Paul D. Gamlin

Melanopsin-expressing ganglion cells in primate retina signal colour and irradiance and project to the LGN

Human vision starts with the activation of rod photoreceptors in dim light and short (S)-, medium (M)-, and long (L)- wavelength-sensitive cone photoreceptors in daylight. Recently a parallel, non-rod, non-cone photoreceptive pathway, arising from a population of retinal ganglion cells, was discovered in nocturnal rodents. These ganglion cells express the putative photopigment melanopsin and by signalling gross changes in light intensity serve the subconscious, ‘non-image-forming’ functions of circadian photoentrainment and pupil constriction. Here we show an anatomically distinct population of ‘giant’, melanopsin-expressing ganglion cells in the primate retina that, in addition to being intrinsically photosensitive, are strongly activated by rods and cones, and display a rare, S-Off, (L + M)-On type of colour-opponent receptive field. The intrinsic, rod and (L + M) cone-derived light responses combine in these giant cells to signal irradiance over the full dynamic range of human vision. In accordance with cone-based colour opponency, the giant cells project to the lateral geniculate nucleus, the thalamic relay to primary visual cortex. Thus, in the diurnal trichromatic primate, ‘non-image-forming’ and conventional ‘image-forming’ retinal pathways are merged, and the melanopsin-based signal might contribute to conscious visual perception.

Human and macaque pupil responses driven by melanopsin-containing retinal ganglion cells

Melanopsin, a novel photopigment, has recently been localized to a population of retinal ganglion cells that display inherent photosensitivity. During continuous light and following light offset, primates are known to exhibit sustained pupilloconstriction responses that resemble closely the photoresponses of intrinsically-photoreceptive ganglion cells. We report that, in the behaving macaque, following pharmacological blockade of conventional photoreceptor signals, significant pupillary responses persist during continuous light and following light offset. These pupil responses display the unique spectral tuning, slow kinetics, and irradiance coding of the sustained, melanopsin-derived ganglion cell photoresponses. We extended our observations to humans by using the sustained pupil response following light offset to document the contribution of these novel ganglion cells to human pupillary responses. Our results indicate that the intrinsic photoresponses of intrinsically-photoreceptive retinal ganglion cells play an important role in the pupillary light reflex and are primarily responsible for the sustained pupilloconstriction that occurs following light offset.

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.

Fireworks in the Primate Retina: In Vitro Photodynamics Reveals Diverse LGN-Projecting Ganglion Cell Types

Diverse cell types and parallel pathways are characteristic of the vertebrate nervous system, yet it remains a challenge to define the basic components of most neural structures. We describe a process termed retrograde photodynamics that allowed us to rapidly make the link between morphology, physiology, and connectivity for ganglion cells in the macaque retina that project to the lateral geniculate nucleus (LGN). Rhodamine dextran injected into the LGN was transported retrogradely and sequestered within the cytoplasm of ganglion cell bodies. Exposure of the retina to light in vitro liberated the tracer and allowed it to diffuse throughout the dendrites, revealing the cells complete morphology. Eight previously unknown LGN-projecting cell types were identified. Cells could also be targeted in vitro for intracellular recording and physiological analysis. The photodynamic process was also observed in pyramidal cells in a rat neocortical slice.

An area for vergence eye movement in primate frontal cortex

To view objects at different distances, humans rely on vergence eye movements to appropriately converge or diverge the eyes and on ocular accommodation to focus the object. Despite the importance of these coordinated eye movements (the ‘near response’) very little is known about the role of the cerebral cortex in their control. As near-response neurons exist within the nucleus reticularis tegmenti pontis, which receives input from the frontal eye field region of frontal cortex, and this cortical region is known to be involved in saccadic and smooth-pursuit eye movements, we propose that a nearby region might play a role in vergence and ocular accommodation. Here we provide evidence from rhesus monkeys that a region of frontal cortex located immediately anterior to the saccade-related frontal eye field region is involved in vergence and ocular accommodation, and in the sensorimotor transformations required for these eye movements. We conclude that the macaque frontal cortex is involved in the control of all voluntary eye movements, and suggest that the definition of the frontal eye fields should be expanded to include this region.

The Influence of Intrinsically Photosensitive Retinal Ganglion Cells on the Spectral Sensitivity and Response Dynamics of the Human Pupillary Light Reflex

Historically, it was assumed that the light-evoked neural signals driving the human pupillary light reflex (PLR) originated exclusively from rod and cone photoreceptors. However, a novel melanopsin-containing photoreceptive cell class has recently been discovered in the mammalian retina. These intrinsically-photosensitive retinal ganglion cells (ipRGCs) project to the pretectum, the retinorecipient area of the brain responsible for the PLR. This study was therefore designed to examine the relative contribution of rod, cone and the melanopsin photoresponses of ipRGCs to the human PLR. We establish that the melanopsin photoresponse of ipRGCs contributes significantly to the maintenance of half maximal pupilloconstriction in response to light stimuli of 30s or longer, even at low photopic irradiances. Furthermore, we show that the melanopsin photoresponse contributes significantly to three-quarter maximal pupilloconstriction in response to light stimuli as short as 2s. We also demonstrate that cone photoresponses driving pupilloconstriction adapt considerably and contribute little after 30s, but rod photoresponses adapt less and contribute significantly to the maintenance of pupilloconstriction in response to steady-state light stimuli at irradiance levels which are below the threshold of the melanopsin photoresponse.

Neuronal circuitry controlling the near response.

