Mechanisms of Synaptic Specificity in Visual Circuits

摘要 有效的感觉处理需要开发精确的线路。感官缺陷很常见 神经发育障碍（NDD），如脆性X综合征（FXS），强调了 正确的布线尽管如此，精确的感觉电路布线的机制和感觉神经传导障碍的病因学仍有待进一步研究。 NDD的功能障碍仍然知之甚少，阻碍了有效治疗的发展。解决这些 知识的差距，我们利用小鼠上级丘（SC）的视觉回路来阐明 电路布线的基本机制和FXS小鼠中发现的新的子电路特异性视觉缺陷 （Fmr1-/y）。具体来说，我们将集中在视网膜编码的空间地形图的机制， 在SC中形成眼睛中的神经节细胞（RGC）和初级视觉皮层（L5V1）中的第5层神经元。 我们和其他人的先前研究表明，SC-RGC中视觉回路发育的每个阶段 映射，视觉映射对齐和回路巩固-依赖于神经元活动;然而， 每一种情况的机制都知之甚少。根据我们以前的和初步的数据，我们建议 一个模型，其中活动依赖机制的基础上，每个阶段的视觉电路发展中， SC不同。我们将在三个具体目标中测试这种模式，利用尖端技术的独特组合， 技术和新的遗传小鼠模型。在目标1中，我们将测试先前开发的计算模型 通过操纵SC（Aim 1A）或视网膜（Aim 1B）中的神经元活动， 在目标2中，我们将确定何时何地 在SC的视觉回路发育过程中需要FMR1。具体来说，我们将阐明阶段特异性 Fmr1在视觉地图对齐（Aim 2A）的发展和维持以及视觉系统成熟中的作用 在供应链中的职能（目标2B），以及在每个区域中的具体作用（目标2C）。在目标3中，我们将建立在我们的 令人兴奋的初步数据表明，视觉体验和Fmr1可能相互作用，以调节维护 和/或成熟的视觉电路在SC。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Fmr 1-/y（Aim 3B）小鼠视觉回路组织和功能的经验。这些 研究将补充那些暴露小鼠在视觉丰富的环境，以测试的可能性， 它可以挽救在Fmr1-/y小鼠中观察到的缺陷（Aim 3C）。这些研究将揭示 感觉回路形成的机制，并建立一个平台，阐明的分子基础， 活动依赖性布线。此外，我们还将深入了解FXS感觉功能障碍的病因， 治疗可能对社交沟通，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.