Glen T. Prusky

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.

Behavioral assessment of visual acuity in mice and rats

We have developed a simple computer-based discrimination task that enables the quick determination of visual acuities in rodents. A grating is displayed randomly on one of two monitors at the wide end of a trapezoidal-shaped tank containing shallow water. Animals are trained to swim toward the screens, and at a fixed distance, choose the screen displaying the grating and escape to a submerged platform hidden below it. Both mice and rats learn the task quickly. Performance falls below 70% when the spatial frequency is increased beyond 0.5 cycles in most C57BU6 mice, and around 1.0 cycles per degree (cpd) in Long-Evans rats.

Variation in visual acuity within pigmented, and between pigmented and albino rat strains

Many researchers assume that laboratory rats have poor vision, and accordingly, that they need not consider differences in the visual function of rats as a consequence of strain or experience. Currently, it is not specifically known whether rat domestication has negatively affected the visual function of laboratory rat strains, what the effects of strain albinism are on rat visual function, or whether there are strain differences in the visual function of laboratory rats that are independent of pigmentation. In order to address these questions, we measured psychophysically the vertical grating acuity of three pigmented (Dark Agouti, Fisher-Norway, Long-Evans) and three albino (Fisher-344, Sprague-Dawley, Wistar) strains of laboratory rats, and compared their acuity with that of wild rats. The grating thresholds of Dark Agouti, Long-Evans and wild strains clustered around 1.0 cycle/degree (c/d) and did not significantly differ from one another. Fisher-Norway rats, however, had a significantly higher threshold of 1.5 c/d. The grating thresholds of Fisher-344, Sprague-Dawley, and Wistar strains, which were clustered around 0.5 c/d, were significantly lower than those of the pigmented strains. These data demonstrate that there is significant strain variability in the visual function of laboratory rats. Domestication of Long-Evans and Dark Agouti strains does not appear to have compromised visual acuity, but in the case of Fisher-Norway rats, selective breeding may have enhanced their acuity. Strain selection associated with albinism, however, appears to have consistently impaired visual acuity. Therefore, a consideration of strain differences in visual function should accompany the selection of a rat model for behavioral tasks that involve vision, or when comparing visuo-behavioral measurements across rat strains.

Developmental plasticity of mouse visual acuity

Monocular deprivation in mice between postnatal days 19 and 32 has been reported to significantly shift ocular dominance within the binocular region of primary visual cortex; however, it is not known whether visual deprivation in mice during this physiologically defined critical period also results in amblyopia, as it does in other mammals. We addressed this uncertainty by psychophysically assessing in adulthood (postnatal day 70 or older) the grating acuity of normal and monocularly deprived mice, using the Visual Water Task. The visual acuity of mice tested with their nondeprived eyes was equivalent to that of normal mice (≈ 0.5 cycles/degree); however, acuity measured with eyes monocularly deprived of vision transiently between postnatal days 19 and 32 was reduced by over 30% (≈ 0.31 cycles/degree). Identical binocular deprivation produced a significant, but smaller, decrease in acuity (≈ 0.38 cycles/degree). The effects of monocular and binocular deprivation were long lasting and occurred only if visual deprivation occurred between postnatal days 19 and 32. These data indicate that the deleterious effects of early visual deprivation on visual acuity in mice are similar to those reported in other mammals, and together with electrophysiological evidence of ocular dominance plasticity, suggest that the mechanisms of mouse visual plasticity are fundamentally the same as that in other mammals. Therefore, the mouse is probably a good model for investigating the basic cellular and molecular mechanisms underlying visual developmental plasticity and amblyopia.

Rod photoreceptors drive circadian photoentrainment across a wide range of light intensities.

In mammals, synchronization of the circadian pacemaker in the hypothalamus is achieved through direct input from the eyes conveyed by intrinsically photosensitive retinal ganglion cells (ipRGCs). Circadian photoentrainment can be maintained by rod and cone photoreceptors, but their functional contributions and their retinal circuits that impinge on ipRGCs are not well understood. Using mice that lack functional rods or in which rods are the only functional photoreceptors, we found that rods were solely responsible for photoentrainment at scotopic light intensities. Rods were also capable of driving circadian photoentrainment at photopic intensities at which they were incapable of supporting a visually guided behavior. Using mice in which cone photoreceptors were ablated, we found that rods signal through cones at high light intensities, but not at low light intensities. Thus, rods use two distinct retinal circuits to drive ipRGC function to support circadian photoentrainment across a wide range of light intensities.

