Physiology of intrinsically photosensitive retinal ganglion cells

描述(申请人提供)：视网膜调节各种潜意识的、对光的适应反应，包括瞳孔收缩、警觉性的急剧提高、调节大脑的激素分泌，以及使生物钟与明/暗周期同步。这些反应的不适当或不恰当的诱导，如发生在倒班工人或盲人身上，可能会导致“时差”症状、冬季抑郁、睡眠障碍、头痛，甚至乳腺癌和前列腺癌。视网膜对潜意识视觉系统的输入是由固有的光敏视网膜神经节细胞(IpRGCs)介导的，它产生基于黑素的内在光反应以及外在的杆/视锥驱动的光反应。这些神经元是最近发现的，关于它们如何对不同种类的光做出反应，以及它们如何与视网膜中的其他细胞相互作用，还有很多需要了解。该应用程序的长期目标是填补这两个知识空白，并利用这些知识帮助开发促进健康和生产力的照明技术、冬季抑郁症的光疗法、更好的眼疾诊断测试，以及改善视障人士状况的医学创新。这项赠款提案包括三个具体目标。在目标1中， 全细胞记录将从使用双光子显微镜鉴定的ipRGC进行，各种药理学工具将被用来剖析这些神经节细胞棒/锥驱动的光反应背后的分子和细胞机制。在目标2中，将使用全细胞记录、免疫组织化学和共聚焦成像来识别接受ipRGC输入的视网膜无长突细胞，表征它们的光诱发反应，并确定它们潜在的生理功能。目的3将使用多电极阵列记录、药理操作和行为分析来确定视网膜色素上皮(RPE)在ipRGCs基于黑素的光反应中的作用。众所周知，RPE对经典光感受器的光敏性是至关重要的，但它们对神经节细胞光感受器的重要性尚未得到充分的研究。

DESCRIPTION (provided by applicant): The retina mediates various subconscious, photoadaptive responses to light, including pupil constriction, acute enhancement of alertness, regulating hormone secretion from the brain, and synchronizing the body clock to the light/dark cycle. Inadequate or mistimed induction of these responses, such as occurs in shift workers or the blind, can lead to "jet lag" symptoms, winter depression, sleep disorders, headache, and even breast and prostate cancer. Retinal input to the subconscious visual system is mediated by the intrinsically photosensitive retinal ganglion cells (ipRGCs), which generate intrinsic, melanopsin-based light responses as well as extrinsic, rod/cone-driven photoresponses. These neurons were discovered recently and much remains to be learned about how they respond to different kinds of light, and how they interact with other cells in the retina. This application's long-term objective is to fill both of these knowledge gaps and use this knowledge to help develop lighting technologies that promote health and productivity, light therapies for winter depression, better diagnostic tests for eye disorders, and medical innovations that ameliorate conditions of the visually impaired. This grant proposal consists of three Specific Aims. In aim 1, whole-cell recordings will be made from ipRGCs identified using two-photon microscopy, and various pharmacological tools will be used to dissect the molecular and cellular mechanisms underlying these ganglion cells' rod/cone-driven responses to light. In aim 2, whole-cell recording, immunohistochemistry and confocal imaging will be used to identify retinal amacrine cells that receive input from ipRGCs, characterize their light-evoked responses, and determine their potential physiological functions. Aim 3 will use multielectrode-array recording, pharmacological manipulation and behavioral assays to determine the role of the retinal pigment epithelium (RPE) in the generation of ipRGCs' melanopsin-based light responses. The RPE is known to be crucial for the photosensitivity of the classical photoreceptors but their importance for ganglion-cell photoreceptors has not been fully investigated.