Regulation of the intrinsic melanopsin-based light response in ipRGCs

点击翻译按钮获取中文摘要

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.