Circadian Organization of the Retina

项目摘要 视网膜既是一个感觉器官，也是一个自我维持的神经生物钟。作为主要的感觉器官 对于视觉，视网膜执行将物理光刺激转换和编码到神经系统的初始步骤。 信号，然后通过视神经将视觉和光信息传递到大脑的其他部分。的 内在的视网膜生物钟将整个视网膜感觉功能塑造成高敏锐度的“日”和高灵敏度 通过调节视网膜神经元和重组视网膜电路，通过节律性基因表达， 以及调节性神经递质如多巴胺和褪黑激素的节律性释放。虽然 视网膜生物钟对视网膜的生理和代谢产生广泛的影响， 视网膜生物钟的细胞和分子机制还没有很好地理解。的长期目标 本研究旨在阐明哺乳动物视网膜昼夜节律的基本机制 生物钟及其对视网膜感觉功能的控制。在即将到来的奖励期内，我们建议审查 特定的昼夜节律钟基因和细胞群在视网膜昼夜节律钟中的功能作用， 视网膜生物钟调节视网膜敏感性的机制。具体而言，我们建议研究 以下问题：具体目标I：视网膜昼夜节律钟的分子组织。使用小鼠 敲除核心生物钟基因Per 1、Per 2、Cry 1、Cry 2、Clock和NPAS 2的品系， 将测试这些基因中的每一个在小鼠视网膜生物钟中的功能作用。具体目标二。 视网膜生物钟的细胞组织。使用单细胞发光成像和细胞- 通过携带核心基因floxed等位基因的小鼠系特异性操纵分子生物钟功能 时钟基因Bmal 1和Cre重组酶的细胞特异性表达，我们将试图确定哪种细胞 视网膜中的细胞群是昼夜节律起搏器。具体目标三。视网膜的生物钟控制 功能使用分子遗传学方法，我们将测试哪些细胞和递质通路是关键的 用于：（1）使用ERG的视网膜灵敏度的昼夜节律控制，和（2）视网膜时钟的光夹带。 这些目标的完成将使我们深入了解视觉功能和 在包括人类在内的许多生物体中，敏感性根据一天中的时间进行调节。这些发现将是 理解正常视网膜功能的基础，视网膜作为生物钟系统的模型， 有助于我们了解临床相关的昼夜节律和多巴胺能视网膜机制 与光感受器退化和近视有关。

PROJECT SUMMARY The retina is both a sensory organ and a self-sustained neural circadian clock. As the primary sensory organ for vision, the retina performs the initial steps of transduction and encoding of physical light stimuli into neural signals, and then transmits visual and photic information to the rest of the brain via the optic nerve. The intrinsic retinal circadian clock shapes overall retinal sensory function into high acuity "day" and high sensitivity "night" states by modulating retinal neurons and reconfiguring retinal circuits through rhythmic gene expression and rhythmic of release of modulatory neurotransmitters such as dopamine and melatonin. Although the retinal circadian clock exerts extensive influence over retinal physiology and metabolism, the underlying cellular and molecular mechanisms of the retinal circadian clock are not well understood. The long-term goal of the research proposed here is to elucidate the fundamental mechanisms of the mammalian retinal circadian clock and its control of retinal sensory function. For the upcoming award period we propose to examine the functional role of specific circadian clock genes and cell populations in the retinal circadian clock, as well as the mechanisms by which the retinal clock modulates retinal sensitivity. Specifically, we propose to examine the following issues: Specific Aim I: Molecular Organization of the Retinal Circadian Clock. Using mouse lines in which the core circadian clock genes Per1, Per2, Cry1, Cry2, Clock and NPAS2 are knocked out we will test the functional role of each of these genes in the mouse retinal circadian clock. Specific Aim II. Cellular Organization of the Retinal Circadian Clock. Using single-cell luminescence imaging and cell- specific manipulation of molecular circadian clock function via mouse lines carrying floxed alleles of the core clock gene Bmal1 and cell-specific expression of Cre recombinase, we will seek to determine which cell populations in the retina are circadian pacemakers. Specific Aim III. Circadian Clock Control of Retinal Function. Using molecular genetic approaches, we will test which cells and transmitter pathways are critical for: (1) circadian control of retinal sensitivity using the ERG, and (2) light entrainment of the retinal clock. Completion of these aims will provide insight into the underlying mechanisms by which visual function and sensitivity is modulated according to time of day in many organisms, including humans. These findings will be fundamental for understanding normal retinal function, the retina as a model biological clock system, and contribute to our understanding of clinically relevant circadian and dopaminergic retinal mechanisms associated with photoreceptor degeneration and myopia.