Trends in Neurosciences
Volume 34, Issue 11, November 2011, Pages 572-580
Journal home page for Trends in Neurosciences

Review
Intrinsically photosensitive retinal ganglion cells: many subtypes, diverse functions

https://doi.org/10.1016/j.tins.2011.07.001Get rights and content

For decades, rods and cones were thought to be the only photoreceptors in the mammalian retina. However, a population of atypical photoreceptive retinal ganglion cells (RGCs) expresses the photopigment melanopsin and is intrinsically photosensitive (ipRGCs). These ipRGCs are crucial for relaying light information from the retina to the brain to control circadian photoentrainment, pupillary light reflex, and sleep. ipRGCs were initially described as a uniform population involved solely in signaling irradiance for non-image forming functions. Recent work, however, has uncovered that ipRGCs are unexpectedly diverse at the molecular, cellular and functional levels, and could even be involved in image formation. This review summarizes our current understanding of the diversity of ipRGCs and their various roles in modulating behavior.

Introduction

Light is an important regulator of physiology and behavior in animals, influencing a variety of non-image forming functions such as melatonin synthesis, daily activity rhythms, and sleep [1]. In mammals, eyes are absolutely required for photoreception 2, 3 and in humans light has additional effects on mood, concentration, and mental health [4]. For decades, rods and cones were thought to be the only photoreceptors in the retina. However, recently discovered retinal ganglion cells (RGCs) that express the photopigment melanopsin are themselves atypical photoreceptors 5, 6. These intrinsically photosensitive RGCs (commonly known as ipRGCs) project to several brain nuclei that regulate non-image forming functions, such as the suprachiasmatic nucleus (SCN) to photoentrain circadian rhythms and the olivary pretectal nucleus (OPN) to control the pupillary light reflex (PLR) 6, 7, 8, 9.

Initially, ipRGCs were thought to be a relatively uniform population of RGCs that can detect light levels (irradiance detectors) 5, 6. Accumulating evidence indicates, however, that ipRGCs consist of several subtypes that are morphologically and physiologically distinct. These ipRGC subtypes contribute differently to non-image and image-forming behaviors. The purpose of this review is to discuss recent advances in our understanding of the morphological and molecular diversity of ipRGCs and their functional roles in light-evoked behaviors.

Section snippets

Discovery and function of ipRGCs

The retina is a highly organized structure, where the cell bodies of distinct neuronal types reside in well-defined nuclear layers and make synaptic connections in two distinct plexiform layers (Figure 1). The classical photoreceptors, rods and cones, transform light energy into an electrical signal and convey information for both image- and non-image-forming visual functions through RGCs, the only neurons in the retina that send axonal projections to the brain. The classical view that rods and

Diversity of ipRGCs

The initial hint that ipRGCs are not a uniform population came from morphological studies using a highly sensitive melanopsin antibody. Immunolabeling revealed melanopsin-positive RGC dendrites in not only the outer sublamina but also in the inner sublamina of the IPL [15]. Arguably the most influential approach in advancing the study of ipRGC structure and function has been the use of genetic mouse models to label or ablate ipRGCs selectively. Detailed anatomical studies utilizing genetic

Phototransduction and chromophore regeneration in ipRGCs

In the absence of the melanopsin protein, ipRGCs lose the intrinsic light response [40]. Ectopic expression of melanopsin in heterologous cell systems further demonstrates its sufficiency to act as a functional photopigment 41, 42, 43, 44, 45. Sequence analysis shows that the melanopsin photopigment closely resembles invertebrate rhodopsins, whose phototransduction pathway leads to the depolarization of photoreceptors through a Gq-mediated signaling cascade and opening of a transient receptor

Axonal projections of ipRGC subtypes

Using the Opn4tau–lacZ line, M1 ipRGCs were shown to project to the SCN and the shell of the OPN for mediation of circadian photoentrainment and the PLR, respectively 6, 8, 9. In addition, M1 ipRGCs project to other brain regions involved in circadian behaviors such as the intergeniculate leaflet (IGL) and the ventral lateral geniculate nucleus (vLGN) 8, 9, and to other structures such as the supraoptic nucleus, ventral subparaventricular zone, medial amygdala, and lateral habenula 8, 9. Non-M1

Behavioral outputs of ipRGCs

The melanopsin field has expanded dramatically in the last few years, providing a deeper understanding of the molecular, cellular, and connectivity features of ipRGCs. Furthermore, behavioral studies have highlighted the diverse and important role of ipRGCs in various light-driven behaviors (Figure 3). Mechanistic insights from this atypical photoreceptive system might also apply more broadly toward understanding the complexity of circuits and modulation of behavior in the central nervous

Future directions

Although M1 ipRGCs have been well studied for irradiance detection, the function of non-M1 cells in light-dependent behaviors and their importance in image forming vision are poorly understood. One pressing question is whether the intrinsic light response of ipRGCs contributes to image formation when functional rods and cones are present. Melanopsin intrinsic light responses convey environmental light levels to the visual cortex even in animals with intact rod/cone function [85]. Determining

Acknowledgments

We sincerely thank Dr. Marnie Halpern at the Carnegie Institution for Science, Drs Rejji Kuruvilla, Haiqing Zhao, Young-Sam Lee, Stewart Hendry, and David Zappulla at the Johns Hopkins University for valuable feedback and Dr. Vladimir Kefalov at Washington University for suggestions on the chromophore visual cycle. We also thank our funding agencies, especially the National Institute of General Medical Sciences, the National Eye Institute and the David and Lucile Packard Foundation.

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