David M. Berson

Central projections of melanopsin-expressing retinal ganglion cells in the mouse.

A rare type of ganglion cell in mammalian retina is directly photosensitive. These novel retinal photoreceptors express the photopigment melanopsin. They send axons directly to the suprachiasmatic nucleus (SCN), intergeniculate leaflet (IGL), and olivary pretectal nucleus (OPN), thereby contributing to photic synchronization of circadian rhythms and the pupillary light reflex. Here, we sought to characterize more fully the projections of these cells to the brain. By targeting tau‐lacZ to the melanopsin gene locus in mice, ganglion cells that would normally express melanopsin were induced to express, instead, the marker enzyme β‐galactosidase. Their axons were visualized by X‐gal histochemistry or anti‐β‐galactosidase immunofluorescence. Established targets were confirmed, including the SCN, IGL, OPN, ventral division of the lateral geniculate nucleus (LGv), and preoptic area, but the overall projections were more widespread than previously recognized. Targets included the lateral nucleus, peri‐supraoptic nucleus, and subparaventricular zone of the hypothalamus, medial amygdala, margin of the lateral habenula, posterior limitans nucleus, superior colliculus, and periaqueductal gray. There were also weak projections to the margins of the dorsal lateral geniculate nucleus. Co‐staining with the cholera toxin B subunit to label all retinal afferents showed that melanopsin ganglion cells provide most of the retinal input to the SCN, IGL, and lateral habenula and much of that to the OPN, but that other ganglion cells do contribute at least some retinal input to these targets. Staining patterns after monocular enucleation revealed that the projections of these cells are overwhelmingly crossed except for the projection to the SCN, which is bilaterally symmetrical. J. Comp. Neurol. 497:326–349, 2006.

Melanopsin cells are the principal conduits for rod-cone input to non-image-forming vision

Rod and cone photoreceptors detect light and relay this information through a multisynaptic pathway to the brain by means of retinal ganglion cells (RGCs). These retinal outputs support not only pattern vision but also non-image-forming (NIF) functions, which include circadian photoentrainment and pupillary light reflex (PLR). In mammals, NIF functions are mediated by rods, cones and the melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs). Rod–cone photoreceptors and ipRGCs are complementary in signalling light intensity for NIF functions. The ipRGCs, in addition to being directly photosensitive, also receive synaptic input from rod–cone networks. To determine how the ipRGCs relay rod–cone light information for both image-forming and non-image-forming functions, we genetically ablated ipRGCs in mice. Here we show that animals lacking ipRGCs retain pattern vision but have deficits in both PLR and circadian photoentrainment that are more extensive than those observed in melanopsin knockouts. The defects in PLR and photoentrainment resemble those observed in animals that lack phototransduction in all three photoreceptor classes. These results indicate that light signals for irradiance detection are dissociated from pattern vision at the retinal ganglion cell level, and animals that cannot detect light for NIF functions are still capable of image formation.

Induction of photosensitivity by heterologous expression of melanopsin.

Melanopsin has been proposed to be the photopigment of the intrinsically photosensitive retinal ganglion cells (ipRGCs); these photoreceptors of the mammalian eye drive circadian and pupillary adjustments through direct projections to the brain. Their action spectrum (λ max ≈ 480 nm) implicates an opsin and melanopsin is the only opsin known to exist in these cells. Melanopsin is required for ipRGC photosensitivity and for behavioural photoresponses that survive disrupted rod and cone function. Heterologously expressed melanopsin apparently binds retinaldehyde and mediates photic activation of G proteins. However, its amino-acid sequence differs from vertebrate photosensory opsins and some have suggested that melanopsin may be a photoisomerase, providing retinoid chromophore to an unidentified opsin. To determine whether melanopsin is a functional sensory photopigment, here we transiently expressed it in HEK293 cells that stably expressed TRPC3 channels. Light triggered a membrane depolarization in these cells and increased intracellular calcium. The light response resembled that of ipRGCs, with almost identical spectral sensitivity (λ max ≈ 479 nm). The phototransduction pathway included Gq or a related G protein, phospholipase C and TRPC3 channels. We conclude that mammalian melanopsin is a functional sensory photopigment, that it is the photopigment of ganglion-cell photoreceptors, and that these photoreceptors may use an invertebrate-like phototransduction cascade.

