Development of Visual Pathways

描述（由申请人提供）：在成熟的哺乳动物视觉系统中，来自两只眼睛的信息在解剖学上被分离成外侧膝状核的层，以及初级视觉皮层的眼优势柱。在过去的半个世纪里，这种分离的发展已经成为大脑中特定连接发展的首要模型。20世纪60年代的开创性工作表明，神经元活动对眼优势柱的正常发育很重要。如果一只眼睛在生命早期视力差或没有视力，那么这只眼睛就会失去与大脑的解剖和功能联系。即使视力不佳的原因已经被修复，使眼睛本身功能正常，也会在以后的生活中导致受影响的眼睛失明。在随后的几年里，许多研究都着眼于改变或取消神经元活动对眼睛特异性分离发展的影响。这些研究结果得出以下结论：1)在发育过程中，视觉系统中的特定连接随着时间的推移而从最初的漫射连接中产生；2)发育过程中视网膜活动的消除维持了最初的不精确连接；3)每只眼睛内神经元放电模式的时间相关性，眼睛之间缺乏相关性是眼睛特异性连接发展的原因。这些结论形成了感觉系统发展领域的教条，并对神经发育障碍、成人大脑可塑性、学习记忆等相关领域产生了重大影响。然而，过去十年的新实验对这些结论都提出了质疑。该提案将通过实现以下具体目标来解决争议。1)眼优势柱的正常发育模式是什么？解剖追踪方法将用于确定服务于两只眼睛的传入事件最初在初级视觉皮层是重叠的还是分离的。2)完全阻断视网膜活动对LGN和皮层中眼特异性分离的发展有何影响？在发育过程中，将使用药物抑制视网膜神经节细胞的动作电位，并研究其对分离的影响。3)视网膜神经节细胞活性的哪些方面对LGN正常的眼特异性发育是重要的？将对改变视网膜活动模式的操作进行比较，以确定活动模式的哪些方面与正常分离或缺乏分离有关。4)相关活动在隔离发展中的作用是什么？光活化分子将用于控制活动模式，以确定两只眼睛之间相邻细胞放电的相关性增加是否会导致眼睛特异性分离的缺乏。这些实验不仅有助于解决重要的基础科学争议，而且还具有临床意义。了解大脑中连接的初始状态，活动缺失或改变的影响，以及正常发育所需的活动模式的关键方面，都将有助于理解和最终治疗神经发育障碍。

DESCRIPTION (provided by applicant): In the mature mammalian visual system, information from the two eyes is anatomically segregated into layers in the lateral geniculate nucleus, and into ocular dominance columns in primary visual cortex. During the past half century, the development of this segregation has served as a premier model for the development of specific connections in the brain. Groundbreaking work in the 1960s showed that neuronal activity is important for the normal development of ocular dominance columns. If poor vision or no vision is experienced by one eye early in life, then that eye loses anatomical and functional connections to the brain. This results in blindness through the affected eye later in life, even if the cause of the poor vision is fixed so that the eye itself functions normally. Many studies over the ensuing years have looked at the effects of altering or abolishing neuronal activity on the development of eye-specific segregation. Findings from these studies lead to the following conclusions: 1) During development, specific connections in the visual system emerge over time from initially diffuse connections, 2) abolishing retinal activity during development maintains the initial imprecise connections, and 3) temporal correlation in the firing patterns of neurons within each eye, and lack of correlation between eyes is responsible for the development of eye-specific connections. These conclusions formed the dogma of the field of development of sensory systems, and significantly influenced related fields such as neurodevelopmental disorders, adult plasticity in the brain, and learning and memory. However, new experiments over the past decade have questioned each of these conclusions. This proposal will address the controversies by performing the following specific aims. 1) What is the normal pattern of development of ocular dominance columns? Anatomical tracing methods will be used to determine whether afferents serving the two eyes are initially overlapping or segregated in primary visual cortex. 2) What is the effect of complete retinal activity blockade on the development of eye-specific segregation in the LGN and cortex? Pharmacological agents will be used to silence retinal ganglion cell action potentials during development, and the effects on segregation will be examined. 3) What aspects of retinal ganglion cell activity are important for normal development of eye-specificity in the LGN? Manipulations that alter patterns of activity in the retina will be compared in order to determine which aspects of activity patterns are associated with normal segregation versus lack of segregation. 4) What is the role of correlated activity in the development of segregation? Light activatable molecules will be used to control activity patterns to determine whether increased correlation of firing of neighboring cells between the two eyes leads to lack of eye-specific segregation. These experiments will not only help to resolve important basic science controversies, but will also have clinical implications. Understanding the initial state of connections in the brain, the effects of absent or altered activity, and the key aspects of activity patterns that are needed for normal development, will all aid in the understanding and eventual treatment of neurodevelopmental disorders. PUBLIC HEALTH RELEVANCE: Neurodevelopmental disorders, including autism, schizophrenia, fetal alcohol syndrome, seizure disorders, attention deficit / hyperactivity disorder, etc. are devastating to families and costly to society. In order to understand and eventually treat these disorders, it is necessary to understand how the brain develops. The current proposal will answer questions about normal development of connections in the brain, and how connections are altered when neuronal activity is affected. The understanding of basic developmental neurobiology gained from these experiments may someday help in the treatment of neurodevelopmental disorders.