Structure and Function of Mammalian Ganglion Cells

描述(申请人提供)：上一个项目期间的工作发现了一种新的哺乳动物视网膜的光感受器，这是一种罕见的视网膜神经节细胞(RGC)，具有轴突投射到下丘脑的昼夜节律起搏器。这些本质上对光敏感的RGC(IpRGC)即使在完全与视网膜突触网络隔离时也会对光做出反应。它们含有一种新的假定的感光色素，黑素，并表现出比传统的感光细胞更低的灵敏度和更慢的时间特性。它们显著的强光反应似乎忠实地编码了环境光线水平。因此，这些细胞构成了代表完整视网膜照度的特殊视网膜输出通道的基础。该系统支持各种非成像视觉反射，包括昼夜节律牵引、瞳孔光反射、生理的季节性适应，以及对血浆褪黑激素水平、睡眠和活动的急性光调制。 在本项目期间，我们将通过研究这些新型光感受器与其他视网膜神经元的相互作用和研究它们的光传导过程来扩大我们对这些新型光感受器的生理学的理解。我们将对杆/锥网络对ipRGC的兴奋和抑制影响的初步证据进行扩展，探索这些相互作用的基础和性质，以及它们对这些细胞在自然条件下的行为的影响。特别是，我们将追踪这些影响到特定的双极细胞和无长突细胞突触网络。我们将测试这些影响是否改变了ipRGC编码刺激强度的方式，或者它们是否赋予了它们的感受野空间或光谱拮抗。我们将确定转导级联中的主要信号成分，从光色素，到各种第二信使，再到光激活的离子通道。我们将直接测试黑色素是感光色素的假设。我们将确定转导级联是否类似于无脊椎动物光感受器中的转导级联，这是由光反应和假定的光变色的无脊椎动物性质所表明的。我们将在初步数据的基础上进一步说明光诱导电导中的环核苷酸门控通道，并将识别将光激活色素耦合到这些或其他光激活通道的上游信号分子。这些发现将促进我们对哺乳动物视网膜中一种新的光感觉系统的功能组织的理解，该系统在与环境照明和太阳周期相关的动态平衡功能中具有明确的角色。

DESCRIPTION (provided by applicant): Work of the last project period identified a novel photoreceptor of the mammalian retina, a rare type of retinal ganglion cell (RGC) with axonal projections to the circadian pacemaker of the hypothalamus. These intrinsically photosensitive RGCs (ipRGCs) respond to light even when completely isolated from retinal synaptic networks. They contain a novel presumptive photopigment, melanopsin, and exhibit much lower sensitivity and more sluggish temporal properties than conventional photoreceptors. Their remarkably tonic light responses appear to faithfully encode ambient light levels. These cells thus form the basis of a specialized retinal output channel representing integrated retinal irradiance. This system supports a variety of 'non-image-forming' visual reflexes, including circadian entrainment, pupillary light reflex, seasonal adaptations in physiology, and acute photic modulation of plasma melatonin levels, sleep and activity. In the present project period, we will extend our understanding of the physiology of these novel photoreceptors through studies of their interactions with other retinal neurons and an examination of their phototransduction process. We will expand upon preliminary evidence for both excitatory and inhibitory influences of rod/cone networks on ipRGCs, exploring the basis and nature of these interactions and their implications for the behavior of these cells under natural conditions. In particular, we will trace these influences to specific bipolar and amacrine cell synaptic networks. We will test whether these influences alter the way in which ipRGCs encode stimulus intensity, or whether they confer either spatial or spectral antagonism upon their receptive fields. We will identify the major signaling components in the transduction cascade, from the photopigment, through various second messengers, to the light-activated ion channels. We will test directly the presumption that melanopsin is the photopigment. We will determine whether the transduction cascade resembles those in invertebrate photoreceptors, as suggested by invertebrate-like properties of the light response and presumptive photopigment. We will expand upon preliminary data implicating cyclic-nucleotide gated channels in the light-evoked conductance and will identify upstream signaling molecules coupling the photoactivated pigment to these or other light-activated channels. The findings will advance our understanding of the functional organization of a novel photosensory system in the mammalian retina with well-defined roles in homeostatic functions related to ambient illumination and the solar cycle.