Synaptic mechanisms and circuitry of retinal interneurons

视网膜中间神经元的突触机制和电路

• 批准号: 10737233
• 负责人: Z JIMMY ZHOU
• 金额: $ 51.71万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737233
• 关键词: Address; Amacrine Cells; Anatomy; Cell physiology; Cells; Chemicals; Classification; Cone; Coupled; Diffusion; Disease; Functional disorder; Gap Junctions; Glutamates; Goals; Image; Impairment; Interneurons; Investigation; Kinetics; Knowledge; Light; Measures; Morphology; Mus; Neurons; Optics; Output; Photoreceptors; Physiological; Physiology; Property; Resolution; Retina; Role; Signal Transduction; Synapses; Synaptic Transmission; Testing; Visual; cell type; ganglion cell; imaging study; insight; millisecond; neuronal circuitry; novel; patch clamp; postsynaptic; presynaptic; receptive field; response; sensor; spatiotemporal; starburst; transcriptomics; transmission process; two-photon; visual information; voltage clamp

Abstract The goal of this proposal is to understand how visual signals are transmitted from the outer to the inner retina through cone bipolar cells (CBC), with a focus on detailed synaptic mechanisms and functional circuits between morphologically and physiologically identified cone bipolar cell types and specific ganglion and amacrine cell types in the whole-mount mouse retina. This investigation is motivated by an important observation that, although recent transcriptomic, connectomic, and imaging studies have significantly advanced our understanding of bipolar cell classification and anatomical structure, our knowledge of the detailed physiology of the synapses and circuits formed by these classified CBC types remains very limited. To address this fundamental gap in our understanding of retinal processing, we developed a new experimental approach, using dual pre- and post-synaptic patch-clamp recording from pairs of morphologically identified CBC types and ganglion cell types in the whole-mount mouse retina in conjunction with two-photon optical recording and targeted expression of genetically encoded glutamate and Ca sensors. This approach allowed us to correlate the anatomical structure of each morphological CBC type with its intrinsic and receptive-field physiology and, more importantly, to directly measure, at a millisecond resolution and under voltage-clamp condition, synaptic transmission from identified CBC types to their postsynaptic targets in a structurally intact retina. Our preliminary results revealed novel kinetic and circuit properties of CBC that suggested a new mechanism of synaptic integration using both chemical and electrical synaptic transmission. Based on these preliminary results, we propose a dual-mode synaptic mechanism by which CBCs transmit both a direct synaptic signal and a gap junction-coupled network signal to their postsynaptic targets. This hypothesized mechanism will be tested through the three Specific Aims. Aim 1, dual patch-clamp characterization of synaptic transmission and functional connectivity between morphologically identified CBC types and a diffused ganglion cell type (W3) in the whole-mount retina. Aim 2, understand the chemical and electrical synaptic interactions underlying signal transmission from identified CBC types to W3 cells in the whole-mount retina. Aim 3, determine the functional impact of different modes of CBC synaptic transmission on diffused and narrowly stratified postsynaptic target cells. Results from this study are expected to provide novel insights into the synaptic mechanisms and functional circuitry of cone bipolar cell types in the mammalian retina and shed light on chemical and electrical synaptic integration in the CNS in general.

抽象的 该提案的目的是了解如何从外部到内部视网膜传输视觉信号 通过锥双极细胞（CBC），重点是详细的突触机制和功能电路 形态学和生理上鉴定出锥双极细胞类型以及特定的神经节和无链氨麦细胞 整个鼠标视网膜中的类型。这项调查是由一个重要的观察结果激发的，该观察结果是 尽管最近的转录组学，连接组和成像研究已经显着提高了我们的 了解双极细胞分类和解剖结构，我们对详细生理学的了解 这些分类的CBC类型形成的突触和电路仍然非常有限。解决这个问题 在我们对视网膜处理的理解时，我们开发了一种新的实验方法 从形态学上鉴定的CBC类型和双重突触后贴片钳记录CBC类型和 整个鼠标视网膜中的神经节细胞类型与两光子光学记录和 遗传编码的谷氨酸和Ca传感器的靶向表达。这种方法使我们能够关联 每种形态学CBC类型的解剖结构，均具有内在的和接受的场生理学以及 更重要的是，以毫秒的分辨率直接测量和在电压钳状态下，突触 从结构完整的视网膜中，从确定的CBC类型到其突触后目标的传播。我们的初步 结果揭示了CBC的新型动力学和电路特性，提出了一种新的突触机制 使用化学和电突触传播的整合。基于这些初步结果，我们 提出了一种双模式突触机制，通过该机制，CBC既传递直接突触信号和间隙 连接耦合的网络信号向其突触后目标。该假设的机制将进行测试 通过三个特定目标。 AIM 1，突触传播的双贴片钳表征和 形态学鉴定的CBC类型与扩散的神经节细胞类型（W3）之间的功能连通性 整个视网膜。 AIM 2，了解信号基础的化学和电突触相互作用 从确定的CBC类型传播到整个视网膜中的W3细胞。目标3，确定功能 CBC突触传播模式对扩散且分层的突触后靶标的影响 细胞。这项研究的结果有望提供有关突触机制和功能性的新见解 哺乳动物视网膜中的锥双极细胞类型的电路，并阐明了化学和电突触的灯光 总体上集成在中枢神经系统中。