The Role of a Novel Population of Intrinsically Photosensitive Retinal Ganglion Cells in the Dorsal Retina

项目摘要 现代技术的变化导致了很大一部分人口的昼夜节律失调。这导致了 新陈代谢、睡眠和情绪障碍的发生率增加。这种功能障碍是由于生物钟的广泛范围造成的。 这调节了生理的许多方面。这些时钟的夹带是通过白天的光和暗来实现的- 由视网膜中一类独特的光感受器感知的夜间周期，称为固有的光敏视网膜 神经节细胞(IpRGC)。与视杆和视锥感光器不同，视杆感受器和视锥感受器是视觉感知的基础， IpRGC形成与大脑非视觉区域的直接连接，并对许多 身体功能的荷尔蒙和神经方面。IpRGC介导的光/暗夹带对健康很重要 维护和中断会导致内源性时钟失调。这一重大的健康负担表明 明确需要昼夜节律调整和维护的方法。 IpRGC负责对整个视网膜周围光线的变化进行编码，但要比 原本就在预料之中。虽然它们只占眼睛中RGC总数的2%-5%，但ipRGC是多样化的，包括 至少6个不同的亚群，投射到30多个不同的大脑区域。虽然这些类中的每一个都表示 黑素，他们被认为有不同的下游信号转导途径。因此，每个子种群都是 提取、编码和投影视觉信息的不同方面，以便影响单独的 光驱动的行为。大多数ipRGC亚群的具体功能尚不清楚。 为了解决这一缺陷，我们将研究以前未描述的ipRGC亚群，仅存在于 视网膜的背侧半球。这些腹侧编码的ipRGC在甘氨酸转运体的控制下表达Cre，并 黑素蛋白和GABA免疫阳性。它们的分布和神经递质类型是这样的特征 在RGC中绝无仅有。我们的目标是了解它们的功能敏感度、中央连接性和信号 转导通路。我将在视网膜的分离制剂中使用电生理学来完成这项工作，CRE依赖的病毒 以及新的光化学工具。我们假设这个位于背部的ipRGC亚群提取， 编码和投影信息的方式不同于更大的ipRGC群体。这将是第一个描述这一现象的研究 新的神经元群体，并将用于产生可应用于未来视网膜研究的技术 还有大脑。 人造光通过ipRGC的功能对生物钟的干扰起作用。然而， 这一新亚群的分布和抑制神经传递可能表明光在脑内的位置 视野对于调节是很重要的。这一信息的临床相关性可能导致基于位置的方法 昼夜节律紊乱患者的重新调整。

Project Summary Modern technological changes have lead to circadian misalignment in large portions of the population. This has resulted in increased rates of metabolic, sleep, and mood disorders. The dysfunction is due to the vast range of biological clocks that regulate many aspects of physiology. Entrainment of these clocks is achieved through the light and dark of the day- night cycle sensed by a unique class of photoreceptors in the retina referred to as the intrinsically photosensitive retinal ganglion cells (ipRGCs). Distinct from the rod and cone photoreceptors, which underlie the majority of visual perception, ipRGCs form direct connections to non-visual areas of the brain and exercise bio-synchronous control over many hormonal and neuronal aspects of body function. ipRGC-mediated light/dark entrainment is important for health maintenance and interruptions can lead to endogenous clock dysregulation. This significant health burden demonstrates a clear need for methods of circadian realignment and maintenance. IpRGCs are responsible for encoding changes in ambient light across the entire retina but are far more complex than originally anticipated. Though they only make up 2-5% of the RGC population in the eye, ipRGCs are diverse, consisting of at least 6 distinct subpopulations that project to more than 30 discrete brain regions. While each of these classes express melanopsin, they are thought to have distinct downstream signal transduction pathways. Therefore, each subpopulation is extracting, encoding, and projecting different aspects of visual information in order to influence a separate collection of light-driven behaviors. The specific functional roles of the majority of ipRGC subpopulations remain unclear. To address this shortcoming we will investigate a previously undescribed subpopulation of ipRGCs present only in the dorsal hemisphere of the retina. These ventral-coding ipRGCs express Cre under control of the glycine transporter and are immunopositive for melanopsin and GABA. Their distribution and neurotransmitter type are characteristics that are thus far unique among RGCs. Our goal is to understand their functional sensitivity, central connectivity, and signal transduction pathways. I will do this using electrophysiology in isolated preparations of retina, Cre-dependent viral tracing, and novel photochemical tools. We hypothesize that this dorsally located subpopulation of ipRGCs extract, encode, and project information differently from the greater ipRGC population. This will be the first study describing this novel neuronal population and will serve to generate techniques that can be applied to future investigations in the retina and brain. Artificial light contributes to interference of the biological clocks through the function of the ipRGCs. However, the distribution and inhibitory neurotransmission of this novel subpopulation may suggest that location of light within the visual field is important for regulation. The clinical relevance of this information may lead to location-based methods of realignment in patients suffering from circadian derangements.