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ABSTRACT: We previously reported in adult mice that visuomotor experience during monocular deprivation (MD) augmented enhancement of visual-cortex-dependent behavior through the non-deprived eye (NDE) during deprivation, and enabled enhanced function to persist after MD. We investigated the physiological substrates of this experience-enabled form of adult cortical plasticity by measuring visual behavior and visually evoked potentials (VEPs) in binocular visual cortex of the same mice before, during, and after MD. MD on its own potentiated VEPs contralateral to the NDE during MD and shifted ocular dominance (OD) in favor of the NDE in both hemispheres. Whereas we expected visuomotor experience during MD to augment these effects, instead enhanced responses contralateral to the NDE, and the OD shift ipsilateral to the NDE were attenuated. However, in the same animals, we measured NMDA receptor-dependent VEP potentiation ipsilateral to the NDE during MD, which persisted after MD. The results indicate that visuomotor experience during adult MD leads to enduring enhancement of behavioral function, not simply by amplifying MD-induced changes in cortical OD, but through an independent process of increasing NDE drive in ipsilateral visual cortex. Because the plasticity is resident in the mature visual cortex and selectively effects gain of visual behavior through experiential means, it may have the therapeutic potential to target and non-invasively treat eye- or visual-field-specific cortical impairment.
Journal of Neuroscience 03/2013; 33(12):5362-6. · 7.11 Impact Factor
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Trevor J McGill,
Glen T Prusky, Robert M Douglas,
Douglas Yasumura,
Michael T Matthes,
Robert J Lowe,
Jacque L Duncan,
Haidong Yang,
Kelly Ahern,
Kate M Daniello,
Byron Silver,
Matthew M Lavail
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ABSTRACT: Purpose. To assess structural, functional, and visual behavioral relationships in mutant rhodopsin transgenic (Tg) rats and to determine whether early optokinetic tracking (OKT) visual experience, known to permanently elevate visual thresholds in normal rats, can enhance vision in rats with photoreceptor degeneration. Methods. Eight lines of pigmented Tg rats and RCS rats were used in this study. OKT thresholds were tested at single ages (1, 2, 3, 4, and 6 months) in naïve groups of rats, or daily in groups that began at eye-opening (P15) or 10 days later (P25). Electroretinogram (ERG) response amplitudes were recorded after OKT testing, and outer nuclear layer (ONL) thickness measurements were then obtained. Results. OKT thresholds, when measured at a single time point in naïve Tg lines beginning at P30, did not decline until months after significant photoreceptor loss. Daily testing of Tg lines resulted mostly with OKT thresholds inversely related to photoreceptor degeneration, with rapid degenerations resulting in sustained OKT thresholds for long periods despite the rapid photoreceptor loss. Slower degenerations resulted in rapid decline of thresholds, long before the loss of most photoreceptors, which was even more pronounced when daily testing began at eye opening. This amplified loss of function was not a result of testing-induced damage to the rod or cone photoreceptors, as ERG amplitudes and ONL thicknesses were the same as untested controls. Conclusions. The unexpected lack of correlation of OKT testing with photoreceptor degeneration in the Tg rats emphasizes the need in behavioral therapeutic studies for careful analysis of visual thresholds of experimental animals prior to therapeutic intervention.
Investigative ophthalmology & visual science 08/2012; 53(10):6232-44. · 3.43 Impact Factor
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ABSTRACT: Animal model studies of amblyopia have generally concluded that enduring effects of monocular deprivation (MD) on visual behavior (i.e., loss of visual acuity) are limited to the deprived eye, and are restricted to juvenile life. We have previously reported, however, that lasting effects of MD on visual function can be elicited in adulthood by stimulating visuomotor experience through the non-deprived eye. To test whether stimulating experience would also induce interocular plasticity of vision in infancy, we assessed in rats from eye-opening on postnatal day (P) 15, the effect of pairing MD with the daily experience of measuring thresholds for optokinetic tracking (OKT). MD with visuomotor experience from P15 to P25 led to a ~60% enhancement of the spatial frequency threshold for OKT through the non-deprived eye during the deprivation, which was followed by loss-of-function (~60% below normal) through both eyes when the deprived eye was opened. Reduced thresholds were maintained into adulthood with binocular OKT experience from P25 to P30. The ability to generate the plasticity and maintain lost function was dependent on visual cortex. Strictly limiting the period of deprivation to infancy by opening the deprived eye at P19 resulted in a comparable loss-of-function. Animals with reduced OKT responses also had significantly reduced visual acuity, measured independently in a discrimination task. Thus, experience-dependent cortical plasticity that can lead to amblyopia is present earlier in life than previously recognized.
