Retinal melanopsin pathway: Signaling & Connectivity

描述（由申请人提供）：除了杆状/锥状通路外，现在已知视网膜中还存在与黑视素相关的光接受通路。该通路涉及表达黑视素的视网膜神经节细胞（mRGCs），这是RGCs的一小部分，它们本身具有光敏性，但也接受来自杆/锥通路的突触输入。与主要投射到大脑中成像视觉中心（膝状核背外侧和上丘）的非核磁共振相控造影不同，核磁共振相控造影主要投射到非成像视觉中心（辅助），如视交叉上核和膝间小叶（昼夜节律光干扰）以及橄榄叶前核（瞳孔光反射）。因此，在非mrgc和mrgc之间似乎存在功能隔离，mrgc不仅有助于非图像形成的光接收，而且还构成了所有非图像相关的光信息到大脑的主要通道。除了视杆/视锥系统和黑视素系统外，眼睛中似乎没有其他的光接收系统向大脑发出信号。本建议的长期目标是详细了解mrgc的光反应和信号传导。目的1是详细研究mrgc光响应的一般生理和生物物理特性。目的2是研究mrgc对光的适应。目的3是研究mrgc中受体电位向动作电位的转化，以及各种电压门控离子通道的作用。目的4是了解mrgc的光转导机制，并确定参与该过程的各种蛋白质。电生理学和小鼠遗传学将被用于研究。这些实验将产生重要的信息，不仅与这个新发现的黑视素系统的基本认识有关，而且还与影响眼睛光检测的疾病状态有关。公共卫生相关性：本应用程序中提出的研究将增强我们对视网膜中新发现的与黑视素相关的光接受系统的理解。从这些研究中获得的任何新信息也将与影响眼睛光探测的疾病状态高度相关。

DESCRIPTION (provided by applicant): Besides the rod/cone pathway, a melanopsin-associated photoreception pathway is now known to exist in the retina. This pathway involves melanopsin-expressing retinal ganglion cells (mRGCs), a small subset of RGCs that are intrinsically photosensitive but also receive synaptic inputs from the rod/cone pathway. Unlike the non-mRGCs, which project predominantly to image-forming visual centers in the brain (the dorsal lateral geniculate nucleus and the superior colliculus), the mRGCs project primarily to non-image-forming (accessory) visual centers such as the suprachiasmatic nucleus and the intergeniculate leaflet (for circadian photoentrainment) as well as the olivary pretectal nucleus (for pupillary light reflex). Thus, there appears to be a functional segregation between non-mRGCs and mRGCs, with the mRGCs not only contributing to non-image-forming photoreception but also constituting the major conduit for all non-image-associated photic information to the brain. Besides the rod/cone system and the melanopsin system, there appears to be no other photoreception system in the eye that signal to the brain. The long-term objective of this proposal is to understand the light responses and the signaling by mRGCs in great detail. Aim 1 is to investigate the general physiological and biophysical properties of the light responses of mRGCs in detail. Aim 2 is to investigate light adaptation by mRGCs. Aim 3 is to investigate the conversion of the receptor potential into action potentials in the mRGCs, and the roles played by the various voltage-gated ion channels. Aim 4 is to understand the phototransduction mechanism in mRGCs and to identify the various proteins involved in this process. Both electrophysiology and mouse genetics will be used for study. These experiments will yield important information not only relevant to the basic understanding of this newly discovered melanopsin system, but also to disease states affecting light detection in the eye. PUBLIC HEALTH RELEVANCE: The studies proposed in this application will enhance our understanding of the newly discovered melanopsin-associated photoreception system in the retina. Any new information derived from these studies will also be highly relevant to disease states affecting light detection by the eye.