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.     

Spatial structure of cone inputs to receptive fields in primate lateral geniculate nucleus.

Human colour vision depends on three classes of cone photoreceptors, those sensitive to short (S), medium (M) or long (L) wavelengths, and on how signals from these cones are combined by neurons in the retina and brain. Macaque monkey colour vision is similar to human, and the receptive fields of macaque visual neurons have been used as an animal model of human colour processing. P retinal ganglion cells and parvocellular neurons are colour-selective neurons in macaque retina and lateral geniculate nucleus. Interactions between cone signals feeding into these neurons are still unclear. On the basis of experimental results with chromatic adaptation, excitatory and inhibitory inputs from L and M cones onto P cells (and parvocellular neurons) were thought to be quite specific (Fig. 1a). But these experiments with spatially diffuse adaptation did not rule out the 'mixed-surround' hypothesis: that there might be one cone-specific mechanism, the receptive field centre, and a surround mechanism connected to all cone types indiscriminately (Fig. 1e). Recent work has tended to support the mixed-surround hypothesis. We report here the development of new stimuli to measure spatial maps of the linear L-, M- and S-cone inputs to test the hypothesis definitively. Our measurements contradict the mixed-surround hypothesis and imply cone specificity in both centre and surround.     

Retinal light adaptation--evidence for a feedback mechanism

Light adaptation is the adjustment of retinal response properties to variations in ambient illumination. It enables the encoding of visual information over a millionfold intensity range, from moonlight to broad daylight, despite the relatively small dynamic range of response of visual neurones. We have studied the effects of light adaptation on the dynamics and sensitivity of visual responses of neurones in the turtle retina, by measuring the responses of horizontal cells in the retina to light which was modulated with a sinusoidal time course around various mean levels. As a quantitative measure of the transduction from light to neural signals, we calculated the gain of response at each frequency. Gain is defined as the amplitude of the modulated response component divided by the amplitude of light modulation. We report here that the gain (mV photon-1) at low temporal frequencies decreased as the mean light level increased. Over a 2 log-unit range of mean light levels, low-frequency gain was inversely proportional to the mean light level, as in Weber's law. However, at high temporal frequencies, the gain was almost independent of mean light level. Our results are reminiscent of Kelly's results on human temporal-frequency sensitivity in various states of light adaptation. We found that a family of horizontal-cell temporal frequency responses, measured at various mean light levels, could be accounted for by a negative feedback model in which the feedback strength is proportional to mean light level.     

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.     

Segregation of object and background motion in the retina

An important task in vision is to detect objects moving within a stationary scene. During normal viewing this is complicated by the presence of eye movements that continually scan the image across the retina, even during fixation. To detect moving objects, the brain must distinguish local motion within the scene from the global retinal image drift due to fixational eye movements. We have found that this process begins in the retina: a subset of retinal ganglion cells responds to motion in the receptive field centre, but only if the wider surround moves with a different trajectory. This selectivity for differential motion is independent of direction, and can be explained by a model of retinal circuitry that invokes pooling over nonlinear interneurons. The suppression by global image motion is probably mediated by polyaxonal, wide-field amacrine cells with transient responses. We show how a population of ganglion cells selective for differential motion can rapidly flag moving objects, and even segregate multiple moving objects.     

Functional connectivity in the retina at the resolution of photoreceptors

To understand a neural circuit requires knowledge of its connectivity. Here we report measurements of functional connectivity between the input and ouput layers of the macaque retina at single-cell resolution and the implications of these for colour vision. Multi-electrode technology was used to record simultaneously from complete populations of the retinal ganglion cell types (midget, parasol and small bistratified) that transmit high-resolution visual signals to the brain. Fine-grained visual stimulation was used to identify the location, type and strength of the functional input of each cone photoreceptor to each ganglion cell. The populations of ON and OFF midget and parasol cells each sampled the complete population of long- and middle-wavelength-sensitive cones. However, only OFF midget cells frequently received strong input from short-wavelength-sensitive cones. ON and OFF midget cells showed a small non-random tendency to selectively sample from either long- or middle-wavelength-sensitive cones to a degree not explained by clumping in the cone mosaic. These measurements reveal computations in a neural circuit at the elementary resolution of individual neurons.     

