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.

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.

Colour vision in humans and Old World monkeys begins with the differential activation of three types of cone photoreceptor which are maximally sensitive to short (S), medium (M) and long (L) wavelengths. Signals from the three cone types are relayed to the retinal ganglion cells via cone-specific bipolar cell types. Colour-coding ganglion cells fall into two major physiological classes: the red-green opponent cells, which receive antagonistic input from M- and L-sensitive cones, and the blue-yellow opponent cells, which receive input from S-sensitive cones, opposed by combined M- and L-cone input. The neural mechanisms producing colour opponency are not understood. It has been assumed that both kinds of opponent signals are transmitted to the lateral geniculate nucleus by one type of ganglion cell, the midget cell. We now report that a distinct non-midget ganglion cell type, the small bistratified cell, corresponds to the physiological type that receives excitatory input from S cones, the 'blue-on' cell. Our results thus demonstrate an anatomically distinct pathway that conveys S-cone signals to the brain. The morphology of the blue-on cell also suggests a novel hypothesis for the retinal circuitry underlying the blue-yellow opponent response.

To study their detailed morphology, ganglion cells of the human retina were stained by intracellular tracer injection, in an in vitro, whole-mount preparation. This report focuses on the dendritic morphology and mosaic organization of the major, presumed color-opponent, ganglion cell class, the midget cells. Midget cells in the central retina were recognized by their extremely small dendritic trees, approximately 5-10 microns in diameter. Between 2 and 6 mm eccentricity, midget cells showed a steep, 10-fold increase in dendritic field size, followed by a more shallow, three- to fourfold increase in the retinal periphery, attaining a maximum diameter of approximately 225 microns. Despite large local variation in dendritic field size, midget cells formed one morphologically distinctive class at all retinal eccentricities. Two midget cell types were distinguished by their dendritic stratification in either the inner or outer portion of the inner plexiform layer (IPL), and presumably correspond to ON- and OFF-center cells respectively. The mosaic organization of the midget cells was examined by intracellularly filling neighboring cells in small patches of retina. For both the inner and outer midget populations, adjacent dendritic trees apposed one another but did not overlap, establishing a coverage of no greater than 1. The two mosaics differed in spatial scale, however: the outer midget cells showed smaller dendritic fields and higher cell density than the inner midget cells. An outer:inner cell density ratio of 1.7:1 was found in the retinal periphery. An estimate of total midget cell density suggested that the proportion of midget cells increases from about 45% of total ganglion cell density in the retinal periphery to about 95% in the central retina. Nyquist frequencies calculated from midget cell spacing closely match a recent measure of human achromatic spatial acuity (Anderson et al., 1991), from approximately 6 degrees to 55 degrees eccentricity. Outside the central retina, midget cell dendrites arborized in clusters within the overall dendritic field. With increasing eccentricity, the dendritic clusters increased in number and remained small (approximately 10-20 microns diameter) relative to the size of the dendritic field. Because neighboring midget cell dendritic trees do not overlap, the mosaic as a whole showed a pattern of clusters and holes. We hypothesize that midget cell dendritic trees may contact individual axon terminals of some midget bipolar cells and avoid contacting others, providing a basis for the formation of cone-specific connections in the IPL.