Cervical motoneuron topography reflects the proximodistal organization of muscles and movements of the rat forelimb: A retrograde carbocyanine dye analysis

Behavioral evidence reveals that the laboratory rat and other rodent species display skilled paw and digit use in handling food during eating and skilled limb use in reaching for food in formal laboratory skilled reaching tests that is comparable to that described in carnivores and primates. Because less is known about the central control of skilled movements in rodents than in carnivores or primates, the purpose of the current study was to examine the relation between the rats spinal motoneurons and the individual forelimb muscles that they innervate. In two experiments, 14 forelimb muscles (in the shoulder and the upper and lower arm segments) were injected with carbocyanine dye tracers. The topography of spinal motoneurons was reconstructed by using fluorescence microscopy. Motor neurons were found to be organized in columns throughout the length of the cervical and upper thoracic area, with 1) extensor motoneurons located more laterally than flexor motoneurons, 2) rostral motoneurons innervating more proximal muscles than caudal motoneurons, and 3) more dorsally located motoneurons innervating more distal muscles. These results reveal that the topography of rodent cervical spinal cord motoneurons is very similar to that of carnivores and of primates, which also are characterized by well‐developed, skilled movements. In addition, the proximal‐distal organization of motoneuron columns parallels the proximal‐to‐distal pattern of forelimb movement used by the rat when reaching. The data from this study enable the development of predictions about the specific movements that would be compromised by experimental transections or other injuries at different levels of the spinal cord in rat models of spinal injury. J. Comp. Neurol. 419:286–296, 2000.

Nicotine receptors are located on lateral geniculate nucleus terminals in cat visual cortex

Using the methods of in vitro receptor autoradiography, we have characterized a population of receptors for nicotine in cat visual cortex that is concentrated primarily in layer IV of areas 17 and 18. Surgically undercutting the visual cortex essentially abolished [3H]nicotine binding in the isolated zone. However, neuron-specific, quinolinic acid lesions of a region of visual cortex had little effect on binding, establishing a presynaptic locus on cortical inputs for these sites. Lesions of the lateral geniculate nucleus abolished binding in the corresponding cortical areas, thus localizing the [3H]nicotine binding sites to lateral geniculate nucleus terminals in the cortex.

A role for melanopsin in alpha retinal ganglion cells and contrast detection

Distinct subclasses of retinal ganglion cells (RGCs) mediate vision and nonimage-forming functions such as circadian photoentrainment. This distinction stems from studies that ablated melanopsin-expressing intrinsically photosensitive RGCs (ipRGCs) and showed deficits in nonimage-forming behaviors, but not image vision. However, we show that the ON alpha RGC, a conventional RGC type, is intrinsically photosensitive in mammals. In addition to their classical response to fast changes in contrast through rod/cone signaling, melanopsin expression allows ON alpha RGCs to signal prior light exposure and environmental luminance over long periods of time. Consistent with the high contrast sensitivity of ON alpha RGCs, mice lacking either melanopsin or ON alpha RGCs have behavioral deficits in contrast sensitivity. These findings indicate a surprising role for melanopsin and ipRGCs in vision.

Enhancement of Vision by Monocular Deprivation in Adult Mice

Plasticity of vision mediated through binocular interactions has been reported in mammals only during a “critical” period in juvenile life, wherein monocular deprivation (MD) causes an enduring loss of visual acuity (amblyopia) selectively through the deprived eye. Here, we report a different form of interocular plasticity of vision in adult mice in which MD leads to an enhancement of the optokinetic response (OKR) selectively through the nondeprived eye. Over 5 d of MD, the spatial frequency sensitivity of the OKR increased gradually, reaching a plateau of ∼36% above pre-deprivation baseline. Eye opening initiated a gradual decline, but sensitivity was maintained above pre-deprivation baseline for 5–6 d. Enhanced function was restricted to the monocular visual field, notwithstanding the dependence of the plasticity on binocular interactions. Activity in visual cortex ipsilateral to the deprived eye was necessary for the characteristic induction of the enhancement, and activity in visual cortex contralateral to the deprived eye was necessary for its maintenance after MD. The plasticity also displayed distinct learning-like properties: Active testing experience was required to attain maximal enhancement and for enhancement to persist after MD, and the duration of enhanced sensitivity after MD was extended by increasing the length of MD, and by repeating MD. These data show that the adult mouse visual system maintains a form of experience-dependent plasticity in which the visual cortex can modulate the normal function of subcortical visual pathways.

Seahorse wins all races: hippocampus participates in both linear and non-linear visual discrimination learning.

Consistent with configural/conjunctive theories of the hippocampus, we report that rats trained on the non-linear transverse patterning discrimination problem (A+ versus B-, B+ versus C-, and C+ versus A) displayed retrograde amnesia when the hippocampus was later damaged. They also failed to relearn the solution to this problem. Damage to the hippocampus following training also produced retrograde amnesia in rats trained on a set of elemental discrimination problems (A+ versus B-, C+ versus D-, and E+ versus F-) that could be solved based on the associative strengths of the individual choice cues. However, in contrast to transverse patterning, rats easily relearned and retained these elemental problems and learned a new set of elemental problems after the damage. These results support two theoretical conclusions: (a) elemental discriminations can be learned by both a system that depends on the hippocampus and a system that does not require the hippocampus, and (b) in the intact animal these two systems competitively interact with the hippocampal-dependent system inhibiting memory formation by the extra-hippocampal system.