Binocular Coordination of Eye Movements

描述(由申请人提供)：发育性感觉性斜视是一个重大的公共卫生问题，因为它影响到2-5%的婴儿人口。以前我们发现，在交替单眼遮挡(AMO)条件下饲养幼猴会复制出一种感觉性斜视综合征，具有较大的水平错位、A/V模式和分离性垂直偏差(DVD)。在前一个周期中的一个重要发现是，神经因素负责产生跨轴眼球运动，导致A/V模式和DVD的出现。包括临床和猴子损伤研究在内的几条证据表明，涉及小脑中线的环路在双眼控制眼睛运动(包括眼睛的排列)方面很重要。因此，在当前的周期中，我们将重点放在通过对小脑顶核(FN)和相邻的后间隔核(PIN)进行单细胞记录和失活研究来确定跨轴运动的实际来源。这些实验被组织成三个具体目标。具体目标1涉及FN和PIN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，并检查神经元对斜视角度或跨轴运动的反应。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在不同于编码跨轴运动的细胞中保持。在具体目标2中，我们将使用GABAA激动剂Muscimol对左侧和右侧FN和PIN进行单侧和双侧灭活。这些实验的总体目标是确定两个靶结构在确定斜视特性方面的相对功能贡献。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跨轴运动作用的相对贡献。目的3建议记录脑桥旁网状结构兴奋性爆发神经元，以确定驱动跨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研究正常猴子的双眼协调而开发的框架来解决跨轴运动的驱动信号的眼性。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-棱镜饲养模型。进行比较研究的主要目的是验证AMO模型。AMO和棱镜饲养模式在发育过程中的双眼视觉体验类型不同，尽管它们都会产生类似的行为结果，如A/V模式和DVD。因此，第二个结果是，这些比较将阐明发育过程中双眼视觉经验类型对动眼神经回路活动模式的影响。本研究的完成将有助于对某些类型斜视的认识和治疗。公共卫生相关性眼球倾斜(斜视)是一种发育障碍，影响到在美国和世界各地出生的相当数量的儿童。更好地了解不同形式斜视的神经机制将有助于开发合理的治疗方法。这个特别的项目将结合动物模型中的各种生理方法和行为来了解A/V模式斜视的具体问题。

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.