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到外侧膝状体核的层中，并被分离到初级视觉皮层的眼优势柱中。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的早期经历了视力差或没有视力，那么这只眼睛就会失去与大脑的解剖和功能联系。这导致受影响的眼睛在以后的生活中失明，即使视力不良的原因是固定的，使眼睛本身功能正常。在随后的几年里，许多研究都着眼于改变或消除神经元活动对眼特异性分离发展的影响。这些研究的结果导致以下结论：1）在发育过程中，视觉系统中的特定连接随着时间的推移从最初的弥散连接中出现，2）在发育过程中消除视网膜活动保持最初的不精确连接，以及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育领域的教条，并对相关领域产生了重大影响，如神经发育障碍，大脑的成人可塑性以及学习和记忆。然而，过去十年的新实验对这些结论提出了质疑。该提案将通过实现以下具体目标来解决争议。1)眼优势柱发育的正常模式是什么？将使用解剖追踪方法来确定服务于双眼的传入最初是否在初级视觉皮层中重叠或分离。2)视网膜活动完全阻断对LGN和皮质中眼特异性分离的发展有什么影响？在发育过程中，将使用药物抑制视网膜神经节细胞动作电位，并检查对分离的影响。3)视网膜神经节细胞活动的哪些方面对于LGN中眼睛特异性的正常发育是重要的？将比较改变视网膜中活动模式的操作，以确定活动模式的哪些方面与正常分离相对于缺乏分离相关。4)在分离的发展过程中，相关活动的作用是什么？光激活分子将用于控制活动模式，以确定两只眼睛之间相邻细胞的激发的相关性增加是否导致缺乏眼睛特异性分离。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，缺乏或改变活动的影响，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。 公共卫生相关性：神经发育障碍，包括自闭症、精神分裂症、胎儿酒精综合征、癫痫、注意力缺陷/多动障碍等，对家庭是毁灭性的，对社会也是代价高昂的。为了了解并最终治疗这些疾病，有必要了解大脑是如何发育的。目前的提议将回答有关大脑连接正常发展的问题，以及当神经元活动受到影响时，连接如何改变。从这些实验中获得的对基本发育神经生物学的理解可能有一天有助于治疗神经发育障碍。

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.