ROD AND CONE SIGNALING PATHWAYS IN MAMMALIAN RETINA

哺乳动物视网膜中的视杆细胞和视锥细胞信号通路

• 批准号: 7767215
• 负责人: Samuel M Wu
• 金额: $ 38.38万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7767215
• 关键词: Amacrine Cells; Biological Models; Brain; Cations; Cells; Chloride Ion; Chlorides; Color; Coupling; Defect; Dyes; Eye; Eye diseases; Functional disorder; Glaucoma; Glutamates; Human; Image; Leber' s disease; Light; Macular degeneration; Mediating; Mus; Mutant Strains Mice; Night Blindness; Output; Pathogenesis; Pathway interactions; Process; Relative (related person); Research; Research Project Grants; Research Proposals; Retina; Retinal; Retinal Cone; Salamander; Signal Pathway; Signal Transduction; Site; Skiing; Snow; Synapses; Techniques; Testing; The Sun; Tigers; Vertebrate Photoreceptors; Vision Disorders; Visual Perception; computerized data processing; ganglion cell; light intensity; neural circuit; operation; public health relevance; response; retinal neuron; retinal rods; voltage clamp

DESCRIPTION (provided by applicant): The overall objective of this new research project is to understand detailed synaptic mechanisms underlying rod and cone signaling pathways in the mammalian retina. Anatomical studies have suggested that rod and cone channels in the mammalian retina follow a specific set of circuitry rules: rods make synapses only on rod depolarizing bipolar cells (DBCRS), and DBCRS do not make output synapses directly on ganglion cells (GCs), but indirectly through AII amacrine cells (AIIACs). AIIACs send rod-mediated signals to ON and OFF GCs by "piggybacking" on the cone depolarizing and hyperpolarizing bipolar cells (DBCCS and HBCCS), which synapse on ON and OFF GCs, respectively. In this research proposal, we plan to systematically investigate these mammalian-specific synaptic circuits by using the mouse retina as a model system. In addition to using whole-cell voltage clamp (with dye-filling), anatomical and pharmacological techniques, we will take advantage of four strains of pathway-specific mutant mice to elucidate how mammalian rod and cone signals are transmitted to BCs, ACs and GCs, and to determine whether the mammalian-specific circuitry rules are totally valid, as recent evidence and our preliminary results suggest that the strict rod/cone input rules may not hold for all mammalian retinal neurons. We will test the overall hypothesis that "subpopulations of mouse DBCRS receive direct synaptic inputs from cones and subpopulations of mouse DBCCS and HBCCS receive direct synaptic inputs from rods, the rod- and cone-mediated signals are further mixed by AIIACs before sending to GCs, and the AC-mediated inhibitory synaptic inputs to BCs and GCs carry mixed rod/cone signals". This application has 3 specific aims focused on studying rod and cone contributions to light-evoked cation and chloride currents (?Ic and ?Ic1, representing glutamatergic and GABAergic/glycinergic synaptic inputs, respectively) in: (1) seven types of bipolar cells (HBCMC/RS, HBCMCS, HBCSCS, DBCC2/MCS, DBCC1/MC/RS, DBCR2S, DBCR1S); (2) AII amacrine cells; and (3) three types of alpha ganglion cells (ON, sOFF and tOFF 1GCs) in the dark-adapted mouse retina. Results obtained will increase our understanding of how parallel channels, such as the rod/cone signaling pathways, process, segregate and integrate information in the eye and in the brain. Since many visual disorders are associated with abnormalities in the rod and cone signaling pathways, this research project will help to identify cellular and synaptic sites responsible for the pathogenesis of these eye diseases. PUBLIC HEALTH RELEVANCE: The eye is the "window" of the brain and human eyes can register an enormous range of light intensities (from objects under starlit sky to snow under bright sun light) by dividing the labor into two parts: rod photoreceptors encode dim images and cone photoreceptors encode bright and color images. Understanding how rod and cone signals are processed by retinal synaptic pathways is a fundamental and essential step for unraveling mechanisms of visual perception and brain operation. Certain forms of macular degeneration, retinitis pigmentosa, congenital stationary night blindness and glaucoma are associated with dysfunction of the rod and cone signaling pathways, and thus results obtained from this project will provide crucial information on how specific defects in the rod and cone synaptic pathways mediate these eye disorders.

描述（由申请人提供）：这项新研究项目的总体目标是了解哺乳动物视网膜中视杆细胞和视锥细胞信号通路的详细突触机制。解剖学研究表明，哺乳动物视网膜中的视杆和视锥通道遵循一组特定的电路规则：视杆只在视杆去极化双极细胞（DBCRS）上形成突触，而DBCRS不直接在神经节细胞（GC）上形成输出突触，而是间接通过AII无长突细胞（AIIAC）。AIIAC通过在视锥去极化和超极化双极细胞（DBCCS和HBCCS）上“捎带”将视杆介导的信号发送到ON和OFF GC，所述视锥去极化和超极化双极细胞分别与ON和OFF GC突触。 在这项研究中，我们计划使用小鼠视网膜作为模型系统，系统地研究这些特定的突触回路。除了使用全细胞电压钳（用染料填充）、解剖学和药理学技术，我们将利用四种途径特异性突变小鼠来阐明哺乳动物视杆和视锥信号是如何传递到BC、AC和GC的，并确定哺乳动物特异性电路规则是否完全有效，最近的证据和我们的初步结果表明，严格的杆/锥输入规则可能不适用于所有哺乳动物视网膜神经元。我们将测试总体假设，即“小鼠DBCRS的亚群从视锥接收直接突触输入，小鼠DBCCS和HBCCS的亚群从视杆接收直接突触输入，视杆和视锥介导的信号在发送到GC之前由AIIAC进一步混合，AC介导的抑制性突触输入到BC和GC携带混合的视杆/视锥信号”。 该应用程序有3个具体的目标，重点是研究杆和锥光诱发的阳离子和氯离子电流的贡献（？IC和？Ic 1，分别代表多巴胺能和GABA能/甘氨酸能突触输入）在：（1）七种类型的双极细胞（HBCMC/RS，HBCMCS，HBCSCS，DBCC 2/MCS，DBCC 1/MC/RS，DBCR 2S，DBCR 1 S）;（2）AII无长突细胞;和（3）三种类型的α神经节细胞（ON，sOFF和tOFF 1GC）在暗适应小鼠视网膜。所获得的结果将增加我们对平行通道（如视杆/视锥信号通路）如何在眼睛和大脑中处理、分离和整合信息的理解。由于许多视觉障碍与视杆细胞和视锥细胞信号通路的异常有关，该研究项目将有助于确定负责这些眼病发病机制的细胞和突触部位。 公共卫生相关性：眼睛是大脑的“窗口”，人眼可以通过将工作分为两部分来记录巨大范围的光强度（从星光灿烂的天空下的物体到明亮的阳光下的雪）：杆状光感受器编码暗淡的图像，而锥状光感受器编码明亮的彩色图像。了解视网膜突触通路如何处理视杆细胞和视锥细胞信号是解开视觉感知和大脑运作机制的基础和重要步骤。某些形式的黄斑变性、色素性视网膜炎、先天性静止性夜盲症和青光眼与视杆细胞和视锥细胞信号通路的功能障碍有关，因此从该项目获得的结果将提供关于视杆细胞和视锥细胞突触通路中的特定缺陷如何介导这些眼部疾病的关键信息。