Assessing direction selectivity map development in the retina

评估视网膜方向选择性图的发育

• 批准号: 10560474
• 负责人: Karina Bistrong
• 金额: $ 4.38万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10560474
• 关键词: Adult; Alzheimer' s Disease; Animals; Anterior; Calcium; Cells; Cerebral cortex; Complex; Data; Development; Disease; Eye; Genetic; Goals; Image; Inferior; Investigation; Knock-out; Knockout Mice; Knowledge; Label; Location; Maps; Mediating; Midbrain structure; Modeling; Motion; Movement; Mus; Neurodegenerative Disorders; Neurodevelopmental Disorder; Nicotinic Receptors; Nose; Optic Nerve; Pathology; Pattern; Peripheral; Pharmacology; Population; Process; Retina; Role; Sensory; Signal Transduction; Source; Spatial Distribution; Specificity; Surface; Synapses; Technology; Testing; Thalamic structure; Thyrotropin-Releasing Hormone Receptors; Variant; Visual; autism spectrum disorder; cholinergic; design; experience; ganglion cell; imaging detection; information processing; insight; interest; mouse model; neural circuit; optic flow; pharmacologic; postnatal; postsynaptic; promoter; response; starburst amacrine cell; stem; synaptic inhibition; tool; two-photon; visual information; visual stimulus; voltage clamp

Project Summary Visual information is processed through a set of neural circuits that organize into functional maps distributed throughout the thalamus, midbrain, and cerebral cortex. However, little is known about how circuits develop and organize in the retina, where this information processing begins. The goal of this proposal is to determine the mechanisms underlying the development of the circuits that mediate direction selectivity (DS) in the retina. Classic studies show that the distribution of preferred directions, referred to as the DS map, align with the cardinal axes–– superior-inferior and anterior- posterior. However, recent characterization has shown that the DS map follows the axes defined by optic flow. As a result, the DS map across the adult retina changes as a function of location, where the clusters are orthogonal to one another closer to the optic nerve and become skewed as distance from the optic nerve increases. This map is present at eye opening. How this complex organization arises prior to eye opening is not known. This prompts an investigation of the developmental factors that contribute to the formation of DS maps. Direction-selective ganglion cells (DSGCs) respond robustly to motion in a preferred direction and weakly to motion in the opposite, or null, direction. In order to achieve this computation, DSGCs receive greater synaptic inhibition during null direction motion from starburst amacrine cells (SACs) via precise wiring patterns. Interestingly, during the developmental period where DSGCs are wiring up with SACs, the retina is spontaneously active. This activity presents itself as waves propagating across the surface of the retina––termed retinal waves. In this proposal, I will explore the role of retinal waves, specifically waves driven by cholinergic signaling, in the development of DS maps. Additionally, I propose to investigate the synaptic basis underlying the formation of this distinct organization across the retinal surface. As a first step towards understanding whether retinal waves influence DS map formation, I will use two-photon population calcium imaging, genetic tools, and pharmacology to assess how the DS map develops in the presence and absence of patterned spontaneous activity across development. To achieve this, I will use a mouse model where cholinergic waves are severely disrupted by knocking out the β2 subunit of the nicotinic acetylcholine receptor (Aim 1). Moreover, given the extent to which asymmetric inhibition is necessary for directional tuning, I propose that the tuning of inhibitory inputs onto DSGCs will change at varied locations in the retina, to account for the skewing of preferred directions. To test this, I will use two-photon-targeted voltage clamp recordings to unmask the synaptic basis of this organization (Aim 2). These findings will provide key insights into the mechanisms that underlie this precise organization during development.

项目摘要 视觉信息是通过一组组织为功能的神经回路处理的 地图分布在整个，脑和大脑皮层的地图。 关于电路在视网膜中的发展和组织方式，然后开始信息处理 该提案的目标是确定电路的发展机制 在视网膜中进行介导方向选择性（DS）。 方向，称为DS地图，与基本轴（占前部和前轴）保持一致 但是，近期表征已显示DS图遵循 结果。 簇与另一个靠近视神经的正交，并随着距离而偏斜 从视神经增加了。 在开眼界之前出现，这尚不清楚。 这有助于形成DS地图。 方向选择性神经节细胞（DSGC）响应在首选方向上对运动的反应强烈 在相反的方向或无效的方向上运动。 从Starburst Amacrine细胞（SAC）中，在无效运动中接收更大的突触吸入。 通过精确的接线方式。 在SAC上，视网膜是自发的活性。 跨越视网膜的视网膜波的表面。 在此提案中，我将探讨视网膜波的作用，特别是由胆碱能驱动的波 信号，在DS图的发展中，我建议研究突触的基础 在整个视网膜表面的第一步中，这一独特的组织的形成是基础。 要理解波影响DS图的形成，我将使用两光子 人口钙成像，遗传工具和药理学，以评估DS图如何发展 在整个发育中的存在和不存在以实现这一目标。 将使用小鼠模型通过敲除β2来破坏胆碱能波 烟碱丙烯胆碱受体的亚基（AIM 1）。 不对称抑制对于定向调节是必要的，我建议对输入的调整 到DSGC上将在视网膜的各种位置发生变化，以解释首选的偏斜 要测试这一点，我将使用两个靶向电压夹 该组织的突触基础（AIM 2）。 在发展过程中这个精确组织的基础的机制。