Experiments in primates have contributed greatly to our understanding of the neural mechanisms involved in the eye movements required to view objects at different distances. Early work focused on the circuitry for generating horizontal vergence eye movements alone. However, vergence eye movements are associated with lens accommodation and are usually accompanied by saccadic eye movements, so more recent work has been directed at understanding the interactions between vergence and accommodation, and between vergence and saccades. A new model explains the neural basis for interactions between vergence and accommodation by a neural network in which pre-motor elements are shared by these two systems. The effects of saccades on vergence eye movements appear to be the result of shared pre-motor circuits as well. Current evidence suggests that pontine omnipause neurons, known to be crucial for the generation of saccades, play an important role in the vergence pre-motor circuitry.

The Post-Illumination Pupil Response Is Reduced in Glaucoma Patients

PURPOSEnThe post-illumination pupil response (PIPR), which is driven by the intrinsic response of melanopsin-containing, intrinsically photosensitive retinal ganglion cells, has previously been characterized in healthy eyes. The present study examined whether the PIPR is affected in patients with glaucoma compared with healthy subjects.nnnMETHODSnSixteen glaucoma patients (mean age, 63.7 years) were tested by presenting a 60°, 10-second light stimulus (13 log quanta/cm(2)/s retinal irradiance) of either 470 nm (blue) or 623 nm (red) to one eye after dilation. The consensual pupil response of the fellow undilated eye was recorded by infrared pupillometry for 50 seconds after light offset. These pupillary responses were compared with those of 19 age-matched controls (mean age, 59 years).nnnRESULTSnThe glaucoma patients displayed a net PIPR (blue PIPR minus red PIPR) that was significantly (t-test, P < 0.001) smaller (0.6 mm, SEM 0.12; P < 0.05) than in age-matched controls (1.3 mm, SEM 0.16; P < 0.001). For the patient population, the magnitude of the net PIPR was inversely correlated with the measured visual field loss (mean deviation) of the tested eye.nnnCONCLUSIONSnThis study demonstrates that there is a significant decrease in the ipRGC-mediated PIPR in glaucomatous patients when compared to age-matched controls. As the severity of the glaucomatous neuropathy increases, there is a correlated decrease in the PIPR. Therefore, this test has the potential for use as a clinical tool in evaluating patients with glaucoma.

THE EDINGER-WESTPHAL NUCLEUS: A HISTORICAL, STRUCTURAL AND FUNCTIONAL PERSPECTIVE ON A DICHOTOMOUS TERMINOLOGY

The eponymous term nucleus of Edinger‐Westphal (EW) has come to be used to describe two juxtaposed and somewhat intermingled cell groups of the midbrain that differ dramatically in their connectivity and neurochemistry. On one hand, the classically defined EW is the part of the oculomotor complex that is the source of the parasympathetic preganglionic motoneuron input to the ciliary ganglion (CG), through which it controls pupil constriction and lens accommodation. On the other hand, EW is applied to a population of centrally projecting neurons involved in sympathetic, consumptive, and stress‐related functions. This terminology problem arose because the name EW has historically been applied to the most prominent cell collection above or between the somatic oculomotor nuclei (III), an assumption based on the known location of the preganglionic motoneurons in monkeys. However, in many mammals, the nucleus designated as EW is not made up of cholinergic, preganglionic motoneurons supplying the CG and instead contains neurons using peptides, such as urocortin 1, with diverse central projections. As a result, the literature has become increasingly confusing. To resolve this problem, we suggest that the term EW be supplemented with terminology based on connectivity. Specifically, we recommend that 1) the cholinergic, preganglionic neurons supplying the CG be termed the Edinger‐Westphal preganglionic (EWpg) population and 2) the centrally projecting, peptidergic neurons be termed the Edinger‐Westphal centrally projecting (EWcp) population. The history of this nomenclature problem and the rationale for our solutions are discussed in this review. J. Comp. Neurol. 519:1413–1434, 2011.

Post-illumination Pupil Response in Subjects without Ocular Disease

PURPOSEnA sustained pupilloconstriction is often observed after the cessation of a bright visual stimulus. This post-illumination pupil response (PIPR) is produced by the intrinsically photosensitive retinal ganglion cells (ipRGCs). The present study was designed to examine the characteristics of the PIPR in a normal population without ocular disease.nnnMETHODSnThirty-seven subjects (mean age, 48.6 years) were tested by presenting a 60 degrees, 10-second light stimulus (13 log quanta/cm(2)/s retinal irradiance) and recording pupillary responses for 50 seconds after light cessation. The light stimuli (470 [blue] and 623 [red] nm) were presented by an optical system to one eye after dilation, while the consensual pupil response of the fellow, undilated eye was recorded by infrared pupillometry.nnnRESULTSnA positive PIPR was seen in all subjects tested. The population average of the PIPR for 470-nm light was 1.5 mm (SEM 0.10, P < 0.05) and the net PIPR (blue PIPR minus red PIPR) was 1.4 mm (SEM 0.09, P < 0.0001). The net PIPR correlated positively with baseline pupil diameter (P < 0.05), but not significantly with age, race, or sex (P > 0.05) in the test population.nnnCONCLUSIONSnAll normal subjects displayed a significant PIPR for a 10-second, 470-nm light stimulus, but not a 623-nm stimulus, which is consistent with the proposed melanopsin-mediated response. In most normal individuals, the amplitude of the PIPR was substantial. This test has the potential to be used as a tool in evaluating subjects with inner retinal dysfunction or melanopsin-related disorders.