Functional organization of the retinal dopaminergic network

视网膜多巴胺能网络的功能组织

• 批准号: 8990483
• 负责人: Dao-Qi Zhang
• 金额: $ 36.93万
• 依托单位: OAKLAND UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8990483
• 关键词: Address; Amacrine Cells; Brain Diseases; Cells; Characteristics; Circadian Rhythms; Cognition; Cone; Defect; Diabetic Retinopathy; Disease; Dissection; Dopamine; Eye; Eye Development; Eye diseases; Feedback; Fluorescence Microscopy; Gene Expression; Genes; Genetic; Glutamate Receptor; Glutamates; Goals; Growth; Health; In Situ; Label; Light; Lighting; Mediating; Modeling; Morphology; Motivation; Neural Pathways; Neurodegenerative Disorders; Neurons; Neurotransmitters; Parkinson Disease; Pathogenesis; Pathway interactions; Periodicity; Photoreceptors; Physiological; Play; Preventive; Processed Genes; Publishing; Reagent; Regulation; Retina; Retinal; Retinal Ganglion Cells; Retinitis Pigmentosa; Role; Sensory; Signal Transduction; Stimulus; Synapses; Testing; Therapeutic; Vertebrate Photoreceptors; Vision; Visual; Work; dopaminergic neuron; information processing; insight; light intensity; melanopsin; motor control; mouse model; neural circuit; novel; novel strategies; patch clamp; response; retinal neuron; retinal rods; transmission process; two-photon; visual information

DESCRIPTION (provided by applicant): Dopaminergic neurons are widely distributed throughout the CNS and play vital roles in sensory functions, motor control, cognition, and motivation. The most accessible dopaminergic neurons of the CNS are located in the vertebrate retina. These neurons are a specialized subpopulation of amacrine cells that play critical roles in modulating retinal circuits, synchronizing the retinal clock, and influencing eye growth. Dopaminergic amacrine neurons are regulated by several factors including light; however, mechanisms involved are mostly unknown. The long-term goal of the proposed study is to understand the mechanisms by which dopaminergic amacrine neurons are regulated by light. We have developed novel strategies and reagents to achieve this goal. Our published studies have revealed that dopaminergic amacrine neurons comprise at least two functional subtypes, transient and sustained responders, which appear to be tuned to distinct aspects of environmental light. In this application, we will extend our previous studies by addressing four specific aims. Aim 1 will test the hypothesis that dopaminergic amacrine neurons are depolarized with persistent increased activity by rods through distinct neural pathways. In Aim 2, we will test the hypothesis that cone-driven dopaminergic amacrine neurons comprise two distinct morphological and functional subtypes (transient ON and ON-OFF). Aim 3 will determine the morphology of sustained dopaminergic amacrine neurons driven by the melanopsin-expressing intrinsically photosensitive retinal ganglion cells and the mechanisms of glutamatergic transmission from the intrinsically photosensitive retinal ganglion cells to dopaminergic amacrine neurons. In Aim 4, we will define the relative contributions of rod, cone, and melanopsin signaling to dopaminergic amacrine neurons across a wide range of light intensities. Successful completion of these aims will provide novel information regarding dopaminergic amacrine neuron subtypes, each subtype's light response characteristics, the neural pathways conveying photosensitive cell signals to dopaminergic amacrine neurons, and a framework for how dopaminergic amacrine neurons encode light stimuli through the three photosensitive cell classes over the entire visual range. This information will advance our understanding of the regulation of retinal dopamine release by light and have important implications for the roles of dopamine in visual information processing, gene expression, and eye development. These studies will also have the potential to yield new insight into the cellular and synaptic mechanisms responsible for pathogenesis of eye and brain disorders associated with dopaminergic abnormalities such as diabetic retinopathy and Parkinson's disease, and to suggest novel preventive and therapeutic strategies for these disorders.

描述（由申请人提供）：多巴胺能神经元广泛分布在整个中枢神经系统中，并在感官功能，运动控制，认知和动机中起着至关重要的作用。中枢神经系统中最容易接近的多巴胺能神经元位于脊椎动物视网膜中。这些神经元是对无长熟细胞的专门亚群，在 调节视网膜电路，同步视网膜时钟并影响眼睛的生长。多巴胺能聚作神经元受光的几个因素调节。但是，涉及的机制大多未知。拟议的研究的长期目标是了解多巴胺能无链氨酸神经元受光调节的机制。我们已经开发了新颖的策略和试剂来实现这一目标。我们已发表的研究表明，多巴胺能合济氨酸神经元至少包括两个功能性亚型，瞬态和持续的响应者，它们似乎已调整为环境光的不同方面。在此应用程序中，我们将通过解决四个具体目标来扩展以前的研究。 AIM 1将检验以下假设：多巴胺能合济氨酸神经元通过不同的神经途径通过杆的持续增强活性去极化。在AIM 2中，我们将检验以下假设：锥体驱动的多巴胺能神经元包括两个不同的形态和功能亚型（瞬时和on-Off）。 AIM 3将确定由表达黑色素蛋白的固有光敏感的视网膜神经节细胞驱动的持续多巴胺能合组织神经元的形态，以及从内在光敏感的视网膜神经节细胞到多巴胺友能症神经元的谷氨酸能传播的机制。在AIM 4中，我们将定义杆，锥和黑色素蛋白信号传导对多巴胺能神经元的相对贡献。这些目标的成功完成将提供有关多巴胺能无链氨酸神经元亚型的新信息，每个亚型的光反应特征，神经途径传达光敏感性的细胞信号到多巴胺蛋白能神经元，以及多巴胺疗法神经元如何通过三个光敏感的细胞范围进行探测的多巴胺疗法神经元如何构造了多巴胺疗法神经元。这些信息将提高我们对视网膜多巴胺通过光释放的调节的理解，并对多巴胺在视觉信息处理，基因表达和眼睛发育中的作用具有重要意义。这些研究还将有可能对导致与多巴胺能异常相关的眼睛和脑部疾病的发病机制（例如糖尿病性视网膜病和帕金森氏病）相关的细胞和突触机制进行新的见解，并建议针对这些疾病的新型预防和治疗策略。