Mechanisms of Synaptic Specificity in Visual Circuits

摘要 高效的感官处理需要开发精确的布线电路。感觉障碍是很常见的 在神经发育障碍(NDDS)中，如脆性X综合征(FXS)，强调了 正确的布线。尽管如此，精确的感觉回路连接和感觉病因学背后的机制 NDDS的功能障碍仍然知之甚少，阻碍了有效治疗的发展。要解决这些问题 在知识空白方面，我们利用小鼠上丘(SC)的视觉回路来阐明 FXS小鼠回路连接的基本机制和发现的新的亚回路特异性视觉缺陷 (FMR1-/y)。具体地说，我们将重点介绍视网膜编码的空间地形图的机制 眼内的神经节细胞(RGC)和初级视皮层(L5V1)的第5层神经元在SC内形成。 我们和其他人之前的研究表明，SC-RGC视觉回路发育的每个阶段 映射、视觉映射对齐和电路整合--依赖于神经元活动；然而， 人们对它们背后的机制知之甚少。根据我们之前和初步的数据，我们建议 一种模型，在该模型中，视觉回路发育的每个阶段背后的活动依赖机制 SC是截然不同的。我们将在三个具体目标上测试该模型，利用尖端技术的独特组合 技术和新颖的小鼠遗传模型。在目标1中，我们将测试以前开发的计算模型 通过操纵SC(目标1A)或视网膜(目标1B)的神经元活动并评估 SC中的地形组织和视觉功能的变化。在目标2中，我们将确定时间和地点 在SC中的视觉电路开发期间需要FMR1。具体地说，我们将阐明特定阶段的 Fmr1在视觉地图对齐的发展和维持(目标2a)和视觉成熟中的作用 在SC中的职能(目标2B)，以及在每个区域中的具体作用(目标2C)。在目标3中，我们将在我们的 令人兴奋的初步数据，表明视觉体验和Fmr1可能相互作用来调节维护 和/或SC中视觉回路的成熟。为了测试这种可能性，我们将确定视觉的要求 对照组(Aim 3A)和Fmr1-/y(Aim 3B)小鼠的视觉回路组织和功能经验。这些 这些研究将与那些将老鼠暴露在视觉丰富的环境中的研究相辅相成，以测试这种可能性 它可以挽救在Fmr1/y小鼠中观察到的缺陷(目标3C)。这些研究将揭示根本 感觉神经回路的形成机制并为阐明其分子基础奠定了基础 依赖活动的布线。此外，我们将获得对FXS感觉功能障碍的病因学的批判性见解， 对这种疾病的治疗可能会对社交障碍、焦虑和 智力发展。

ABSTRACT Efficient sensory processing requires the development of precisely wired circuits. Sensory deficits are common in neurodevelopmental disorders (NDDs), such as fragile X syndrome (FXS), underscoring the importance of proper wiring. Despite this, the mechanisms underlying precise sensory circuit wiring and the etiology of sensory dysfunction in NDDs remain poorly understood, precluding development of effective therapies. To address these gaps in knowledge, we have utilized the visual circuitry of the mouse superior colliculus (SC) to elucidate fundamental mechanisms of circuit wiring and uncovered novel sub-circuit-specific visual deficits in FXS mice (Fmr1-/y). Specifically, we will focus on the mechanisms by which topographic maps of space encoded by retinal ganglion cells (RGCs) in the eye and Layer 5 neurons in primary visual cortex (L5V1) are formed in the SC. Previous studies by us and others suggest that each stage of visual circuit development in the SC - RGC mapping, visual map alignment, and circuit consolidation - is dependent on neuronal activity; however, the mechanisms underlying each are poorly understood. Based on our previous and preliminary data, we propose a model in which the activity-dependent mechanisms underlying each stage of visual circuit development in the SC are distinct. We will test this model in three specific aims, leveraging a unique combination of cutting-edge techniques and novel genetic mouse models. In Aim 1, we will test previously developed computational models of L5V1 alignment by manipulating neuronal activity in the SC (Aim 1A) or retina (Aim 1B) and evaluating changes in topographic organization and visual function in the SC. In Aim 2, we will determine when and where Fmr1 is required during visual circuit development in the SC. Specifically, we will elucidate the stage-specific roles of Fmr1 in the development and maintenance of visual map alignment (Aim 2A) and maturation of visual function in the SC (Aim 2B), as well as the region-specific roles in each (Aim 2C). In Aim 3, we will build on our exciting preliminary data, suggesting that visual experience and Fmr1 may interact to regulate the maintenance and/or maturation of visual circuits in the SC. To test this possibility, we will determine the requirement of visual experience for visual circuit organization and function in control (Aim 3A) and Fmr1-/y (Aim 3B) mice. These studies will be complemented with those exposing mice to a visually-enriched environment to test the possibility that it may rescue deficits observed in Fmr1-/y mice (Aim 3C). These studies will uncover fundamental mechanisms of sensory circuit formation and establish a platform for elucidating the molecular underpinnings of activity-dependent wiring. Further, we will gain critical insight into the etiology of sensory dysfunction in FXS, the treatment of which could have reverberating positive impacts on deficits in social communication, anxiety, and intellectual development.