Role of synaptic integration in early visual processing

突触整合在早期视觉处理中的作用

基本信息

批准号：
9915909
负责人：
Raunak Sinha
金额：
$ 24.9万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9915909
关键词：
Affect Anatomy Behavior Cell physiology Cells Characteristics Complex Degenerative Disorder Dendrites Development Disease Electron Microscopy Engineering Exhibits Feedback Genetic Goals Human Individual Interneurons Kinetics Knowledge Location Macular degeneration Maps Mediating Mus Nature Neural Pathways Neurons Outcome Output Perception Peripheral Phase Play Primates Process Property Prosthesis Public Health Regulation Research Retina Retinal Diseases Role Shapes Signal Transduction Site Structure Synapses Techniques Testing Therapeutic Intervention Time Transgenic Organisms Vision Visual Visual Fields Visual Perception Work base cell type fovea centralis ganglion cell innovation insight light microscopy neural circuit neurotransmission postsynaptic postsynaptic neurons presynaptic public health relevance receptor response retinal prosthesis sensory feedback sensory stimulus synaptic inhibition tool visual information visual processing

项目摘要

DESCRIPTION (provided by applicant): To restore vision, we must understand how information is processed in the retina and what circuit mechanisms shape the retinal output. One such mechanism is the interaction between converging excitatory and inhibitory signals, which plays a central role in regulating key properties of a neuronal output across most neural circuits. The nature of this interaction can be diverse based on 1) site of action and 2) temporal dynamics and determines how a neuron integrates the excitatory and inhibitory inputs (synaptic integration) to produce a response. This is exemplified in the retina where inhibitory interneurons can act postsynaptically on the dendrites of ganglion cells or presynaptically on bipolar cell terminals. Moreover, synaptic inhibition can exhibit a variety of temporal relationships (motifs) with excitation in the retina such as feedforward, feedback and crossover inhibition. An emerging theme of recent work in non-primate retina has been the surprisingly complex functions performed by ganglion cells, which rely heavily on inhibition and the mechanisms of synaptic integration. However, several fundamental questions remain unaddressed. How does synaptic integration regulate the output of key retinal circuits that dominate our visual perception? For instance, the primate fovea accounts for ~50% of the retinal output and yet we know nothing about the functional properties of excitatory and inhibitory inputs and how ganglion cells integrate these inputs. Secondly, what is the relative contribution of synaptic inhibition acting on pre vs postsynaptic neurons in shaping visual signals? The long-term goal of this project is to understand how retinal circuits use different modes of synaptic integration to drive distinct functions and visually guided behavior. The current objective is to identify what mode of synaptic integration shapes responses across distinct ganglion cell types and how it depends on the site of action. My central hypothesis is that there are different motifs by which excitatory and inhibitory inputs interact and the relation between the motifs and ganglion cell function is of direct relevance to behavior. In Aim 1, we will determine the properties of excitatory and inhibitory inputs, how they interact in time and their impact on output of diverse ganglion cell types in primate fovea. Moreover, we will determine if the functional properties change with retinal location underlying the retinal basis of known differences in visual perception across visual field. In Aim 2, we will dissect the role of presynaptic inhibition in ganglion cell function in distinct retinal circuits using transgenic approaches in mouse retina that will selectively eliminate inhibitory receptors in specific bipolar cell types. A common theme of both Aims will be to map the anatomical correlate of synaptic inhibition and excitation in the above retinal circuits using a combination of light and electron microscopy techniques. This will help construct a structure-function framework for how synaptic integration shapes retinal output. The approach is innovative because we will determine ganglion cell function in the fovea, which has so far been largely obscure. Moreover, we will be able to isolate the role of presynaptic inhibition using transgenic manipulation in mouse retina. The proposed works is significant because it will provide a structure-function framework for understanding how synaptic integration refines GC function in key retinal circuits and thus bridge the gap between anatomy, function and behavior. Knowledge about function at the level of individual circuits will be crucial to understanding the retinal substrates for diverse visual behavior and for identifying targets in retinal diseases for therapeutic interventions.

描述（由申请人提供）：为了恢复视力，我们必须了解信息在视网膜中是如何处理的，以及什么电路机制塑造了视网膜输出，其中一种机制是会聚的兴奋性信号和抑制性信号之间的相互作用，它在调节中发挥着核心作用。大多数神经回路的神经输出的关键属性可以根据 1) 作用部位和 2) 时间动态而变化，并决定神经如何整合兴奋性和抑制性输入。（突触整合）以产生反应，这在视网膜中得到了例证，其中抑制性中间神经元可以在突触后作用于神经节细胞的树突或突触前作用于双极细胞末端。此外，突触抑制可以表现出多种与兴奋相关的时间关系（基序）。视网膜中的前馈、反馈和交叉抑制是非灵长类视网膜最近研究的一个新主题，它所执行的功能令人惊讶地复杂。然而，一些基本问题仍未解决，例如，突触整合如何调节主导我们视觉感知的关键视网膜回路的输出？视网膜输出的百分比，但我们对兴奋性和抑制性输入的功能特性以及神经节细胞如何输入这些输入一无所知。其次，突触抑制作用于前与抑制的相对贡献是什么。该项目的长期目标是了解视网膜回路如何使用不同的突触整合模式来驱动不同的功能和视觉引导的行为。不同的神经节细胞类型以及它如何取决于作用部位我的中心假设是兴奋性和抑制性输入相互作用的方式不同以及它们之间的关系。主题和神经节细胞功能之间的关系与行为直接相关。确定兴奋性和抑制性输入的特性、它们如何及时相互作用以及它们对灵长类动物中央凹中不同神经节细胞类型输出的影响此外，我们将确定功能特性是否随着已知视觉差异的视网膜基础的视网膜位置而变化。在目标 2 中，我们将使用小鼠视网膜中的转基因方法来剖析突触前抑制在不同视网膜回路中神经节细胞功能中的作用，该方法将选择性地消除抑制。特定双相受体这两个目标的一个共同主题是结合光学和电子显微镜技术来绘制上述视网膜回路中突触抑制和兴奋的解剖学相关性，这将有助于构建突触整合如何形成的结构功能框架。该方法是创新的，因为我们将确定中央凹中的神经节细胞功能，而迄今为止这在很大程度上是模糊的。此外，我们将能够使用转基因来分离突触前抑制的作用。所提出的工作意义重大，因为它将提供一个结构-功能框架，用于理解突触整合如何完善关键视网膜回路中的 GC 功能，从而弥合解剖学、功能和行为层面的功能知识之间的差距。单个电路对于了解不同视觉行为的视网膜基质以及确定视网膜疾病治疗干预的目标至关重要。