Role of Arc in synaptic/experience-dependent plasticity in mouse visual cortex

Arc 在小鼠视觉皮层突触/经验依赖性可塑性中的作用

• 批准号: 8658247
• 负责人: Jason D Shepherd
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8658247
• 关键词: Acute; Affect; Alzheimer' s Disease; Angelman Syndrome; Behavior; Behavioral; Brain; Calcium; Cells; Chemosensitization; Contralateral; Coupled; Data; Development; Electrophysiology (science); Excitatory Synapse; Exhibits; Fragile X Syndrome; Functional disorder; Gene Expression; Gene Proteins; Gene Targeting; Genes; Genetic Transcription; Glutamate Receptor; Goals; Homeostasis; Image; Immediate-Early Genes; In Vitro; Individual; Information Storage; Ipsilateral; Knockout Mice; Knowledge; Link; Long-Term Potentiation; Measures; Mediating; Mental Depression; Mentors; Modification; Molecular; Mus; Nature; Neurons; Neurosciences; Ocular Dominance; Phase; Phenotype; Photons; Play; Postdoctoral Fellow; Preparation; Process; Regulation; Role; Shapes; Slice; Stimulus; Surface; Synapses; Synaptic Transmission; Synaptic plasticity; Syndrome; Testing; Ursidae Family; Visual; Visual Cortex; experience; graduate student; in vivo; insight; nervous system disorder; neural circuit; protein expression; relating to nervous system; research study; response; tool; trafficking

A major challenge in neuroscience is to understand how neuronal networks are modified through experience and how proteins/genes contribute to circuit modification. Neural circuits are refined during development through activity-dependent gene and protein expression. Similar macromolecular synthesis is essential for long-term forms of synaptic plasticity such as long-term potentiation (LTP) and depression (LTD). Efforts to identify molecules that underlie these forms of plasticity have revealed a set of genes that target to excitatory synapses. Among these, Arc is the most tightly coupled to behavioral encoding of information in neuronal circuits. Arc homeostatically regulates surface AMPA type glutamate receptors (AMPARs) by directly interacting with the endocytic machinery. However, very little is known about Arc's function at the level of neuronal circuits or its precise in vivo role in mediating information storage. The visual cortex is an ideal preparation to probe these questions as visual experience can be modulated to induce gross changes in neuronal activity. The overall goal of this proposal is to investigate the mechanisms that underlie Arc's role in modifying neural circuits in response to visual experience and how these processes are disrupted in neurological disorders. In previous experiments, we find that Arc plays a fundamental role in experience- dependent plasticity in mouse visual cortex (V1). Arc knock out mice exhibit deficits in ocular dominance plasticity and in a newly discovered form of experience-dependent plasticity, stimulus-specific response potentiation. We also uncover an experience and Arc-dependent component to establishing the contralateral to ipsilateral ratio. How does Arc regulate experience-dependent plasticity in the visual cortex? The goal of aim 1 is to investigate the mechanisms underlying these phenotypes by utilizing slice electrophysiology in V1 cortical slices and investigating the role of Arc in 3 different types of synaptic plasticity; LTD, LTP and synaptic scaling. In vivo electrophysiology provides a powerful tool to assess experience-dependent plasticity, but it is difficult to identify specific networks of individual cells. The goal of aim 2 is to investigate the role of Arc in experience- dependent plasticity at the single cell level using 2-photon calcium imaging in vivo, which can measure neuronal activity in many cells with spatial precision. Aim 3 will directly test whether Arc mediates plasticity through its role in AMPAR trafficking. Finally, aim 4 intends to test the idea that Arc levels are critical for normal synaptic homeostasis and that abnormal Arc levels contribute to the synaptic dysfunction observed in neurological disorders, including Alzheimer's disease, Fragile X and Angelman Syndromes.

神经科学的一个主要挑战是了解神经元网络是如何通过经验进行修改的 以及蛋白质/基因如何对电路修改做出贡献。神经回路在发育过程中得到完善 通过活性依赖的基因和蛋白质表达。类似的大分子合成是必不可少的 突触可塑性的长期形式，例如长时程增强（LTP）和抑制（LTD）。努力 确定这些可塑性形式的基础分子揭示了一组靶向兴奋性的基因， 突触其中，Arc与神经元中的行为信息编码耦合最紧密。 电路. Arc通过直接调节AMPA型谷氨酸受体（AMPAR）的表达， 与内吞机制相互作用。然而，很少有人知道弧的功能， 神经元回路或其在介导信息存储中的精确体内作用。视觉皮层是一个理想的 准备探索这些问题，因为视觉体验可以调节，以引起 神经元活动本提案的总体目标是研究Arc在以下方面的作用机制： 修改神经回路，以响应视觉体验，以及这些过程是如何被破坏的， 神经系统疾病在之前的实验中，我们发现Arc在经验中起着基础性的作用- 小鼠视觉皮层的依赖性可塑性（V1）。Arc基因敲除小鼠表现出眼优势缺陷 可塑性和新发现的经验依赖性可塑性形式，刺激特异性反应 增强作用我们还发现了一个经验和弧依赖的组成部分，以建立对侧， 同侧比率Arc如何调节视觉皮层中的经验依赖可塑性？aim 1的目标 目的是利用V1皮层脑片电生理研究这些表型的机制 切片并研究Arc在3种不同类型的突触可塑性中的作用; LTD，LTP和突触缩放。 在体电生理学提供了一个强有力的工具来评估经验依赖的可塑性，但它是困难的， 识别单个细胞的特定网络。目标2的目标是研究弧在经验中的作用- 在体内使用双光子钙成像在单细胞水平的依赖性可塑性，其可以测量 神经元活动在许多细胞中的空间精度。目标3将直接测试Arc是否介导可塑性 通过其在AMPAR贩运中的作用。最后，目标4旨在测试Arc水平对于正常至关重要的想法 突触内稳态和异常Arc水平有助于观察到突触功能障碍， 神经系统疾病，包括阿尔茨海默氏病，脆性X和Angelman Syndrome。