Structural Basis of Amblyopia and Strabismus

描述(申请人提供)：本项目的最终目标是了解两种疾病导致视力丧失的神经机制：弱视和斜视。这些疾病加在一起，影响了美国约2%的儿童。当一只眼睛在儿童早期被剥夺了正常的视觉刺激时，就会发生弱视。例如，先天性白内障通过阻止视网膜接收清晰聚焦的图像而损害视力。即使在白内障摘除后，眼睛的视力仍然很差，因为视觉剥夺导致了突触连接的异常连接和大脑细胞活动的中断。在正常猴子中，为每只眼睛服务的初级视觉皮质中的突触连接被组织成一个平行的、交替的带状系统，称为眼优势柱。在某些形式的弱视中，这些柱状细胞收缩，细胞对剥夺的眼睛失去反应。在具体目标#1中，将通过检查从有单眼视力丧失病史的患者身上获得的死后视皮层标本，使用代谢标记细胞色素氧化酶(CO)来研究人类眼优势柱的组织方式。弱视和斜视的代谢活动模式也将被研究，并在V2区的正常受试者中进行研究，V2区是下一个专门用于视觉处理的皮质区域。在特定的目标2中，将追踪从眼优势柱到猕猴V2区的连接。该假说认为，弱视患者眼球优势柱细胞向V2区投射的丢失并不是弱视的重要因素，因为它阻碍了视觉信息向高级中枢的正常传输。在具体目标#3中，将研究负责视觉抑制的神经机制。在斜视中，儿童无法保持眼睛的正常排列。他们通过抑制一只眼睛的图像来避免双重视觉。将通过测试斜视猕猴的视觉功能和眼睛注视偏好来研究这种情况是如何发生的。分视视野将被用来绘制视野中视觉抑制的模式。在这些心理物理测试完成后，清醒动物的单个细胞将被记录下来，因为它们在每只眼睛之间来回切换注视。目标将是确定细胞的放电频率是如何通过视觉抑制来调节的。ISO取向和交叉取向的光栅将被用来寻找双眼的促进和抑制，并测试这些影响是否取决于哪一只眼睛在感知上占优势。最后，视野中的区域抑制区域将与眼优势柱中的CO活动模式相关联。假说是受抑制眼柱的新陈代谢活动会减少。这些实验对弱视和斜视的结构基础的新见解可能会导致改进预防和治疗这些疾病的方法。

DESCRIPTION (provided by applicant): The ultimate objective of this project is to understand the neural mechanisms responsible for visual loss caused by two diseases: amblyopia and strabismus. Together, these conditions affect about 2% of the children in the United States. Amblyopia develops when one eye is deprived of normal visual stimulation during early childhood. For example, a congenital cataract impairs vision by preventing the retina from receiving clearly focused images. Even after the cataract is removed, the visual acuity in the eye remains poor, because visual deprivation has caused abnormal wiring of synaptic connections and disruption of cellular activity in the brain. In normal monkeys the synaptic connections in the primary visual cortex serving each eye are organized into a system of parallel, alternating bands, called ocular dominance columns. In some forms of amblyopia, these columns shrink and their cells lose responsiveness to the deprived eye. In Specific Aim #1, a metabolic label, cytochrome oxidase (CO), will be used to how ocular dominance columns are organized in humans, by examining post-mortem specimens of visual cortex obtained from patients with a history of visual loss in one eye. Patterns of metabolic activity will also be studied in amblyopia and strabismus, and in normal subjects in area V2, the next cortical area devoted to visual processing. In Specific Aim #2, connections will be traced from ocular dominance columns to area V2 in the macaque. The hypothesis is that a loss of projections from cells in the deprived eye's ocular dominance columns to area V2 is unimportant factor in amblyopia, because it prevents the normal transfer of visual information to higher centers. In Specific Aim #3, the neural mechanisms responsible for visual suppression will be examined. In strabismus, children fail to maintain normal alignment of the eyes. They avoid double vision by suppressing the image from one eye. How this occurs will be studied in strabismic macaques by testing their visual function and ocular fixation preference. Dichoptic perimetry will be employed to map patterns of visual suppression in the visual fields. After these psychophysical tests are completed, recordings will be made from single cells in awake animals, as they switch fixation back and forth between each eye. The goal will be to determine how the firing rate of cells is modulated by visual suppression. Iso-oriented and cross-oriented gratings will be used to search for binocular facilitation and suppression, and to test whether these effects depend upon which eye is perceptually dominant. Finally, areas of regional suppression in the visual fields will be correlated with patterns of CO activity in the ocular dominance columns. The hypothesis is that metabolic activity will be reduced in the suppressed eye's columns. New insights from these experiments into the structural basis of amblyopia and strabismus may lead to improved methods of preventing and treating these diseases.