Strange vision: ganglion cells as circadian photoreceptors

A novel photoreceptor of the mammalian retina has recently been discovered and characterized. The novel cells differ radically from the classical rod and cone photoreceptors. They use a unique photopigment, most probably melanopsin. They have lower sensitivity and spatiotemporal resolution than rods or cones and they seem specialized to encode ambient light intensity. Most surprisingly, they are ganglion cells and, thus, communicate directly with the brain. These intrinsically photosensitive retinal ganglion cells (ipRGCs) help to synchronize circadian rhythms with the solar day. They also contribute to the pupillary light reflex and other behavioral and physiological responses to environmental illumination.

Melanopsin-Expressing Retinal Ganglion-Cell Photoreceptors: Cellular Diversity and Role in Pattern Vision

Using the photopigment melanopsin, intrinsically photosensitive retinal ganglion cells (ipRGCs) respond directly to light to drive circadian clock resetting and pupillary constriction. We now report that ipRGCs are more abundant and diverse than previously appreciated, project more widely within the brain, and can support spatial visual perception. A Cre-based melanopsin reporter mouse line revealed at least five subtypes of ipRGCs with distinct morphological and physiological characteristics. Collectively, these cells project beyond the known brain targets of ipRGCs to heavily innervate the superior colliculus and dorsal lateral geniculate nucleus, retinotopically organized nuclei mediating object localization and discrimination. Mice lacking classical rod-cone photoreception, and thus entirely dependent on melanopsin for light detection, were able to discriminate grating stimuli from equiluminant gray and had measurable visual acuity. Thus, nonclassical retinal photoreception occurs within diverse cell types and influences circuits and functions encompassing luminance as well as spatial information.

Measuring and using light in the melanopsin age

Light is a potent stimulus for regulating circadian, hormonal, and behavioral systems. In addition, light therapy is effective for certain affective disorders, sleep problems, and circadian rhythm disruption. These biological and behavioral effects of light are influenced by a distinct photoreceptor in the eye, melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs), in addition to conventional rods and cones. We summarize the neurophysiology of this newly described sensory pathway and consider implications for the measurement, production, and application of light. A new light-measurement strategy taking account of the complex photoreceptive inputs to these non-visual responses is proposed for use by researchers, and simple suggestions for artificial/architectural lighting are provided for regulatory authorities, lighting manufacturers, designers, and engineers.

Histochemical identification and afferent connections of subdivisions in the lateralis posterior-pulvinar complex and related thalamic nuclei in the cat.

Abstract Fiber pathways of the extrageniculate visual system have been shown in the cat to define an orderly sequence of adjoining, roughly parallel zones within the posterolateral thalamus. The present study provides evidence that these and related thalamic subdivisions can be identified histochemically by their differing contents of acetylthiocholinesterase. The brains of fifty cats were prepared for acetylthiocholinesterase histochemistry by the methods of Geneser-Jensen & Blackstad and Karnovsky & Roots. Serial sections were cut in each of the three Horsley-Clarke planes and a standard transverse cholinesterase series, containing occasional reference sections stained for myelin or Nissl substance, was used to assemble graphic reconstructions of the main cholinesterase subdivisions. Patterns of afferent connections were visualized by anterograde axon transport or fiber-degeneration techniques and recorded in thirteen sets of detailed chartings. In nine sets, serially adjoining sections processed by the cholinesterase and anterograde methods were directly compared and plotted together. The caudal part of the lateral thalamic region was divided into two main subdivisions: the lateralis posterior-pulvinar complex, which receives extrageniculate visual input, and the complex comprising the nuclei lateralis medialis and suprageniculatus (LM-Sg), which receives fiber projections from auditory association cortex and the deep layers of the superior colliculus. The latter complex occupies a ventromedial zone alongside the lateralis posterior-pulvinar complex. It is distinguished in the cholinesterase stain by prominent 0.5–1.5 mm wide patches of high enzyme activity that appear against a pale background. Within the lateralis posterior-pulvinar complex, three zones could be distinguished: (1) the medial part of the nucleus lateralis posterior (LPm) is rich in cholinesterase activity and receives input from the superficial collicular layers; (2) the lateral part of the nucleus lateralis posterior and the nucleus posterior of Rioch (LP1-NP) have much weaker cholinesterase activity and receive input from the striate cortex and other areas of visual cortex; (3) the pulvinar, the most lateral of the subdivisions, is a zone of high cholinesterase activity in which some pale patches appear. It receives input from the pretectum and is associated with a differentiated lateral marginal zone receiving direct projections from the retina and area 17. The intermediate nucleus of the lateral group was divided into two parts. The pars caudalis (LIc) has a mottled appearance in the cholinesterase stain; it receives an ascending input from the pretectotectal border zone and a descending projection from parietal cortex including area 7. The pars oralis of the intermediate nucleus (LIo) is rich in cholinesterase activity; it receives a descending projection from the anterior parietal cortex comprising in part area 5. These two intermediate subdivisions were flanked dorsally and rostrally by the nucleus lateralis dorsalis. The cholinesterase material suggested a division of the lateralis dorsalis into at least medial and lateral parts, but the connections of these regions were not analyzed in detail. The finding of clear chemoarchitectural subdivisions in the lateralis posterior-pulvinar complex and adjoining regions has practical significance as a guide to thalamic organization and raises the possibility that some extrageniculate and related transthalamic pathways may be differentiated from one another by the neurotransmitters they employ in the thalamus.

