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

项目摘要 现代技术变革导致大部分人口的昼夜节律失调。这导致 代谢、睡眠和情绪障碍的发病率增加。这种功能障碍是由于生物钟的巨大变化 调节生理学的许多方面。这些时钟的牵引是通过白天的光明和黑暗实现的- 由视网膜中的一类独特的光感受器感知的夜间周期称为固有光敏视网膜 神经节细胞（ipRGC）。与视杆细胞和视锥细胞不同，视杆细胞和视锥细胞是大部分视觉感知的基础， ipRGC与大脑的非视觉区域形成直接连接，并对许多视觉区域进行生物同步控制。 荷尔蒙和神经元方面的身体功能。ipRGC介导的光/暗夹带对健康很重要 维持和中断可导致内源性生物钟失调。这一巨大的健康负担表明， 明确需要昼夜节律调整和维持的方法。 IpRGC负责编码整个视网膜上的环境光变化，但远比 最初预计。虽然他们只占眼睛中RGC人口的2-5%，但ipRGC是多样化的，包括 至少有6个不同的亚群，投射到30多个离散的大脑区域。虽然每个类都表示 由于它们与黑视蛋白的相互作用，它们被认为具有不同的下游信号转导途径。因此，每个亚群 提取、编码和投影视觉信息的不同方面，以影响视觉信息的单独集合。 光驱动的行为。大多数ipRGC亚群的具体功能作用仍不清楚。 为了解决这一缺点，我们将研究先前未描述的仅存在于大肠杆菌中的ipRGC亚群。 视网膜的背侧半球。这些腹侧编码ipRGC在甘氨酸转运蛋白的控制下表达Cre，并且是 黑视素和GABA免疫阳性它们的分布和神经递质类型是因此 在RGC中是独一无二的。我们的目标是了解它们的功能敏感性、中枢连接性和信号 转导途径。我将使用电生理学在视网膜分离制剂，依赖肌酐的病毒， 追踪和新型光化学工具。我们假设这种位于背侧的ipRGC提取物亚群， 编码和投射信息与更大的ipRGC群体不同。这将是第一个描述这一点的研究 新的神经元群体，并将有助于产生技术，可应用于未来的调查，在视网膜 和大脑。 人造光通过ipRGC的功能有助于干扰生物钟。但 这种新的亚群的分布和抑制性神经传递可能表明，光在 视野对于调节是重要的。这些信息的临床相关性可能会导致基于位置的方法， 在患有昼夜节律紊乱的患者中进行重新排列。

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.