Chromatic sensitivity of ganglion cells in the peripheral primate retina

Visual abilities change over the visual field. For example, our ability to detect movement is better in peripheral vision than in foveal vision, but colour discrimination is markedly worse. The deterioration of colour vision has been attributed to reduced colour specificity in cells of the midget, parvocellular (PC) visual pathway in the peripheral retina. We have measured the colour specificity (red-green chromatic modulation sensitivity) of PC cells at eccentricities between 20 and 50 degrees in the macaque retina. Here we show that most peripheral PC cells have red-green modulation sensitivity close to that of foveal PC cells. This result is incompatible with the view that PC pathway cells in peripheral retina make indiscriminate connections ('random wiring') with retinal circuits devoted to different spectral types of cone photoreceptors. We show that selective cone connections can be maintained by dendritic field anisotropy, consistent with the morphology of PC cell dendritic fields in peripheral retina. Our results also imply that postretinal mechanisms contribute to the psychophysically demonstrated deterioration of colour discrimination in the peripheral visual field.     

褐菖鲉视网膜感受系统及其适应特性研究

褐菖鲉Sebastiscus marmoratus的暗适应时程特别长,用LogIs=0的光强漂白后,阈值需要经4.5h暗适应才能回到原来暗视水平.而明适应进程很短,只需要3min就达稳定,这与网膜变化一致。它的网膜具有视杆和视维两种不同光感受系统,但是,暗适应曲线无明显平台和转折,强光明适应曲线也未出现R型变化.因此,其视锥感光功能可能在某种程度上发生退化,适于弱光视觉,这些视觉特性可能与其长期生活于近海底层礁石间弱光环境的习性相适应。     

Directionally selective calcium signals in dendrites of starburst amacrine cells

The detection of image motion is fundamental to vision. In many species, unique classes of retinal ganglion cells selectively respond to visual stimuli that move in specific directions. It is not known which retinal cell first performs the neural computations that give rise to directional selectivity in the ganglion cell. A prominent candidate has been an interneuron called the 'starburst amacrine cell'. Using two-photon optical recordings of intracellular calcium concentration, here we find that individual dendritic branches of starburst cells act as independent computation modules. Dendritic calcium signals, but not somatic membrane voltage, are directionally selective for stimuli that move centrifugally from the cell soma. This demonstrates that direction selectivity is computed locally in dendritic branches at a stage before ganglion cells.     

Illusory shifts in visual direction accompany adaptation of saccadic eye movements.

A central problem in human vision is to explain how the visual world remains stable despite the continual displacements of the retinal image produced by rapid saccadic movements of the eyes. Perceived stability has been attributed to 'efferent-copy' signals, representing the saccadic motor commands, that cancel the effects of saccade-related retinal displacements. Here we show, by means of a perceptual illusion, that traditional cancellation theories cannot explain stability. The perceptual illusion was produced by first inducing adaptive changes in saccadic gain (ratio of saccade size to target eccentricity). Following adaptation, subjects experienced an illusory mislocalization in which widely separated targets flashed before and after saccades appeared to be in the same place. The illusion shows that the perceptual system did not take the adaptive changes into account. Perceptual localization is based on signals representing the size of the initially-intended saccade, not the size of the saccade that is ultimately executed. Signals representing intended saccades initiate a visual comparison process used to maintain perceptual stability across saccades and to generate the oculomotor error signals that ensure saccadic accuracy.     

