Regulation of the intrinsic melanopsin-based light response in ipRGCs

摘要 光对人类的生理和行为有着深远的影响。在哺乳动物中， 神经节细胞（ipRGC）在光依赖性行为，包括昼夜光诱导， 瞳孔对光反射、睡眠、情绪、记忆和学习。最初被认为是一个同质种群， 现在已知ipRGC是小鼠中具有六种亚型（M1 - 6）的细胞的多样化集合。这些亚型 在许多方面不同，包括黑视素的表达水平，树突分层，突触 输入，发射模式，以及大脑中的中央投射目标。这些ipRGC通过整合 基于黑视素内源性光转导和由常规视杆和视锥驱动的外源性突触输入 外视网膜光感受器早期的研究表明，黑视素光转导只利用一个 Gq信号级联，导致Plc β 4和TrpC家族离子通道的激活。该模型 然而，由于在非M1 ipRGC中发现了替代信号传导途径， 信号成分仍然存在争议。这些调查结果揭示了一个巨大的差距， 了解黑视素光传导级联下游成分的身份。 此外，我们最近发现，黑视素信号可以调节多巴胺，一个众所周知的 视网膜中的神经调节剂，在细胞培养系统中。我们的总体目标是了解 基于黑视蛋白的信号传导途径的复杂性及其在不同ipRGC亚型中的调节有助于 to the large大array数组of behaviors行为.在具体目标1中，我们将确定生理和行为 M1 ipRGC中多巴胺依赖性黑视素磷酸化的结果，使用敲入小鼠 模型，其中黑视蛋白中的磷酸化位点发生突变。在具体目标2中，我们将确定不同的角色 通过光转导的亚型选择性操纵M1和M4 ipRGCs的光依赖性行为 途径。这些研究将提供一个关键的理解的生化和分子机制， 这种光通过调节昼夜节律、睡眠、情绪 记忆和学习

Abstract Light has a profound effect on human physiology and behavior. In mammals, intrinsically photosensitive retinal ganglion cells (ipRGCs) play a key role in light-dependent behaviors, including circadian photoentrainment, pupillary light reflex, sleep, mood, memory and learning. Originally thought to be a homogeneous population, ipRGCs are now known to be a diverse collection of cells with six subtypes (M1-6) in mouse. These subtypes differ in many ways, including expression levels of the photopigment melanopsin, dendritic stratification, synaptic inputs, firing patterns, and central projection targets in the brain. These ipRGCs respond to light by integrating intrinsic melanopsin-based phototransduction and extrinsic synaptic inputs driven by conventional rod and cone outer retinal photoreceptors. Early studies suggested that melanopsin phototransduction utilizes exclusively a Gq-signaling cascade that leads to the activation of Plc4 and TrpC-family ion channels. This model has been challenged, however, by discovery of alternative signaling pathways in non-M1 ipRGCs, but the precise identity of the signaling components remains controversial. These findings have thereby revealed a large gap in knowledge about the identity of the downstream components of melanopsin’s phototransduction cascade. Furthermore, we have recently shown that melanopsin signaling can be regulated by dopamine, a well-known neuromodulator in the retina, in a cell culture system. Our overall goal for this proposal is to understand how the complexity of the melanopsin-based signaling pathway and its regulation in distinct ipRGC subtypes contributes to the large array of behaviors. In Specific Aim 1, we will determine the physiological and behavioral consequences of dopamine-dependent melanopsin phosphorylation in M1 ipRGCs, using a knock-in mouse model, in which phosphorylation sites in melanopsin are mutated. In Specific Aim 2, we will identify distinct roles of M1 and M4 ipRGCs in light-dependent behaviors by subtype-selective manipulation of phototransduction pathways. These studies will provide a critical understanding of the biochemical and molecular mechanisms by which light influences human health and performance through the regulation of circadian rhythms, sleep, mood, memory and learning.