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: 10387986
• 负责人: Karina Bistrong
• 金额: $ 4.29万
• 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/10387986
• 关键词: Adult; Alzheimer' s Disease; Animals; Anterior; Calcium; Cells; Cerebral cortex; Complex; Data; Development; Disease; Eye; 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 genetics; information processing; insight; interest; mouse model; neural circuit; optic flow; 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 视觉信息通过一组神经回路进行处理，这些神经回路组织成功能性的 分布在丘脑、中脑和大脑皮层的地图。然而， 关于视网膜中的电路是如何发展和组织的，视网膜是信息处理的起点。的 这项建议的目的是确定电路发展的机制， 介导视网膜中的方向选择性（DS）。经典研究表明， 方向，称为DS图，与主轴对齐-上-下和前- 后面然而，最近的表征表明，DS图遵循由下式定义的轴： 光流因此，成人视网膜上的DS图作为位置的函数而变化，其中 簇在更靠近视神经处彼此正交 从视神经发出的信号会增加这张地图是在眼睛睁开。这个复杂的组织 在眼睛睁开之前出现是未知的。这促使人们对发展因素进行调查， 这有助于DS地图的形成。 方向选择性神经节细胞（DSGCs）对首选方向的运动反应强烈 而对相反方向或零方向的运动影响很小。为了实现这种计算，DSGCs 在星爆状无长突细胞（SAC）的零方向运动期间接受更大的突触抑制 通过精确的线路图有趣的是，在发育期间， 视网膜是自发活动的。这种活动表现为波传播 在视网膜的表面--称为视网膜波。 在这个建议中，我将探讨视网膜波的作用，特别是胆碱能驱动的波， 在DS地图的开发中。此外，我建议研究突触基础 这是视网膜表面形成这种独特组织的基础。作为第一步 为了了解视网膜波是否影响DS图的形成，我将使用双光子 群体钙成像，遗传工具和药理学，以评估DS地图如何在 在整个发育过程中是否存在模式化的自发活动。为了实现这一点，我 将使用小鼠模型，通过敲除β2 烟碱乙酰胆碱受体亚基（Aim 1）。此外，考虑到 不对称抑制对于定向调谐是必要的，我建议抑制性输入的调谐 在DSGCs上的图像将在视网膜中的不同位置处改变，以解释优选的图像的偏斜。 方向为了验证这一点，我将使用双光子靶向电压钳记录来揭示 该组织的突触基础（目的2）。这些发现将提供关键的见解， 在发育过程中，这种精确组织的基础机制。