SYNAPTIC ORGANIZATION AND VISUAL PROCESSING IN INTERNEURON CIRCUITS OF THE RETINA

视网膜中间神经元回路中的突触组织和视觉处理

• 批准号: 9337454
• 负责人: Daniel Kerschensteiner
• 金额: $ 34.31万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9337454
• 关键词: Address; Amacrine Cells; Anatomy; Antigen-Presenting Cells; Architecture; Behavior; Benchmarking; Brain; Cells; Characteristics; Data; Diabetic Retinopathy; Early identification; Event; Functional disorder; Glycine; Interneurons; Knowledge; Link; Mammals; Mediating; Motion; Mus; Nervous system structure; Neuromodulator; Neurons; Neurotransmitters; Optics; Output; Pathway interactions; Pattern; Photoreceptors; Reporting; Retina; Retinal; Retinal Diseases; Retinal Ganglion Cells; Retinitis Pigmentosa; SLC17A8 gene; Signal Transduction; Stimulus; Structure; Synapses; System; Testing; Training; Vision; Visual; Visual Motion; behavioral response; cell type; detector; experimental study; gamma-Aminobutyric Acid; ganglion cell; insight; interdisciplinary approach; neural circuit; object motion; operation; optogenetics; preference; reconstruction; response; restoration; visual processing

In many parts of the nervous system, interneurons, which mediate local interactions within a circuit, are more diverse than projection neurons, which transmit information between subsequent circuits in a pathway. Due in part to this diversity, the functions of many interneurons are unknown and general operating principles of interneuron circuits remain to be identified. The diversity of interneurons may be greatest in the retina, where approximately 40 distinct types of amacrine cells (ACs) form specific patterns of connections with bipolar cells, which transmit photoreceptor signals from the outer to the inner retina, and retinal ganglion cells, which transmit retinal information to the brain. Most AC types release GABA or glycine, and many release excitatory neurotransmitters or neuromodulators as well (i.e. dual transmitter neurons), further enhancing the diversity of their signals. Here, we will analyze the contributions of specific AC types to motion processing in the retina and to characteristic behaviors elicited by different forms of visual motion. In doing so, we will test a set of general principles (i.e. functional modularity), which we hypothesize govern the operation of AC circuits. We recently identified VGluT3-expressing ACs (VG3-ACs) as local motion detectors in the retina, and showed that VG3-ACs provide excitatory input to object motion sensitive ganglion cells. The selectivity of this circuit relies on fast inhibitory inputs that cancel responses to global motion stimuli. Which AC type(s) provide this input is currently unknown. Preliminary results show that two genetically identified wide-field AC types form inhibitory connections with object motion sensitive ganglion cells. In Aim 1, we will test whether either or both AC types inhibit additional tiers of the excitatory axis of this circuit (i.e. bipolar cells, VG3-ACs). We will then use mice in which these ACs are transiently or stably silenced, or are removed from mature retinas, to probe the functional contribution of their input to motion processing in the object motion sensitive circuit. In addition, we will assess their influence on orienting responses of mice to local motion stimuli. Optogenetic experiments suggest that VG3-ACs provide excitatory input to additional ganglion cell types, with distinct motion preferences. Whether this input occurs during vision, and how VG3-ACs contribute to motion processing in these circuits and influence characteristic behaviors elicited by different forms of visual motion is unclear. In Aim 2, we will test the functional significance and anatomical basis of excitatory input from VG3-ACs to different motion sensitive ganglion cells and assess changes in behavioral responses to visual motion in mice in which VG3-ACs are transiently or stably silenced, or are removed from mature retinas. Intriguingly, preliminary results indicate that VG3-ACs provide selective inhibitory input to a ganglion cell that is suppressed by motion. We will analyze the patterns and function of these connections and test the contribution of this target-specific use of dual transmitters to suppressive responses of these ganglion cells.

在神经系统的许多部分，介导回路内局部相互作用的中间神经元， 与投射神经元不同，投射神经元在通路中的后续回路之间传递信息。年到期 作为这种多样性的一部分，许多中间神经元的功能是未知的， 中间神经元回路仍有待确定。中间神经元的多样性可能在视网膜中最大， 大约40种不同类型的无长突细胞（AC）与双极细胞形成特定的连接模式， 其将光感受器信号从外部视网膜传递到内部视网膜，以及视网膜神经节细胞，其将光感受器信号从外部视网膜传递到内部视网膜。 视网膜信息传递给大脑大多数AC类型释放GABA或甘氨酸，许多AC类型释放兴奋性 神经递质或神经调质（即双递质神经元），进一步增强了神经元的多样性。 他们的信号。在这里，我们将分析特定AC类型对视网膜运动处理的贡献， 由不同形式的视觉运动引起的特征行为。在此过程中，我们将测试一组通用的 原则（即功能模块化），我们假设管理交流电路的操作。我们最近 鉴定了表达VGluT 3的AC（VG 3-AC）作为视网膜中的局部运动检测器，并表明VG 3-AC 为对象运动敏感神经节细胞提供兴奋性输入。该电路的选择性依赖于快速 抑制性输入，消除对全局运动刺激的反应。目前提供此输入的AC类型是 未知初步结果表明，两个遗传鉴定的宽场AC类型形成抑制性连接 对物体运动敏感的神经节细胞。在目标1中，我们将测试其中一种或两种AC类型是否抑制额外的 该回路的兴奋轴的层级（即双极细胞，VG 3-AC）。然后我们将使用这些AC 暂时或稳定沉默，或从成熟视网膜中取出，以探测它们的功能贡献。 输入到对象运动敏感电路中的运动处理。此外，我们还将评估其对 小鼠对局部运动刺激的定向反应。光遗传学实验表明，VG 3-AC提供了 兴奋性输入额外的神经节细胞类型，具有不同的运动偏好。无论此输入是否发生 在视觉过程中，以及VG 3-AC如何有助于这些回路中的运动处理并影响特性 由不同形式的视觉运动引起的行为尚不清楚。在目标2中，我们将测试功能显著性 VG 3-AC对不同运动敏感神经节细胞兴奋性输入的解剖学基础， 在VG 3-AC短暂或稳定沉默的小鼠中对视觉运动的行为反应的变化， 或从成熟视网膜中取出。有趣的是，初步结果表明，VG 3-AC提供了选择性的免疫原性。 对神经节细胞的抑制性输入被运动抑制。我们将分析这些的模式和功能 连接，并测试双发射器的这种目标特异性使用对 这些神经节细胞