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 地图分布在整个丘脑，中脑和大脑皮层中。但是，鲜为人知 关于电路如何在此信息处理开始的视网膜中开发和组织。 该提议的目标是确定电路发展的基础机制 介导视网膜中的方向选择性（DS）。经典研究表明，首选的分布 方向，称为DS图，与基本轴 - 上和前 - 后部。但是，最近的表征表明，DS图遵循由定义的轴 光流。结果，跨成人视网膜的DS图随位置的函数而变化，其中 群集彼此之间是正交的，更靠近视神经，并随着距离而倾斜 从视神经增加。这张地图在开眼界中存在。这个复杂的组织如何 尚不清楚在开眼界之前出现。这促使对发展因素进行调查 这有助于形成DS地图。 方向选择性神经节细胞（DSGC）对沿首选方向运动的反应强烈 并且在相反的方向或无效方向上运动。为了实现此计算，DSGCS 从星爆肿瘤细胞（SACS）的无效运动期间接收更大的突触抑制作用 通过精确的接线方式。有趣的是，在DSGC接线的发育期间 视网膜带有SAC，具有赞助。随着波浪的传播，此活动呈现出来 跨越视网膜的残留波的表面。 在此提案中，我将探讨残留波的作用，特别是由胆碱能驱动的波 信号传导，在DS地图的发展中。此外，我建议研究突触基础 在整个视网膜表面形成了这个独特的组织的基础。作为第一步 为了了解视网膜波是否影响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如何映射开发 在整个发展中存在和不存在图案化的赞助活动。为此，我 将使用小鼠模型通过敲除β2来严重破坏胆碱能的模型 烟碱乙酰胆碱受体的亚基（AIM 1）。而且，考虑到多大程度上 不对称抑制是定向调谐的必要条件，我建议调整抑制性输入 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 方向。为了测试这一点，我将使用两个靶向的电压夹记录来揭示 该组织的突触基础（AIM 2）。这些发现将为您提供关键见解 在发展过程中这个精确组织的基础的机制。