Mechanisms and Role of Spontaneous Retinal Waves in Visual Development.

项目总结 这一提议中的实验将促进我们对负责发展的机制的理解 哺乳动物大脑中精确的神经回路。模式活动对神经的正常发育至关重要 神经回路和活动依赖的回路精化缺陷与神经发育障碍有关 如脆性X综合征、自闭症和弱视。弱视是导致单眼视觉的最常见原因 年轻人和中年人的残疾，大约每100名儿童中就有3人受到影响。弱视是 以空间视觉、空间对比敏感度和其他任务中的一系列缺陷为特征。然而， 这种适应不良的机制还没有被很好地理解。我们将采用广泛的技术， 包括分子生物学、细胞生物学、神经解剖学、电生理学和高级光学 体外和体内成像技术。我们的实验集中在中脑上层的神经回路上。 小鼠的丘脑和视皮层。在视网膜之外，这些区域是最大的视觉结构 大脑。上丘是一种感觉运动结构，已经成为一种理想的模型系统 检查神经回路的发育和功能。视觉皮质是一个规范的模型系统，用于 哺乳动物高级脑功能和发育的研究。人们普遍假设分子线索 负责建立粗大的大脑回路特征，以及依赖活动的过程 随后将这些电路细化到功能精确度。视觉电路功能的出现早于 感觉体验的开始表明，视觉地图的形成首先是由非活动启动的 机制，如轴突引导分子，然后通过预视相关的自发活动来提炼，以及 后来在睁开眼睛后通过视觉体验保持和锐化。自发性视网膜神经节破裂 细胞会根据其主要的兴奋性驱动力，产生随年龄变化的活动波。最初 在体外，I期波发生在出生前，并由视网膜之间的缝隙连接介导 神经节细胞。第二阶段从出生到出生10岁左右，由胆碱能星爆型无长突细胞介导。 细胞。III期波起源于谷氨酸能，双极细胞提供主要的兴奋性驱动。 视网膜神经节细胞从出生后10天起至睁眼。这个项目旨在研究特定的时空 视网膜波的特征和潜在的细胞机制对视网膜病变的发展具有指导作用 眼前皮层和皮质下回路的高阶回路和神经元反应特性 开场了。

PROJECT SUMMARY Experiments in this proposal will advance our understanding of mechanisms responsible for the development of precise neural circuitry in the mammalian brain. Patterned activity is critical for normal development of neural circuits, and deficits in activity-dependent circuit refinement are associated with neurodevelopmental disorders such as Fragile X syndrome, autism, and amblyopia. Amblyopia is the most common cause of monocular visual impairment among young and middle-aged adults, with approximately 3 in 100 children effected. Amblyopia is characterized by a range of deficits in spatial vision, spatial contrast sensitivity, and other tasks. However, the mechanisms of this maladaptation are not well understood. We will employ a broad range of techniques, including molecular biological, cell biological, neuroanatomical, electrophysiological and advanced optical imaging techniques in vitro and in vivo. We focus our experiments on neural circuits in the midbrain superior colliculus and visual cortex of the mouse. Beyond the retina, these areas are the largest visual structures in the brain. The superior colliculus is a sensory motor structure that has emerged as an ideal model system for the examination of neural circuit development and function. The visual cortex is a canonical model system for the study of higher order brain function and development in mammals. It is widely hypothesized that molecular cues are responsible for the establishment of gross brain circuit features, and activity dependent processes subsequently refine these circuits to functional precision. The emergence of visual circuit features before the onset of sensory experience suggests that visual map formation is first initiated by activity-independent mechanisms, such as axon guidance molecules, then refined by pre-vision correlated spontaneous activity, and later maintained and sharpened by visual experience after eye-opening. Spontaneous bursting of retinal ganglion cells results in propagating waves of activity that change with age based on their primary excitatory drive. Initially characterized in vitro, stage I waves occur before birth and are mediated by gap junctions between retinal ganglion cells. Stage II occur from birth until around P10 and are mediated by cholinergic starburst amacrine cells. Stage III waves are glutamatergic in origin, with bipolar cells providing the primary excitatory drive onto retinal ganglion cells from P10 until eye-opening. This project aims to examine the specific spatiotemporal features and the underlying cellular mechanisms by which retinal waves are instructive for the development of higher order circuits and neuronal response properties, in both subcortical and cortical circuits, prior to eye opening.