Biology of Photosensitive Ganglion Cells

描述（由申请人提供）：我们已经确定了哺乳动物视网膜的一种新的光感受器，一种罕见的视网膜神经节细胞（RGC），它直接支配下丘脑的昼夜节律起搏器。这些具有内在光敏性的RGCs （ipRGCs）即使在与其他视网膜神经元突触分离的情况下也对光有反应。它们含有一种新的视蛋白——光色素——黑视素。它们比杆状细胞和锥状细胞表现出更低的灵敏度和更迟钝的动力学。它们显著的强光反应编码了环境光水平。除了在昼夜同步中发挥关键作用外，这些细胞还形成了一个专门的视网膜输出通道，该通道发出综合视网膜辐射的信号，并驱动各种“非图像形成”的视觉反射，如瞳孔光反射、生理上的季节性适应、夜间褪黑激素释放的光抑制以及睡眠、警觉性和活动的调节。我们建议第一次直接研究iprgc是否像杆状细胞和锥状细胞一样，表现出光和暗适应，根据当前或最近的光暴露调整它们的灵敏度。这种适应极大地扩展了视杆细胞和视锥细胞的动态范围，使它们共同包含了生理光水平的全部光谱。在一些“非图像形成”的视觉反应中，适应性显得很弱或不存在。虽然这可能表明iprgc缺乏适应性，但一些行为证据和我们的初步电生理数据表明，iprgc在某些条件下确实具有适应性。表征这些细胞的适应性是推进我们对昼夜节律光接受和其他非成像光系统理解的关键一步。我们将在操纵先前的光照射后对ipRGC对光的反应进行细胞内记录。我们将评估任何适应的幅度、时间进程和光谱依赖性。我们还将确定这些是否发生在光感受器本身，改变光传导级联的增益，或者它们是否需要与其他视网膜细胞相互作用。这些研究还将确定ipRGCs的敏感性是否受昼夜节律控制。这些发现将促进我们对哺乳动物视网膜中新型光感觉系统的功能组织的理解，该系统在昼夜节律定时和其他与环境光照和太阳周期相关的稳态功能中具有明确的作用。

DESCRIPTION (provided by applicant): We have identified a novel photoreceptor of the mammalian retina, a rare retinal ganglion cell (RGC) that directly innervates the circadian pacemaker of the hypothalamus. These intrinsically photosensitive RGCs (ipRGCs) respond to light even when synaptically isolated from other retinal neurons. They contain the novel opsin photopigment melanopsin. They exhibit lower sensitivity and more sluggish kinetics than rods and cones. Their remarkably tonic light responses encode ambient light levels. Besides their key role in circadian synchronization, these cells form a specialized retinal output channel that signals integrated retinal irradiance and drives a variety of 'non-image-forming' visual reflexes such as the pupillary light reflex, seasonal adaptations in physiology, photic inhibition of nocturnal melatonin release, and modulation of sleep, alertness and activity. We propose the first direct investigation of whether ipRGCs, like rods and cones, exhibit light and dark adaptation, adjusting their sensitivity according to current or recent light exposure. Such adaptation greatly extends the dynamic range of rods and cones so that together they encompass the full spectrum of physiological light levels. Adaptation appears weak or absent in some 'non-image-forming' visual responses. While this might suggest a lack of adaptation in ipRGCs, some behavioral evidence and our preliminary electrophysiological data suggest that ipRGCs do adapt under some conditions. Characterizing adaptation in these cells is a critical step in advancing our understanding of circadian photoreception and other non- image-forming photic systems. We will make intracellular recordings of ipRGC responses to light after manipulating prior light exposure. We will assess the magnitude, time course and spectral dependency of any adaptation. We will also determine whether these occur within the photoreceptor itself, altering the gain of the phototransduction cascade, or whether they require interactions with other retinal cells. The studies will also determine whether ipRGCs sensitivity is under circadian control. The findings will advance our understanding of the functional organization of a novel photosensory system in the mammalian retina with well-defined roles in circadian timing and other homeostatic functions related to ambient illumination and the solar cycle.