Frontiers in Systems Neuroscience 01/2011; 5:44.
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ABSTRACT: Because repairing visual dysfunction is the primary goal of therapy for retinal disease, a quantification of visual function
is imperative for the evaluation of potential treatments for these diseases. The Visual Water Task and the Virtual Optokinetic
System have been developed to conduct behavioral tests of vision in rodent models of retinal disease. These tests are less
invasive and often more sensitive than physiological or anatomical measures of retinal function. Moreover, discrepancies between
different measures of retinal function suggest that central and retinal adaptations may complicate the disease process.
Key wordsVision-Retinal disease-Behavior-Acuity
12/2009: pages 13-24;
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ABSTRACT: The subject of neural coding has generated much debate. A key issue is whether the nervous system uses coarse or fine coding. Each has different strengths and weaknesses and, therefore, different implications for how the brain computes. For example, the strength of coarse coding is that it is robust to fluctuations in spike arrival times; downstream neurons do not have to keep track of the details of the spike train. The weakness, though, is that individual cells cannot carry much information, so downstream neurons have to pool signals across cells and/or time to obtain enough information to represent the sensory world and guide behavior. In contrast, with fine coding, individual cells can carry much more information, but downstream neurons have to resolve spike train structure to obtain it. Here, we set up a strategy to determine which codes are viable, and we apply it to the retina as a model system. We recorded from all the retinal output cells an animal uses to solve a task, evaluated the cells' spike trains for as long as the animal evaluates them, and used optimal, i.e., Bayesian, decoding. This approach makes it possible to obtain an upper bound on the performance of codes and thus eliminate those that are insufficient, that is, those that cannot account for behavioral performance. Our results show that standard coarse coding (spike count coding) is insufficient; finer, more information-rich codes are necessary.
Proceedings of the National Academy of Sciences 05/2009; 106(14):5936-41. · 9.68 Impact Factor
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ABSTRACT: 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.
Journal of Neuroscience 10/2008; 28(39):9817-27. · 7.11 Impact Factor
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Trevor J McGill,
Glen T Prusky, Robert M Douglas,
Douglas Yasumura,
Michael T Matthes,
George Nune,
Kate Donohue-Rolfe,
Haidong Yang,
Diana Niculescu,
William W Hauswirth,
Sergej V Girman,
Raymond D Lund,
Jacque L Duncan,
Matthew M LaVail
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ABSTRACT: CNTF is a neuroprotective agent for retinal degenerations that can cause reduced electroretinogram (ERG) amplitudes. The goal of the present study was to determine the effects of intraocular delivery of CNTF on normal rat visual function.
Full-field scotopic and photopic ERG amplitudes and spatial frequency thresholds of the optokinetic response (OKR) of adult Long-Evans rats were measured before and after intravitreous injection of CNTF or subretinal delivery of adenoassociated virus-vectored CNTF (AAV-CNTF) into one eye. Visual acuity was also measured by using the Visual Water Task in AAV-CNTF-injected animals. Multiunit luminance thresholds were recorded in the superior colliculus after CNTF injection, and the eyes were examined histologically.
In eyes injected with a high dose of CNTF, ERG amplitudes and OKR thresholds measured through CNTF-injected eyes were decreased by 45% to 70% within 6 days after injection. ERG amplitudes had begun to recover by 21 days, whereas OKR thresholds only began to recover after 56 days. Neither OKR thresholds nor ERG amplitudes fully recovered until 90 to 100 days. When measured in the superior colliculus at 2 weeks after CNTF injection, luminance thresholds were elevated by 0.35 log units. In AAV-CNTF-injected eyes, OKR thresholds, and visual acuity were reduced by approximately 50% for at least 6 months, and scotopic and photopic ERG b-waves were reduced by 30% to 50%. Photoreceptor loss occurred in the injected regions in some of the eyes. By contrast, comparison of dose-response analysis with a dose-response study of light damage strongly suggests that therapeutic doses of CNTF exist that do not suppress ERG responses.
Intraocular delivery of CNTF, which preserves photoreceptors in animal models of retinal degeneration, impairs visual function in normal rats at very high doses, but not at lower doses that still provide protection from constant light damage.
Investigative Ophthalmology & Visual Science 01/2008; 48(12):5756-66. · 3.60 Impact Factor
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ABSTRACT: Many conditions adversely affecting learning, memory, and cognition are associated with reductions in forebrain acetylcholine (ACh), most notably aging and Alzheimer's 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.
Neuropsychopharmacology 04/2007; 32(3):505-13. · 7.99 Impact Factor
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ABSTRACT: To evaluate the efficacy of immunologically compatible Schwann cells transplanted without immunosuppression in the RCS rat retina to preserve vision.