Ocular dominance shift in kitten visual cortex caused by imbalance in retinal electrical activity

Monocular lid suture during the sensitive period early in the life of a kitten disrupts normal development of inputs from the two eyes to the visual cortex, causing a decrease in the fraction of cortical cells responding to the deprived eye. Such an ocular dominance shift has been assumed to depend on patterned visual experience, because no change in cortical physiology is produced by inequalities between the two eyes in retinal illumination or temporally modulated diffuse light stimulation. A higher-level process, involving gating signals from areas outside striate cortex, has been proposed to ensure that sustained changes in synaptic efficacy occur only in response to behaviourally significant visual inputs. To test whether such a process is necessary for ocular dominance plasticity, we treated 4-week-old kittens with visual deprivation and monocular tetrodotoxin (TTX) injections to create an imbalance in the electrical activities of the two retinas in the absence of patterned vision. After 1 week of treatment we determined the ocular dominance distribution of single units in primary visual cortex. In all kittens studied, a significant ocular dominance shift was found. In addition to this physiological change, there was an anatomical change in the lateral geniculate nucleus, where cells were larger in laminae receiving input from the more active eye. Our results indicate that patterned vision is not necessary for visual cortical plasticity, and that an imbalance in spontaneous retinal activity alone can produce a significant ocular dominance shift.     

Differences in the kinetics of rod and cone synaptic transmission

Photoreceptors of the vertebrate retina hyperpolarize in response to light. The hyperpolarization elicited by a brief flash is approximately ten times slower in rods than in cones of the same retina. We have examined the amplification and temporal properties of synaptic transfer of rod and cone signals to a common postsynaptic element, the horizontal cell. We find that the kinetics of signal transfer at these chemical synapses parallels the speed of the light-evoked signals themselves.     

The influence of visual motion on fast reaching movements to a stationary object

One of the most important functions of vision is to direct actions to objects. However, every time that vision is used to guide an action, retinal motion signals are produced by the movement of the eye and head as the person looks at the object or by the motion of other objects in the scene. To reach for the object accurately, the visuomotor system must separate information about the position of the stationary target from background retinal motion signals-a long-standing problem that is poorly understood. Here we show that the visuomotor system does not distinguish between these two information sources: when observers made fast reaching movements to a briefly presented stationary target, their hand shifted in a direction consistent with the motion of a distant and unrelated stimulus, a result contrary to most other findings. This can be seen early in the hand's trajectory (approximately 120 ms) and occurs continuously from programming of the movement through to its execution. The visuomotor system might make use of the motion signals arising from eye and head movements to update the positions of targets rapidly and redirect the hand to compensate for body movements.     

Retinal receptors in rodents maximally sensitive to ultraviolet light

High sensitivity to near-ultraviolet light is a fundamental feature of vision in many invertebrates. Among vertebrates there are some amphibians, birds and fishes that are also sensitive to near-ultraviolet wavelengths. This sensitivity can be achieved through a class of cone photoreceptor containing an ultraviolet-sensitive pigment. Although these receptors were thought not to exist in the eyes of mammals, we now report that some rodents have a retinal mechanism that is maximally sensitive to ultraviolet light.     

Cortical magnification factor and the ganglion cell density of the primate retina

It has long been contentious whether the large representation of the fovea in the primate visual cortex (V1) indicates a selective magnification of this part of the retina, or whether it merely reflects the density of retinal ganglion cells. The measurement of the retinal ganglion-cell density is complicated by lateral displacements of cells around the fovea and the presence of displaced amacrine cells in the ganglion cell layer. We have now identified displaced amacrine cells by GABA immunohistochemistry and by retrograde degeneration of ganglion cells. By reconstructing the fovea from serial sections, we were able to compare the densities of cones, cone pedicles and ganglion cells; in this way we found that there are more than three ganglion cells per foveal cone. Between the central and the peripheral retina, the ganglion cell density changes by a factor of 1,000-2,000, which is within the range of estimates of the cortical magnification factor. There is therefore no need to postulate a selective magnification of the fovea in the geniculate and/or the visual cortex.     

GABA and GAD immunoreactivity of photoreceptor terminals in primate retina

Within the vertebrate retina, two types of photoreceptor cells--the rods and cones--transduce visual signals and convey this information through synapses with bipolar and horizontal cells. Although the neurotransmitter at these first-order synapses has not been identified, electrophysiological studies suggest that it might be excitatory. In the present study, however, we have found photoreceptor terminals in the rhesus monkey retina which are immunoreactive with antibodies to either gamma-aminobutyric acid (GABA) or L-glutamic acid decarboxylase (GAD, an enzyme involved in the synthesis of GABA). In the perifoveal region of the retina, approximately 25% of presynaptic profiles having ultrastructural characteristics of either rod or cone terminals are immunoreactive with one or the other antibody. This evidence for a putatively inhibitory neurotransmitter in photoreceptor terminals challenges present understanding of retinal synaptic function.     

