Rod/cone gap junctions initiate an irradiance pathway

杆/锥间隙连接启动辐照度路径

基本信息

批准号：
9765331
负责人：
STEPHEN C MASSEY
金额：
$ 53.56万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9765331
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 Retinal Ganglion Cells 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

项目摘要

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.

本质光敏视网膜神经节细胞（ipRGC）在传输非成像信息中发挥关键作用最近的证据表明 ipRGC 与意识视觉和意识视觉有关。尽管具有根本重要性，但诸如偏头痛和季节性情感障碍等严重疾病。 ipRGC 在视觉过程中的作用、控制 ipRGC 功能的潜在突触机制和电路 IpRGC 表达自己的感光色素 - 黑视蛋白，并且在高光强度下表达内在的。然而，令人惊讶的是，在较低的强度下，即使在明视范围内， ipRGC 主要由视杆而非视锥细胞驱动。这些数据表明持续信号。源自视杆细胞的光必须穿过视网膜，将有关辐照度的信息传递给 ipRGC。建议，我们将测试主要假设，即通过哺乳动物视网膜的辐照度路径是通过杆锥间隙连接驱动。我们的初步研究提供的证据表明，一种新颖的辐照路径包含以下要素：杆→杆/锥间隙连接→锥→ON锥双极细胞→异位突触→M1型ipRGC和多巴胺能无长突细胞 (DAC) 反过来，M1 ipRGC 驱动非图像形成视觉行为，例如瞳孔光反射和昼夜节律光诱导，而多巴胺释放可能控制网络适应为了测试这些假设，我们开发并验证了几个含有 Cx36 的小鼠品系。已在视杆细胞或视锥细胞中被有条件地删除，因此缺乏视杆细胞/视锥细胞间隙连接。在目标 1 中，我们将检验以下假设：驱动 PLR、昼夜节律需要杆/锥间隙连接光夹带和负掩蔽、非成像视觉功能也由 M1 ipRGC 驱动。在目标 2 中，我们将检验视杆/视锥间隙连接对于多巴胺的释放也至关重要的假设，此外，我们将测试多巴胺依赖性网络的假设。适应依赖于通过杆/锥间隙连接的辐照路径。在目标 3 中，我们将在两个关键点测试辐照度路径的功能：棒/锥间隙连接处和内丛状层中的异位双极突触。总之，我们建议棒/锥耦合产生通过 ipRGC 传输的辐照度信号，而不是不仅控制着瞳孔的光反射，它还夹带着每天的生物钟的生物影响。生物钟是普遍存在的，但它可能是通过前两种细胞类型之间的间隙连接来驱动的。此外，多巴胺和近视之间也存在联系。控制多巴胺的释放，这可能为治疗近视提供一种新方法。