Syngeneic (dystrophic RCS) Schwann cells harvested from sciatic nerves were cultured and transplanted into one eye of dystrophic RCS rats at an early stage of retinal degeneration. Allogeneic (Long-Evans) Schwann cells and unoperated eyes served as controls. Vision through transplanted and unoperated eyes was then quantified using two visual behavior tasks, one measuring the spatial frequency and contrast sensitivity thresholds of the optokinetic response (OKR) and the other measuring grating acuity in a perception task.
Spatial frequency thresholds measured through syngeneically transplanted eyes maintained near normal spatial frequency sensitivity for approximately 30 weeks, whereas thresholds through control eyes deteriorated to less than 20% of normal over the same period. Contrast sensitivity was preserved through syngeneically transplanted eyes better than through allogeneic and unoperated eyes, at all spatial frequencies. Grating acuity measured through syngeneically transplanted eyes was maintained at approximately 60% of normal, whereas acuity of allogeneically transplanted eyes was significantly lower at approximately 40% of normal.
The ability of immunoprivileged Schwann cell transplants to preserve vision in RCS rats indicates that transplantation of syngeneic Schwann cells holds promise as a preventive treatment for retinal degenerative disease.
Investigative Ophthalmology & Visual Science 04/2007; 48(4):1906-12. · 3.60 Impact Factor
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ABSTRACT: 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 approximately 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.
Journal of Neuroscience 12/2006; 26(45):11554-61. · 7.11 Impact Factor
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ABSTRACT: To develop a simple, rapid method of quantifying the spatial vision of mice.
A rotating cylinder covered with a vertical sine wave grating was calculated and drawn in virtual three-dimensional (3-D) space on four computer monitors facing to form a square. C57BL/6 mice standing unrestrained on a platform in the center of the square tracked the grating with reflexive head and neck movements. The spatial frequency of the grating was clamped at the viewing position by repeatedly recentering the cylinder on the head. Acuity was quantified by increasing the spatial frequency of the grating until an optomotor response could not be elicited. Contrast sensitivity was measured at spatial frequencies between 0.03 and 0.35 cyc/deg.
Grating acuity was measurable on the day of eye opening (postnatal day [P]15: mean acuity, 0.031 cyc/deg) and reached a maximum (approximately 0.4 cyc/deg) by P24. A peak in the contrast sensitivity function emerged on P16 (4.7, or 21% contrast at 0.064 cyc/deg). The peak remained at 0.064 cyc/deg and climbed to a maximum sensitivity of 24.5, or 4% contrast, by P29. Acuity was obtained in each mouse in <10 minutes, and a detailed contrast sensitivity curve was generated in approximately 30 minutes.
The virtual optomotor system provides a simple and precise method for rapidly quantifying mouse vision. Behavioral measures of vision in mice are essential for interpreting the results of experiments designed to reveal the cellular and molecular mechanisms of vision and visual development and for evaluating potential treatments for visual diseases.
Investigative Ophthalmology & Visual Science 01/2005; 45(12):4611-6. · 3.60 Impact Factor
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ABSTRACT: To examine how spatial vision deteriorates in the RCS rat over time as a background to experimental studies aimed at limiting photoreceptor degeneration.
The Visual Water Task was used to quantify the grating acuity of pigmented dystrophic RCS rats as they aged and to compare both grating acuity and contrast sensitivity in nondystrophic RCS rats with those parameters in normal pigmented laboratory rats (Long-Evans).
Nondystrophic rats had grating acuities and contrast sensitivity functions that were similar to those obtained from Long-Evans rats. The grating acuity of dystrophic rats deteriorated from 80% of normal at 1 month of age to blindness by 11 months. Acuity declined rapidly to 0.32 cyc/deg over the first 4 months, with a slower decline thereafter.
Robust measures of vision can be achieved in RCS rats using the Visual Water Task, and with this test, no visual dysfunction can be detected in the background strain. The course of functional deterioration in dystrophic rats is highly predictable, allowing the approach to be used to explore the substrates of the deterioration in vision and to monitor the effects of therapeutic retinal interventions on spatial vision.
Investigative Ophthalmology & Visual Science 04/2004; 45(3):932-6. · 3.60 Impact Factor
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ABSTRACT: 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 ( approximately 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% ( approximately 0.31 cycles/degree). Identical binocular deprivation produced a significant, but smaller, decrease in acuity ( approximately 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.
European Journal of Neuroscience 02/2003; 17(1):167-73. · 3.63 Impact Factor
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ABSTRACT: 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.
Behavioural Brain Research 12/2002; 136(2):339-48. · 3.42 Impact Factor
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ABSTRACT: 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.
Behavioural Brain Research.