Melanopsin and rod-cone photoreceptive systems account for all major accessory visual functions in mice

In the mammalian retina, besides the conventional rod-cone system, a melanopsin-associated photoreceptive system exists that conveys photic information for accessory visual functions such as pupillary light reflex and circadian photo-entrainment. On ablation of the melanopsin gene, retinal ganglion cells that normally express melanopsin are no longer intrinsically photosensitive. Furthermore, pupil reflex, light-induced phase delays of the circadian clock and period lengthening of the circadian rhythm in constant light are all partially impaired. Here, we investigated whether additional photoreceptive systems participate in these responses. Using mice lacking rods and cones, we measured the action spectrum for phase-shifting the circadian rhythm of locomotor behaviour. This spectrum matches that for the pupillary light reflex in mice of the same genotype, and that for the intrinsic photosensitivity of the melanopsin-expressing retinal ganglion cells. We have also generated mice lacking melanopsin coupled with disabled rod and cone phototransduction mechanisms. These animals have an intact retina but fail to show any significant pupil reflex, to entrain to light/dark cycles, and to show any masking response to light. Thus, the rod-cone and melanopsin systems together seem to provide all of the photic input for these accessory visual functions.     

Functions of the ON and OFF channels of the visual system

In the mammalian eye, the ON-centre and OFF-centre retinal ganglion cells form two major pathways projecting to central visual structures from the retina. These two pathways originate at the bipolar cell level: one class of bipolar cells becomes hyperpolarized in response to light, as do all photoreceptor cells, and the other class becomes depolarized on exposure to light, thereby inverting the receptor signal. It has recently become possible to examine the functional role of the ON-pathway in vision by selectively blocking it at the bipolar cell level using the glutamate neurotransmitter analogue 2-amino-4-phosphonobutyrate (APB)1. APB application to monkey, cat and rabbit retinas abolishes ON responses in retinal ganglion cells, the lateral geniculate nucleus and the visual cortex but has no effect on the centre-surround antagonism of OFF cells or the orientation and direction selectivities in the cortex2-5. These and related findings6-11 suggest that the ON and OFF pathways remain largely separate through the lateral geniculate nucleus and that in the cortex, contrary to some hypotheses, they are not directly involved in mechanisms giving rise to orientation and direction selectivities. We have examined the roles of the ON and OFF channels in vision in rhesus monkeys trained to do visual detection and discrimination tasks. We report here that the ON channel is reversibly blocked by injection of APB into the vitreous. Detection of light increment but not of light decrement is severely impaired, and there is a pronounced loss in contrast sensitivity. The perception of shape, colour, flicker, movement and stereo images is only mildly impaired, but longer times are required for their discrimination. Our results suggest that two reasons that the mammalian visual system has both ON and OFF channels is to yield equal sensitivity and rapid information transfer for both incremental and decremental light stimuli and to facilitate high contrast sensitivity.     

Polymorphism of the long-wavelength cone in normal human colour vision

Colour vision is based on the presence of multiple classes of cone each of which contains a different type of photopigment. Colour matching tests have long revealed that the normal human has three cone types. Results from these tests have also been used to provide estimates of cone spectral sensitivities. There are significant variations in colour matches made by individuals whose colour vision is classified as normal. Some of this is due to individual differences in preretinal absorption and photopigment density, but some is also believed to arise because there is variation in the spectral positioning of the cone pigments among those who have normal colour vision. We have used a sensitive colour matching test to examine the magnitude and nature of this individual variation and here report evidence for the existence of two different long-wavelength cone mechanisms in normal humans. The different patterns of colour matches made by male and female subjects indicate these two mechanisms are inherited as an X-chromosome linked trait.