Function and circuitry of adaptive inhibition in the retina

视网膜适应性抑制的功能和电路

• 批准号: 8660301
• 负责人: STEPHEN A BACCUS
• 金额: $ 38.47万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8660301
• 关键词: Amacrine Cells; Back; Brain; Cells; Code; Complement; Complex; Computer Simulation; Disease; Electronics; Environment; Future; Goals; Individual; Inner Plexiform Layer; Interneurons; Intervention; Knowledge; Learning; Measures; Methods; Modeling; Morphology; Mus; Neurons; Neurophysiology - biologic function; Output; Pharmacology; Play; Population; Population Heterogeneity; Process; Property; Prosthesis; Recording of previous events; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Retinal Ganglion Cells; Role; Salamander; Sensory; Signal Transduction; Staging; Stem cells; Stimulus; Structure; Synapses; System; Testing; Validation; Visual; Whole-Cell Recordings; base; behavior change; cell type; design; falls; ganglion cell; information processing; mathematical model; neural circuit; novel; novel strategies; public health relevance; receptive field; relating to nervous system; research study; response; retinal prosthesis; sensory system; spatiotemporal; therapy design; transmission process

DESCRIPTION (provided by applicant): A critical function of the vertebrate retina is to change its sensitivity based on the recent history of the stimulus in order to maintain a visual response when the environment changes. This process, known as adaptation, occurs in multiple forms, although many aspects of the cellular and circuit origin of these computations remain unknown. Recently, it was found that certain retinal ganglion cells increase their sensitivity following a strong stimulus. These sensitizing ganglion cells maintain a high sensitivity to weak stimuli, even when other types of ganglion cells adapt and fall below threshold. This proposal aims to analyze the circuit basis for the adaptive computation of sensitization. To understand sensitization arises, we have developed a novel approach to directly measure the functional role of individual retinal interneurons. We record the intracellular visual response from a single interneuron, while simultaneously recording from a population of retinal ganglion cells using a multielectrode array. Then, by playing back an altered version of the cell's own signal using injected current, we directly probe how that cell's output changes the behavior of the circuit. Mathematical models are used to explain how the responses of interneurons combine together to yield the responses of ganglion cells. Amacrine cells are a diverse population of inhibitory interneurons in the retina, most with unknown function. Some amacrine cells are known to adapt to the contrast of the stimulus, but the functional role of this process is unknown. The goal of this proposal is test the hypothesis that adaptive inhibition generates sensitization, and to develop a quantitative circuit level description of how sensitization arises. The specific goals are: 1) In the salamander and mouse retina, we will measure the spatiotemporal structure of how adaptive excitation and inhibition combine to generate sensitization, and capture these properties with a computational model. Using pharmacology, we will identify the broad class of amacrine cells that are essential to sensitization. 2) Using intracellular and multielectrode recording, we will measure the computation of sensitization through salamander retinal circuitry by recording from interneurons during sensitization, and then directly measure their connectivity to different classes of ganglion cells. Synaptic currents in salamander and mouse ganglion cells will be analyzed using whole cell recordings. 3) We will directly measure how changes in transmission from single inhibitory amacrine cells generate sensitization in the intact salamander retina. Understanding how a diverse population of neurons combines to perform neural functions is a critical barrier to our understanding of retinal mechanisms and diseases involving the degeneration of the retinal circuitry. These findings will be essential to understanding basic mechanisms of how retinal circuitry processes information and will be useful in the design of electronic retinal prosthesis systems.

描述（由申请人提供）：脊椎动物视网膜的一个关键功能是根据最近的刺激历史改变其敏感性，以便在环境变化时保持视觉反应。这个过程被称为适应，以多种形式发生，尽管这些计算的细胞和电路起源的许多方面仍然未知。最近，人们发现某些视网膜神经节细胞在受到强烈刺激后敏感性会增加。即使其他类型的神经节细胞适应并低于阈值，这些敏化神经节细胞仍对微弱刺激保持高度敏感性。该提案旨在分析敏化自适应计算的电路基础。为了了解敏化的产生，我们开发了一种新方法来直接测量单个视网膜中间神经元的功能作用。我们记录单个中间神经元的细胞内视觉反应，同时使用多电极阵列记录视网膜神经节细胞群。然后，通过使用注入电流回放细胞自身信号的改变版本，我们直接探测该细胞的输出如何改变电路的行为。数学模型用于解释中间神经元的反应如何组合在一起以产生神经节细胞的反应。无长突细胞是视网膜中多种抑制性中间神经元，其中大多数功能未知。已知一些无长突细胞能够适应刺激的对比度，但该过程的功能作用尚不清楚。该提案的目标是测试适应性抑制产生敏化的假设，并开发敏化如何产生的定量电路水平描述。具体目标是：1）在蝾螈和小鼠视网膜中，我们将测量自适应兴奋和抑制如何结合产生敏化的时空结构，并通过计算模型捕获这些特性。利用药理学，我们将鉴定出对致敏至关重要的一类无长突细胞。 2）使用细胞内和多电极记录，我们将通过在敏化过程中记录中间神经元来测量蝾螈视网膜电路的敏化计算，然后直接测量它们与不同类别神经节细胞的连接性。将使用全细胞记录来分析蝾螈和小鼠神经节细胞的突触电流。 3）我们将直接测量单个抑制性无长突细胞的传输变化如何在完整的蝾螈视网膜中产生敏化。了解不同的神经元群体如何结合起来执行神经功能是我们理解视网膜机制和涉及视网膜电路退化的疾病的关键障碍。这些发现对于理解视网膜电路如何处理信息的基本机制至关重要，并将有助于电子视网膜假体系统的设计。