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：
9198015
负责人：
Raunak Sinha
金额：
$ 9万
依托单位：
UNIVERSITY OF WASHINGTON
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 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9198015
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 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（由应用程序提供）：要恢复视觉，我们必须了解如何在视网膜中处理信息以及哪种电路机制塑造了视网膜输出。这样的机制是融合运动和抑制信号之间的相互作用，这在大多数神经元电路中神经元输出的调节关键特性中起着核心作用。这种相互作用的性质可以基于1）作用部位和2）临时动力学，并确定神经元如何整合兴奋和抑制输入（突触整合）以产生响应。这在视网膜中举例说明了抑制性中间神经元可以在神经节细胞的树突上或在双极细胞末端进行抑制性中间神经元作用。此外，突触抑制可以在视网膜中表现出各种临时关系（主题），例如前饲，反馈和交叉抑制。在非青春期视网膜中最近作品的一个新兴主题是神经节细胞执行的令人惊讶的复合功能，该功能严重依赖于抑制和突触整合的机制。但是，几个基本问题仍然没有解决。合成整合如何调节主导我们视觉感知的关键视网膜电路的输出？例如，灵长类动脉丛占视网膜输出的约50％，但我们对兴奋性和抑制性输入的功能性能以及神经节细胞如何整合这些输入一无所知。其次，在塑造视觉信号时，突触抑制作用与突触后神经元的相对贡献是什么？该项目的长期目标是了解视网膜电路如何使用不同的突触集成模式来推动不同的功能和视觉指导性行为。当前的目的是确定突触整合模式的塑造跨不同神经节细胞类型的响应及其如何依赖于动作部位。我的核心假设是，兴奋和抑制投入相互作用的基序和关系有不同的基础。在基序和神经节细胞功能之间与行为直接相关。在AIM 1中，我们将确定兴奋性和抑制性输入的特性，它们如何在时间上相互作用以及对原发性中央凹的潜水神经节细胞类型的产量的影响。此外，我们将确定功能性能是否随着视觉视野视觉感知的已知差异的视网膜位置而发生变化。在AIM 2中，我们将使用小鼠视网膜中的转基因方法在不同的视网膜回路中剖析神经节细胞功能中突触前抑制作用的作用细胞类型。这两个目的的一个共同主题是绘制上述残留电路中突触抑制和兴奋的解剖学相关性，结合了光和电子显微镜技术。这将有助于构建一个结构功能框架，以构建合成整合如何塑造视网膜输出。该方法具有创新性，因为我们将确定中央凹中的神经节细胞功能，到目前为止，这在很大程度上是晦涩的。此外，我们将能够隔离提出的作品的作用，因为它将提供一个结构功能框架，以了解合成整合炼油厂如何在关键视网膜电路中的功能，从而弥合解剖学，功能和行为之间的差距。关于在单个电路级别的功能的知识对于理解潜水员视觉行为的视网膜底物以及确定治疗干预措施的残留疾病靶标至关重要。