Biology of Photosensitive Ganglion Cells

描述（由申请人提供）：我们已经鉴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），其直接支配下丘脑的昼夜节律起搏器。这些固有光敏RGC（ipRGC）即使在与其他视网膜神经元突触隔离时也对光作出响应。它们含有新的视蛋白色素黑视蛋白。与视杆细胞和视锥细胞相比，它们表现出较低的敏感性和更缓慢的动力学。它们对外界光线的强烈反应会对周围的光线进行编码。除了它们在昼夜节律同步中的关键作用之外，这些细胞形成一个专门的视网膜输出通道，该通道发出综合视网膜辐照度的信号并驱动各种“非成像”视觉反射，例如瞳孔光反射、生理学中的季节性适应、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。我们提出了第一个直接调查是否ipRGC，像杆和锥，表现出光和暗适应，根据当前或最近的曝光调整其敏感性。这种适应极大地扩展了视杆细胞和视锥细胞的动态范围，使得它们一起包含生理光水平的全光谱。在一些“非图像形成”的视觉反应中，适应显得很弱或不存在。虽然这可能表明ipRGC缺乏适应，但一些行为证据和我们的初步电生理数据表明，ipRGC在某些条件下确实适应。表征这些细胞中的适应性是推进我们对昼夜光感受和其他非成像光系统的理解的关键一步。我们将在操纵先前的光暴露后进行ipRGC对光的响应的细胞内记录。我们将评估任何适应的幅度、时间过程和光谱依赖性。我们还将确定这些是否发生在感光细胞本身，改变光转导级联的增益，或者它们是否需要与其他视网膜细胞的相互作用。这些研究还将确定ipRGC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一种新型感光系统的功能组织的理解，该系统在昼夜节律计时和与环境照明和太阳周期相关的其他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.