Robert M. Douglas

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.

Serotonin facilitates synaptic plasticity in kitten visual cortex: an in vitro study

We have addressed the role of serotonin-2C (5-HT2C) receptors in the development and maintenance of synaptic plasticity in the kitten visual cortex. In visual cortical slices, taken from 40- to 80-day-old kittens, bath application of serotonin markedly facilitated the induction of both long-term depression (LTD) and long-term potentiation (LTP). Field potential responses to white matter stimulation were recorded from layer IV after a regime of low frequency stimulation (LFS; 1 Hz, 15 min), which reliably induced LTP or LTD in younger kittens (less than 30 days of age). At 40-80 days, this protocol almost never induced LTD or LTP in layer IV. However, in 50% of the visual cortical slices studied in 40-80-day-old kittens, LTD or LTP was induced, if serotonin (1 or 10 microM) was co-applied with LFS. No such serotonin facilitation of long-term plasticity was ever detected in > 120-day-old animals, indicating that serotonin facilitates synaptic plasticity within a defined period of visual cortical development. Serotonergic 5-HT2C receptors are likely to contribute to the synaptic plasticity observed in layer IV, since mesulergine, an antagonist of the 5-HT2C receptor, completely blocked synaptic modifications induced by the combination of low frequency stimulation and serotonin application.

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.

Environmental enrichment from birth enhances visual acuity but not place learning in mice.

The effect of richness of the environment on behavioral function was investigated in C57B6 mice. Animals were raised in either enriched (group-housed in large clear plexiglas cages with stimulating objects) or restricted (group housed in opaque white plastic cages with no stimulating objects) environmental conditions and their spatial learning and visual acuity were measured as adults. The performance of enriched and restricted groups were indistinguishable in place and cued versions of the Morris water task; however, the visual acuity of the enriched group, measured in a grating versus gray version of the visual water task, was 18% higher than the restricted group. These data demonstrate that the function of the mouse visual system can be significantly influenced by the nature of early visual input. They also indicate that the effects of environmental enrichment are manifested differently in behavioral measures of spatial learning and visual acuity.

Experience-dependent plasticity of visual acuity in rats.

Rats have become a popular model for investigating the mechanisms underlying ocular dominance plasticity; however, no quantitative assessment of the effects of visual deprivation on behavioural acuity has been reported in this species. We measured the spatial acuity of monocularly and binocularly deprived rats with a visual discrimination task. The average spatial acuity of normal rats and rats deprived of vision after postnatal day 40 was ≈ 1 cycle/degree. Monocular deprivation up to postnatal day 40 resulted in a 30% decrease in acuity and there was no recovery after 8 months. Identical binocular deprivation produced a comparable but significantly smaller reduction in acuity. The deleterious effects of monocular and binocular deprivation on visual acuity indicate that the development of cortical receptive field properties related to spatial tuning are affected by both monocular and binocular deprivation. The similarities in the effects of visual deprivation on visual acuity between rats and other mammals confirm that rats are a good model system for studying the cellular and molecular mechanisms underlying experience‐dependent visual plasticity.

Experience-Dependent Plasticity from Eye Opening Enables Lasting, Visual Cortex-Dependent Enhancement of Motion Vision

Developmentally regulated plasticity of vision has generally been associated with “sensitive” or “critical” periods in juvenile life, wherein visual deprivation leads to loss of visual function. Here we report an enabling form of visual plasticity that commences in infant rats from eye opening, in which daily threshold testing of optokinetic tracking, amid otherwise normal visual experience, stimulates enduring, visual cortex-dependent enhancement (>60%) of the spatial frequency threshold for tracking. The perceptual ability to use spatial frequency in discriminating between moving visual stimuli is also improved by the testing experience. The capacity for inducing enhancement is transitory and effectively limited to infancy; however, enhanced responses are not consolidated and maintained unless in-kind testing experience continues uninterrupted into juvenile life. The data show that selective visual experience from infancy can alone enable visual function. They also indicate that plasticity associated with visual deprivation may not be the only cause of developmental visual dysfunction, because we found that experientially inducing enhancement in late infancy, without subsequent reinforcement of the experience in early juvenile life, can lead to enduring loss of function.

Reduced visual acuity impairs place but not cued learning in the Morris water task.

The Morris water task is a standard method for testing spatial learning in rodents. In a place version of the task, animals utilize multiple visual cues to learn the location of a hidden platform. The ability of animals to locate a cued platform is often used to qualitatively test for possible non-cognitive contributions to deficient place learning, including reduced visual function. We investigated the role of visual acuity in water maze performance quantitatively by depriving rats of pattern vision during a critical period for visual plasticity, which reduced their acuity by approximately 27% and then tested them in typical place and cued platform configurations of the Morris water task. Animals with reduced visual acuity had a significant deficit in place learning, but eventually reached the same escape latency as non-deprived animals. Deprived and non-deprived animals, however, did not differ in their ability to locate a cued platform following place learning. These data indicate that reduced visual acuity in rats can influence measurement of their place learning and that a typical cued platform version of the task cannot detect a modest, but significant, visual deficit.

Cognitive Deficits in Rats after Forebrain Cholinergic Depletion are Reversed by a Novel NO Mimetic Nitrate Ester

Many conditions adversely affecting learning, memory, and cognition are associated with reductions in forebrain acetylcholine (ACh), most notably aging and Alzheimers disease. In the current study, we demonstrate that bilateral depletion of neocortical and hippocampal ACh in rats produces deficits in a spatial learning task and in a recently described, delayed visual matching-to-sample task. Oral administration of the novel nitrate, GT1061 (4-methyl-5-(2-nitroxyethyl) thiazole HCl), and the acetylcholinesterase inhibitor, donepezil, reversed the cognitive deficits in both memory tasks in a dose-dependent manner. GT1061 was superior in the delayed matching-to-sample task. GT1061 was absorbed rapidly after oral administration, crossed the blood brain barrier, and achieved brain concentrations that were slightly higher than those found in plasma. The activity of GT1061 was NO mimetic: soluble guanylyl cyclase (sGC) was activated, but selectivity was observed for sGC in the hippocampus relative to the vasculature; and hippocampal levels of phosphorylated ERK1/2, which is a postulated intermediary in the formation of long-term memory, were increased. The beneficial effect on visual and spatial memory task performance supports the concept that stimulating the NO/sGC/cGMP signal transduction system can provide new, effective treatments for cognitive disorders. This approach may be superior to that of current drugs that attempt only to salvage the residual function of damaged cholinergic neurons.