Functional organization of the retinal dopaminergic network

描述(申请人提供)：多巴胺能神经元广泛分布于整个中枢神经系统，在感觉功能、运动控制、认知和动机中发挥重要作用。中枢神经系统中最容易接触到的多巴胺能神经元位于脊椎动物的视网膜。这些神经元是一种特殊的无长突细胞亚群，在 调节视网膜回路，使视网膜时钟同步，并影响眼睛的生长。多巴胺能无长突神经元受包括光在内的多种因素的调节；然而，涉及的机制大多不清楚。这项拟议研究的长期目标是了解多巴胺能无长突神经元受光调节的机制。我们已经开发了新的策略和试剂来实现这一目标。我们已发表的研究表明，多巴胺能无长突神经元至少包括两种功能亚型，瞬时反应和持续反应，它们似乎与环境光的不同方面有关。在本申请中，我们将通过解决四个具体目标来扩展我们之前的研究。目的1验证以下假设：多巴胺能无长突神经元通过不同的神经通路被视杆细胞去极化并持续增加活动。在目标2中，我们将检验锥体驱动的多巴胺能无长突神经元包括两个不同的形态和功能亚型(瞬时开和开-关)的假设。目的3将确定由表达黑素的固有光敏性视网膜神经节细胞驱动的多巴胺能无长突神经元的形态，以及固有光敏视网膜神经节细胞向多巴胺能无长突神经元传递谷氨酸的机制。在目标4中，我们将确定视杆细胞、视锥细胞和黑素蛋白信号在广泛的光强度范围内对多巴胺能无长突神经元的相对贡献。这些目标的成功完成将提供有关多巴胺能无长突神经元亚型、每种亚型的光反应特性、将光敏感细胞信号传递到多巴胺能无长突神经元的神经通路，以及多巴胺能无长突神经元如何在整个视觉范围内通过三种光敏细胞类别编码光刺激的框架。这些信息将促进我们对光对视网膜多巴胺释放的调节的理解，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的意义。这些研究还有可能对与糖尿病视网膜病变和帕金森病等多巴胺能异常相关的眼和脑疾病的发病机制产生新的洞察，并提出新的预防和治疗策略。

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.