的和磷酸化的CaMKII和ERK蛋白，这些蛋白在不同数量的视觉体验和快速眼动睡眠后被牺牲b)确定皮质内PAN-CaMK、选择性CaMKII和ERK抑制对巩固眼优势可塑性的影响c)然后使用模仿和遮挡实验来确定REM睡眠的影响是由CaMK、CaMKII还是ERK激酶活性介导的。我们的研究结果将为经验和内源性大脑活动如何引导皮质回路发育和可塑性提供新的见解。他们还将提供有关正常和异常睡眠如何影响哺乳动物大脑发育的新信息。