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

神经科学中的一个主要挑战是理解神经元网络是如何通过经验来修改的 以及蛋白质/基因如何对电路修饰做出贡献。神经回路在发育过程中被提炼 通过活性依赖的基因和蛋白质表达。类似的大分子合成对于 突触可塑性的长期形式，如长时程增强(LTP)和抑制(LTD)。努力实现 识别这些形式的可塑性背后的分子已经揭示了一组以兴奋为目标的基因 突触。其中，Arc与神经元中信息的行为编码关系最为密切 电路。ARC直接内稳态调节表面AMPA型谷氨酸受体(AMPAR) 与内吞机制相互作用。然而，对于Arc在以下级别的功能知之甚少 神经元回路或其在体内调节信息存储的精确作用。视觉皮质是一种理想的 准备探索这些问题，因为视觉体验可以被调节以在 神经元活动。这项提案的总体目标是调查Arc在 改变神经回路以响应视觉体验，以及这些过程是如何在 神经紊乱。在之前的实验中，我们发现Arc在经验中起着基础性的作用- 小鼠视皮质的依赖可塑性(V1)。弧形基因敲除小鼠表现出眼睛优势缺陷 可塑性和一种新发现的经验依赖型可塑性、刺激特异性反应 增强功能。我们还揭示了建立对侧的经验和弧形依赖组件 同侧比。Arc是如何调节视皮层的经验依赖性可塑性的？目标1的目标 是利用V1皮层的薄片电生理学来研究这些表型的机制 并研究Arc在三种不同类型突触可塑性中的作用：LTD、LTP和突触伸缩。 活体电生理学为评估经验依赖的可塑性提供了有力的工具，但很难 识别单个细胞的特定网络。目标2的目标是研究Arc在体验中的作用- 利用体内双光子钙成像在单细胞水平上的依赖可塑性，可以测量 许多细胞中的神经元活动具有空间精确度。目标3将直接测试弧形是否调节可塑性 通过其在AMPAR贩运中的作用。最后，目标4打算测试弧光水平对正常状态至关重要这一观点 突触内稳态和Arc水平异常是突触功能障碍的原因 神经系统疾病，包括阿尔茨海默氏症、脆性X综合征和安杰曼综合征。

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.