The role of Arc in the experience-dependent development of the visual cortex

项目摘要 由经验驱动的神经元活动导致新生儿大脑中连接的快速细化 通过突触可塑性的机制。发育过程中感官体验的缺陷会导致 一种感觉知觉的终身损伤，如弱视。此外，突触功能障碍 在发育的关键窗口期间的可塑性可能导致神经发育障碍，如Angelman 脆性X综合征和精神分裂症。理解经验的作用和机制 因此，发育中的依赖性可塑性对于治疗这些疾病至关重要。Arc是一种即时的早期 一种对神经元活动作出反应而快速转录和翻译的基因，它介导神经元的功能和结构 兴奋性突触的变化ARC是视觉系统中经验依赖性突触可塑性所必需的 皮层然而，Arc在经验依赖性精细化和结构突触变化中的作用， 在视觉皮层的发育过程中发生的是未知的。这一建议旨在测试假设，弧- 依赖AMPA受体的内吞作用和突触消除是这种经历所必需的 视觉皮层的独立发展。 目的1探讨Arc在视皮层视觉反应特性发育中的作用 神经元在第1部分中，在体内双光子钙成像将被用来记录视觉诱发反应， 野生型和Arc KO小鼠在发育过程中的视觉皮层。视觉反应是已知的发展， 在早期生活中的不同阶段，以经验依赖的方式，预测是弧是必要的， 这一过程，因此Arc KO小鼠将无法产生这种视觉反应。第2部分将 确定Arc在介导视觉体验依赖性细化中的作用的分子机制 皮质发育过程中。在体内需要ARC依赖性AMPAR内吞作用的假设将是 通过病毒拯救策略进行测试。该方法使用野生型或突变型Arc在细胞中的病毒表达。 Arc KO小鼠的视觉皮层，并决定是否发展正常的视觉反应特性 是通过双光子钙成像来实现的目标2将讨论弧在结构变化中的作用， 在单眼剥夺和正常发育过程中出现的树突棘。假设Arc 在单眼剥夺和发育过程中对脊柱消除是必要的。这两个目标将 阐明Arc在结构和功能性突触可塑性中的作用，这是神经元发育的基础。 视觉皮层

Project Summary Neuronal activity, driven by experience, leads to rapid refinement of the connections in the newborn brain through the mechanisms of synaptic plasticity. Defects in sensory experience during development can lead to a lifelong impairment in sensory perception, such as in amblyopia. Additionally, dysfunction in synaptic plasticity during key windows of development can lead to neurodevelopmental disorders such as Angelman syndrome, Fragile-X syndrome, and schizophrenia. Understanding the role and mechanisms of experience dependent plasticity in development is therefore crucial to treating these disorders. Arc is an immediate early gene rapidly transcribed and translated in response to neuronal activity that mediates functional and structural changes at excitatory synapses. Arc is required for experience-dependent synaptic plasticity in the visual cortex. However, the role of Arc in the experience-dependent refinement and structural synaptic changes that occur during development in the visual cortex is unknown. This proposal seeks to test the hypothesis that Arc- dependent AMPA receptor endocytosis and synapse elimination are required for the experience dependent development of the visual cortex. Aim 1 will determine the role of Arc in the development of visual response properties of visual cortex neurons. In part 1, in vivo two-photon calcium imaging will be used to record visually evoked responses in the visual cortex of wild type and Arc KO mice during development. Visual responses are known to develop in distinct stages during early life in an experience dependent way, and the prediction is that Arc is necessary for this process, and therefore Arc KO mice will fail to have this development of visual responses. Part 2 will determine the molecular mechanisms of Arc’s role in mediating experience-dependent refinement of the visual cortex during development. The hypothesis that Arc-dependent AMPAR endocytosis is required in vivo will be tested through a viral rescue strategy. This approach uses viral expression of wild type or mutant Arc in the visual cortex of Arc KO mice, and determines whether the development of normal visual response properties occurs by using two-photon calcium imaging. Aim 2 will address the role of Arc in the structural changes of dendritic spines that occur during monocular deprivation and normal development. The hypothesis is that Arc is necessary for spine elimination during monocular deprivation and development. These two aims will elucidate the role of Arc in structural and functional synaptic plasticity that underlies the development of the visual cortex.