Binocular Coordination of Eye Movements

描述（由申请人提供）：感觉源性发育性斜视是一个重要的公共卫生问题，因为它影响2-5%的婴儿人口。以前，我们表明，饲养的条件下，交替单眼闭塞（AMO）的婴儿猴再现了感觉性斜视综合征与大的水平错位，A/V模式，和分离的垂直偏差（DVD）。上一个周期的一个重要发现是，神经因素负责产生导致A/V模式和DVD出现的跨轴眼球运动。包括临床和猴病变研究在内的多项证据表明，涉及中线小脑的回路在双眼控制眼球运动（包括眼睛对齐）中很重要。因此，在当前的周期中，我们专注于通过在小脑顶核（FN）和相邻的后间核（PIN）中进行单细胞记录和失活研究来确定跨轴运动的实际来源。实验分为三个具体目标。具体目标1涉及FN和PIN中的神经元记录。这里的一般方法是识别每个结构中的神经元亚型，并检查神经元反应与斜视角度或交叉轴运动的相关性。我们正在测试的假设之一是，与水平错位相关的神经活动是否维持在与编码交叉轴运动的细胞不同的细胞中。在具体目标2中，我们将使用GABAA激动剂蝇蕈醇对左侧和右侧FN和PIN进行单侧和双侧失活。这些实验的总体目标是确定两个目标结构在定义斜视特性中的相对功能贡献。将测试几个假设，这些假设将阐明FN和PIN在大脑一侧或两侧的作用以及对产生眼睛错位和交叉轴运动作用的相对贡献。目的3提出记录从旁正中脑桥网状结构的兴奋性爆发神经元，以确定驱动交叉轴运动的脉冲信号是单眼还是双眼编码的。这里的策略是使用通过正常猴子的双眼协调研究开发的框架来解决跨轴运动的驱动信号的视力。所有目标中的第二个主题是比较AMO模型和更传统地用于感觉性斜视的模型，棱镜直立模型。进行比较研究的主要目的是验证AMO模型。AMO和棱镜养育模型在发育过程中的双眼视觉体验类型不同，但它们都产生类似的行为结果，如A/V模式和DVD。因此，第二个结果是，这些比较将澄清在发展过程中的双眼视觉经验的类型对眼回路内的活动模式的影响。完成我们的研究将有助于了解和治疗某些类型的斜视。眼位不正（斜视）是一种发育障碍，影响了美国和世界各地出生的大量儿童。更好地了解不同形式的斜视所影响的神经机制将有助于合理地开发基于治疗的方法。这个特殊的项目将联合收割机在动物模型中结合各种生理学方法和行为，以了解A/V型斜视的具体问题。

Description (provided by applicant): Developmental strabismus of sensory origin is a significant public health problem since it affects 2-5% of the infant population. Previously we showed that rearing infant monkeys under conditions of alternate monocular occlusion (AMO) reproduced a sensory strabismus syndrome with large horizontal misalignment, A/V patterns, and Dissociated Vertical Deviation (DVD). An important finding in the previous cycle was that neural factors were responsible for generating cross-axis eye movements that lead to appearance of A/V patterns and DVD. Several lines of evidence including clinical and monkey lesion studies suggest that circuits involving the midline cerebellum are important in binocular control of eye movements including alignment of the eyes. Therefore, in the current cycle, we focus on identifying the actual source for cross-axis movements by performing single cell recording and inactivation studies in the Fastigial Nucleus (FN) and the adjacent Posterior Interposed Nucleus (PIN) of the cerebellum. The experiments are organized into three specific aims. Specific aim 1 involves neuronal recording in the FN and PIN. The general approach here is to identify neuronal subtypes in each structure and examine neuronal responses for correlation to strabismus angle or cross-axis movements. One of the hypotheses that we are testing is whether neural activity related to the horizontal misalignment is maintained in cells different from those that encode cross-axis movements. In specific aim 2, we will perform unilateral and bilateral inactivation of the left and right FN and PIN using the GABAA agonist muscimol. The overall goal of these experiments is to determine relative functional contribution of the two target structures in defining properties of strabismus. Several hypotheses that will clarify roles of FN and PIN on one or both sides of the brain and relative contribution towards producing eye misalignment and cross-axis movement role will be tested. Aim 3 proposes recording from excitatory burst neurons in the paramedian pontine reticular formation to determine whether the pulse signal that drives cross-axis movements is encoded monocularly or binocularly. The strategy here is to use the framework developed via studies of binocular coordination in normal monkeys to address ocularity of drive signals for cross-axis movements. A second theme within all the aims is to compare the AMO model and a more traditionally used model for sensory strabismus, the prism-rearing model. The main goal in performing comparative studies is to validate the AMO model. The AMO and prism-rearing models differ in the type of binocular visual experience during development though they both produce similar behavioral outcomes such as A/V patterns and DVD. Therefore a second outcome is that these comparisons will clarify effect of type of binocular visual experience during development on patterns of activity within oculomotor circuits. Completion of our studies will be of benefit to the understanding and treatment of certain types of strabismus. PUBLIC HEALTH RELEVANCE Ocular misalignment (strabismus) is a developmental disorder that affects a significant number of children born in the United States and around the world. A better understanding of neural mechanisms that are affected in the different forms of strabismus will help develop rationally based therapy. This particular project will combine various physiological methods and behavior in an animal model to understand the specific problem of A/V-pattern strabismus.