The influence of study habits on myopia in Jewish teenagers.

The prevalence and degree of myopia were measured in 870 teenagers, males and females. We found a statistically significant higher prevalence and degree of myopia in a group of 193 Orthodox Jewish male students who differed from the rest in their study habits. Orthodox schooling is characterized by sustained near vision and frequent changes in accommodation due to the swaying habit during study and the variety of print size. A possible myopic effect of this unique visual demand is postulated.

Synaptic influences on rat ganglion‐cell photoreceptors

The intrinsically photosensitive retinal ganglion cells (ipRGCs) provide a conduit through which rods and cones can access brain circuits mediating circadian entrainment, pupillary constriction and other non‐image‐forming visual functions. We characterized synaptic inputs to ipRGCs in rats using whole‐cell and multielectrode array recording techniques. In constant darkness all ipRGCs received spontaneous excitatory and inhibitory synaptic inputs. Light stimulation evoked in all ipRGCs both synaptically driven (‘extrinsic’) and autonomous melanopsin‐based (‘intrinsic’) responses. The extrinsic light responses were depolarizing, about 5 log units more sensitive than the intrinsic light response, and transient near threshold but sustained to brighter light. Pharmacological data showed that ON bipolar cells and amacrine cells make the most prominent direct contributions to these extrinsic light responses, whereas OFF bipolar cells make a very weak contribution. The spatial extent of the synaptically driven light responses was comparable to that of the intrinsic photoresponse, suggesting that synaptic contacts are made onto the entire dendritic field of the ipRGCs. These synaptic influences increase the sensitivity of ipRGCs to light, and also extend their temporal bandpass to higher frequencies. These extrinsic ipRGC light responses can explain some of the previously reported properties of circadian photoentrainment and other non‐image‐forming visual behaviours.

Intraretinal signaling by ganglion cell photoreceptors to dopaminergic amacrine neurons

Retinal dopaminergic amacrine neurons (DA neurons) play a central role in reconfiguring retinal function according to prevailing illumination conditions, yet the mechanisms by which light regulates their activity are poorly understood. We investigated the means by which sustained light responses are evoked in DA neurons. Sustained light responses were driven by cationic currents and persisted in vitro and in vivo in the presence of L-AP4, a blocker of retinal ON-bipolar cells. Several characteristics of these L-AP4-resistant light responses suggested that they were driven by melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs), including long latencies, marked poststimulus persistence, and a peak spectral sensitivity of 478 nm. Furthermore, sustained DA neuron light responses, but not transient DA neuron responses, persisted in rod/cone degenerate retinas, in which ipRGCs account for virtually all remaining retinal phototransduction. Thus, ganglion-cell photoreceptors provide excitatory drive to DA neurons, most likely by way of the coramification of their dendrites and the processes of DA neurons in the inner plexiform layer. This unprecedented centrifugal outflow of ganglion-cell signals within the retina provides a novel basis for the restructuring of retinal circuits by light.