Rod/cone gap junctions initiate an irradiance pathway

杆/锥间隙连接启动辐照度路径

• 批准号: 10441265
• 负责人: STEPHEN C MASSEY
• 金额: $ 51.96万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10441265
• 关键词: Address; Amacrine Cells; Behavior; Behavioral; Biological; Brain; Cell Nucleus; Cell physiology; Cells; Cone; Conscious; Coupling; Data; Development; Dopamine; Electroretinography; Elements; Eye Development; Gap Junctions; Goals; Image; Inner Plexiform Layer; Intervention; Intrinsic drive; Knockout Mice; Knowledge; Lead; Life; Light; Lighting; Link; Masks; Measures; Mediating; Migraine; Mus; Myopia; Output; Pain; Pathway interactions; Photosensitivity; Play; Pupil light reflex; Retina; Retinal Ganglion Cells; Rod; Seasonal Affective Disorder; Signal Pathway; Signal Transduction; Stratification; Synapses; Testing; Travel; Vertebrate Photoreceptors; Vision; Visual; Visual system structure; cell type; circadian; circadian pacemaker; daily functioning; light intensity; melanopsin; novel; novel strategies; preservation; response; retinal rods; ribbon synapse; sensory system; suprachiasmatic nucleus; visual information; visual process; Address; Amacrine Cells; Behavior; Behavioral; Biological; Brain; Cell Nucleus; Cell physiology; Cells; Cone; Conscious; Coupling; Data; Development; Dopamine; Electroretinography; Elements; Eye Development; Gap Junctions; Goals; Image; Inner Plexiform Layer; Intervention; Intrinsic drive; Knockout Mice; Knowledge; Lead; Life; Light; Lighting; Link; Masks; Measures; Mediating; Migraine; Mus; Myopia; Output; Pain; Pathway interactions; Photosensitivity; Play; Pupil light reflex; Retina; Retinal Ganglion Cells; Rod; Seasonal Affective Disorder; Signal Pathway; Signal Transduction; Stratification; Synapses; Testing; Travel; Vertebrate Photoreceptors; Vision; Visual; Visual system structure; cell type; circadian; circadian pacemaker; daily functioning; light intensity; melanopsin; novel; novel strategies; preservation; response; retinal rods; ribbon synapse; sensory system; suprachiasmatic nucleus; visual information; visual process

Intrinsically photosensitive retinal ganglion cells (ipRGCs) play a key role in transmitting non-image-forming visual information to the brain. Recent evidence has implicated ipRGCs in conscious vision as well as in serious conditions such as migraine pain and seasonal affective disorder. Despite the fundamental importance of ipRGCs in the visual process, the underlying synaptic mechanisms and circuits that control ipRGC function are unknown. IpRGCs express their own photopigment - melanopsin and, at high light intensities, intrinsic responses drive ipRGC function. However, surprisingly, at lower intensities, even in the photopic range, ipRGCs are predominantly driven by rods and not cones. These data suggest that a sustained signal originating from rods must travel through the retina to carry information about irradiance to ipRGCs. In this proposal, we will test the primary hypothesis that the irradiance pathway through the mammalian retina is driven via rod-to-cone gap junctions. Our preliminary studies provide evidence that a novel irradiance pathway contains the following elements: rod→rod/cone gap junction→cone→ON cone bipolar cell→ectopic synapse→M1-type ipRGCs and dopaminergic amacrine cells (DACs). In turn, M1 ipRGCs drive non-image-forming visual behavior such as the pupillary light reflex and circadian photoentrainment, while dopamine release may control network adaptation in the retina. To test these hypotheses, we have developed and validated several mouse lines in which Cx36 has been conditionally deleted in either rods or cones, and therefore lack rod/cone gap junctions. In Aim 1, we will test the hypothesis that rod/cone gap junctions are required to drive the PLR, circadian photoentrainment and negative masking, non-imaging-forming visual functions also driven by M1 ipRGCs. In Aim 2, we will test the hypothesis that rod/cone gap junctions are also essential for the release of dopamine, in the mammalian retina. Furthermore, we will test the hypothesis that dopamine-dependent network adaptation relies on the irradiance pathway via rod/cone gap junctions. In Aim 3, we will test the function of the irradiance pathway at two key points: rod/cone gap junctions and ectopic bipolar synapses in the inner plexiform layer. In summary, we propose that rod/cone coupling generates an irradiance signal transmitted via ipRGCs that not only controls the pupillary light reflex, it also entrains the circadian clock every day. The biological influence of the circadian clock is pervasive yet it may be driven via gap junctions between the first two cell types in the visual system. Furthermore, there is a link between dopamine and myopia. If, in turn, the irradiance pathway controls dopamine release, this may inform a new approach to myopia.

本质上具有光敏性视网膜神经节细胞（IPRGC）在传输非图像形成中起关键作用 向大脑的视觉信息。最近的证据已在有意识的视觉和中实施了IPRGC 严重的疾病，例如偏头痛疼痛和季节性情感障碍。尽管有基本的进口 IPRGC在视觉过程中，控制IPRGC功能的基本突触机制和电路 是未知的。 IPRGCs表达自己的照片，黑色素蛋白，在高光强度下，内在 响应驱动IPRGC功能。但是，令人惊讶的是，在较低的实例，即使在光波范围内， IPRGC主要由杆而不是锥体驱动。这些数据表明持续信号 起源于杆必须穿过视网膜，以将有关辐照度的信息携带到IPRGC。在这个 提案，我们将测试主要假设，即通过哺乳动物视网膜的辐照度途径是 通过杆到杆的间隙连接驱动。 我们的初步研究提供了证据，表明新型辐照度途径包含以下要素： 杆→杆/锥形间隙连接→锥→在锥双极单元上→异位突触→M1型IPRGC和 多巴胺能无链氨氨酸细胞（DACS）。反过来，M1 IPRGC驱动非图像形成的视觉行为，例如 瞳孔灯反射和昼夜节律光介质，而多巴胺释放可能会控制网络适应 在视网膜中。为了检验这些假设，我们已经开发并验证了几种CX36的鼠标线条 有条件地在杆或锥体中被删除，因此缺乏杆/锥间隙连接。 在AIM 1中，我们将测试以下假设：驾驶PLR需要杆/锥间隙连接 M1 IPRGC驱动的光登录和负面掩盖，非成像的视觉功能也是如此。 在AIM 2中，我们将检验以下假设：杆/锥间隙连接对于释放多巴胺也至关重要。 在哺乳动物视网膜中。此外，我们将测试多巴胺依赖性网络的假设 适应性依赖于通过杆/锥间隙连接的辐照道通路。 在AIM 3中，我们将在两个关键点测试辐照道途径的功能：杆/锥形连接和 内丛状层中的异位双极突触。 总而言之，我们建议杆/锥耦合产生通过IPRGC传输的辐照信号 仅控制瞳孔灯光的反射，它也每天都会进入昼夜节律。生物学影响 昼夜节律无处 视觉系统。此外，多巴胺与近视之间存在联系。如果反过来是辐照道路 控制多巴胺的释放，这可能会导致一种新的近视方法。