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Intrinsically photosensitive retinal ganglion cells (ipRGGs) are the most recently discovered photoreceptor class in the human retina. This Element integrates new knowledge and perspectives from visual neuroscience, psychology, sleep science and architecture to discuss how melanopsin-mediated ipRGC functions can be measured and their circuits manipulated. It reveals contemporary and emerging lighting technologies as powerful tools to set mind, brain and behaviour.
Melanopsin is a visual pigment, expressed in intrinsically photosensitive retinal ganglion cells (ipRGCs) of the mammalian retina, that plays a major role in non-image forming visual behaviors like the pupillary light reflex, circadian photoentrainment, and sleep. It is hypothesized that melanopsin-mediated phototransduction is terminated by the phosphorylation of melanopsin’s C-terminus by a G-protein coupled receptor kinase, followed by -arrestin activation and binding. Little is known about the contribution of melanopsin phosphorylation to ipRGC physiology and its influence on non-image forming behaviors. We investigated the role of melanopsin C-terminus phosphorylation on non-image forming behaviors by generating a phosphorylation deficient melanopsin mutant that lacks all putative C-terminal phosphorylation sites (C-phosphonull).
The unique visual pigment melanopsin is expressed in a small subset of intrinsically photosensitive retinal ganglion cells (ipRGCs) within the mammalian retina. The axons of ipRGCs primarily project to brain nuclei that regulate non-image forming visual functions including circadian photoentrainment, pupillary light reflex, and sleep. Unlike rods and cones which hyperpolarize in response to light, ipRGCs depolarize likely through the activation of a Gq-mediated phototransduction cascade. IpRGCs exhibit very poor temporal resolution with sluggish on/off kinetics and a high threshold of activation. Despite this, ipRGCs respond robustly to prolonged illumination and are capable of firing sustained action potentials beyond the lifetime of the stimulus. These response characteristics raise questions about how melanopsin signaling is regulated within the retina. Typically, visual pigment signaling is deactivated by receptor phosphorylation and arrestin binding which act to attenuate and inhibit G-protein binding, respectively. In this work, I investigate the role of arrestin in melanopsin signaling and identify a region within the C-terminal tail of melanopsin that is required for proper activation and deactivation. Using a combination of in vitro and in vivo approaches, I provide evidence for a light- and phosphorylation-dependent deactivation of melanopsin by Beta-arrestin. This work is the first description of a visual pigment deactivation mechanism mediated by Beta-arrestin and is consistent with canonical deactivation mechanism described for other non-visual G-protein coupled receptors (GPCRs). Additionally, I demonstrate that removal or mutation of a region within the proximal portion of melanopsin's C-tail delays the activation and deactivation of the photoresponse. I also show that this region is conserved within the melanopsin family implying important functional significance. Based on these results, I hypothesize that a 9th helix in the C-tail of melanopsin serves two purposes; 1) to stabilize ICL3 and form a portion of the G-protein binding domain and 2) to tether the C-tail close to the membrane surface, facilitating receptor phosphorylation and arrestin binding.
Leading authors review the state-of-the-art in their field of investigation, and provide their views and perspectives for future researchChapters are extensively referenced to provide readers with a comprehensive list of resources on the topics coveredAll chapters include comprehensive background information and are written in a clear form that is also accessible to the non-specialist Leading authors review the state-of-the-art in their field of investigation, and provide their views and perspectives for future research Chapters are extensively referenced to provide readers with a comprehensive list of resources on the topics covered All chapters include comprehensive background information and are written in a clear form that is also accessible to the non-specialist
Melanopsin-expressing retinal ganglion cells (mRGC) are intrinsically photosensitive and combine their melanopsin-based photoresponses with rod and cone signals to convey light information to a subset of retinal brain targets. mRGC axons to non-image forming (NIF) visual centers are essential for the proper functioning of processes like circadian photoentrainment and pupillary light reflex. Surprisingly, mRGCs also send axons to image-forming regions of the brain. It is unknown how mRGCs mediate such diverse functions. Classically, a cell's morphology and location in a biological system is a direct reflection of its synaptic connections and, by definition, their function. mRGCs can be divided into five subtypes (M1-M5) based on morphology and dendritic stratification in the inner plexiform layer. In the classical sense, since M1s send axons to only a subset of mRGC-target regions and are the only subtype that monostratify in the OFF-sublamina, M1s likely serve a distinct function from other subtypes. However, M1s, like all mRGCs, exhibit an ON-response. This reveals a hole in what we understand about intraretinal connectivity and attenuates the weight that should be afforded to stratification in determining function. While the other mRGC subtypes have distinct morphology and branching patterns, it is unknown whether they serve specific functions. Thus, in order to explore the structure-function relationship of mRGC subtypes, we must consider connectivity. Unfortunately, the variable expression of melanopsin protein between subtypes and across the architecture of a single mRGC and the lack of unique markers for up- and downstream interactors has precluded rigorous study of mRGC connectivity in the retina and central targets. We use a correlated light and electron microscopy label and serial blockface scanning electron microscopy to explore the architecture and synaptic partners of mRGCs in an attempt to better understand the connectivity of mRGC subtypes. We show significant differences in the ultrastructure of mRGC axonal terminals in mRGC-recipient brain regions, stratification-specific differences in mRGC dendrites, and catalog the intraretinal connections specific to mRGC subtypes.
John Dowling’s The Retina, published in 1987, quickly became the most widely recognized introduction to the structure and function of retinal cells. In this Revised Edition, Dowling draws on twenty-five years of new research to produce an interdisciplinary synthesis focused on how retinal function contributes to our understanding of brain mechanisms. The retina is a part of the brain pushed out into the eye during development. It retains many characteristics of other brain regions and hence has yielded significant insights on brain mechanisms. Visual processing begins there as a result of neuronal interactions in two synaptic layers that initiate an analysis of space, color, and movement. In humans, visual signals from 126 million photoreceptors funnel down to one million ganglion cells that convey at least a dozen representations of a visual scene to higher brain regions. The Revised Edition calls attention to general principles applicable to all vertebrate retinas, while showing how the visual needs of different animals are reflected in their retinal variations. It includes completely new chapters on color vision and retinal degenerations and genetics, as well as sections on retinal development and visual pigment biochemistry, and presents the latest knowledge and theories on how the retina is organized anatomically, physiologically, and pharmacologically. The clarity of writing and illustration that made The Retina a book of choice for a quarter century among graduate students, postdoctoral fellows, vision researchers, and teachers of upper-level courses on vision is retained in Dowling’s new easy-to-read Revised Edition.
This advanced text, first published in 2006, takes a developmental approach to the presentation of our understanding of how vertebrates construct a retina. Written by experts in the field, each of the seventeen chapters covers a specific step in the process, focusing on the underlying molecular, cellular, and physiological mechanisms. There is also a special section on emerging technologies, including genomics, zebrafish genetics, and stem cell biology that are starting to yield important insights into retinal development. Primarily aimed at professionals, both biologists and clinicians working with the retina, this book provides a concise view of vertebrate retinal development. Since the retina is 'an approachable part of the brain', this book will also be attractive to all neuroscientists interested in development, as processes required to build this exquisitely organized system are ultimately relevant to all other parts of the central nervous system.
Pituitary Adenylate Cyclase-Activating Polypeptide is the first volume to be written on the neuropeptide PACAP. It covers all domains of PACAP from molecular and cellular aspects to physiological activities and promises for new therapeutic strategies. Pituitary Adenylate Cyclase-Activating Polypeptide is the twentieth volume published in the Endocrine Updates book series under the Series Editorship of Shlomo Melmed, MD.