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Fig. 4. Spatial contrast sensitivity function. These results are replotted from behavioral measurements made in a water escape task [50]. Each data point (triangle) represents the mean sensitivity values for five C57BL/6 mice (±1 standard error of the mean [SEM]). The downward arrow indicates the predicted cutoff frequency. See text for further discussion.
of spatially antagonistic interactions in the visual system, while the latter reflects an approach to the acuity limit with the extrapolation of the descending limb to targets of 100% contrast (the cutoff frequency, indicated by the small arrow in Fig. 4), roughly equivalent to classical measures of visual acuity. So determined, the estimated visual acuity is about 0.5–0.6c/deg. As judged by these measurements, the mouse has low spatial acuity and low contrast sensitivity (maximum ~6). For comparative context, comparable measurements made on pigmented rats yield estimated visual acuities of about 1.1 c/deg with peak contrast sensitivity of about 20 [51].
A number of other measurements of visual acuity in the mouse have yielded similar values, between about 0.5 and 0.6 c/deg [39, 41, 44], while still others have produced lower estimates, around 0.4 c/deg [43] or even lower [52]. These lower estimates were obtained using OKN measures, and it seems possible the difference may reflect the fact that information about the highest spatial frequencies is not processed along the subcortical pathways that underlie OKN. The fact that spatial resolution is significantly poorer in mice with lesions of the visual cortex supports that interpretation [50]. Alternatively, studies in human subjects showed that spatial resolution is heavily dependent on light level, and it might simply be that the effective retinal illumination differs among these various mouse studies. In any case, it should not be automatically assumed that the various means for assessing mouse spatial acuity all index the same processes.
So far, there is little information about abilities of mice to make discriminations of temporally varying stimuli. One study has shown that mice can discriminate flickering lights up to frequencies of about 25 Hz [42], and a full spectral sensitivity function was derived based on discrimination of monochromatic lights flickering at 20 Hz [35]. Since genetic manipulations of the mouse retina can influence the timing of signals, a better baseline for understanding mouse temporal resolution would be welcome.
Color Vision
Like most other mammals, mice have two classes of cone photopigment (Fig. 1). When appropriately tested, animals with such complements are typically shown to have
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Fig. 5. Results from a test for the presence of color vision in the mouse. In a threealternative forced-choice discrimination task mice were required to distinguish various longer test wavelengths from a 370-nm light (open circles) and then, in a subsequent test, various shorter test wavelengths from a 510-nm light (filled triangles). The data points represent asymptotic performance levels achieved when the wavelength pairs were equated to appear equally bright to the mouse. The horizontal dashed line indicates the level of chance performance. (Data taken from [35].)
a dimension of color vision; technically, they are dichromats [3]. For example, the rat retina contains two types of cone pigment having spectral absorption properties very similar to those found in the mouse, and from this arrangement rats derive some color vision [53]. Unlike what is apparently the case in rat, the mouse cone pigments are to some variable extent coexpressed in individual photoreceptors, and as noted, this provides what would seem an unfavorable substrate for producing color vision.
An experiment was performed to see if pigment coexpression provides an insurmountable barrier to color vision in the mouse. For this, animals were tested in an appetitive forced-choice discrimination task [35]. Following a training procedure designed to make it possible to obviate cues other than those provided by the spectral differences between lights, it was found that mice could successfully discriminate pure-wavelength differences. Discrimination results shown in Fig. 5 illustrate the fact that mice can discriminate lights of about 400 nm and longer from a UV light, and that the reverse is also possible. The biology that underlies this capacity remains to be understood, but this result makes clear that coexpression of pigments in mouse cones cannot be complete and the same for all cones. A less-obvious point may also be drawn from this color vision experiment. The demonstration of color vision in the mouse required extensive training and testing of highly motivated animals. It seems quite likely that much briefer testing periods, as are typical of the rapid tests often used for screening of visual defects, would have failed to detect the presence of color vision in the mouse. Thus, it is worth keeping in mind that rapid visual screening tests may be inadequate for assessing relatively less-robust visual capacities that may persist after genetic manipulations or indeed be produced in this same fashion.
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ALTERATIONS IN MOUSE VISION CONSEQUENT
TO GENETIC MANIPULATIONS
A significant number of human visual diseases stem from alterations in the physiology of the photoreceptors. A robust literature body has emerged that examines the consequences of genetic manipulations that ultimately influence photoreceptor operation in the mouse. A significant fraction of these studies is intended to provide models for advancing understanding of human disease. A few examples of this work relevant to the theme of this chapter are reviewed here.
Targeted Deletions of Rods or Cones
Retinitis pigmentosa (RP) is a heterogeneous collection of hereditary disorders characterized by progressive retinal degeneration that first destroys rods and then later leads to progressive cone loss. A number of different mouse models have been developed in which there is a loss of rods early in development. These animals can be used to study the dynamics of change as a model for some types of RP and can be exploited to study cone function in the absence of rods. One such model is the rhodopsin knockout mouse, an animal with a mutation in exon 2 of the rod opsin gene. Rhodopsin knockout animals homozygous for the mutation (Rho−/−) show a complete loss of rod signal [54, 55]. Early in development, cone signals in these animals are normal (or even larger than normal), but subsequently they also degenerate, with a consequent loss of cone signal that is effectively complete by 3 months of age. Although the timing of photoreceptor loss is much compressed relative to what it is in humans, the sequence of degenerative change in these mice is similar to that seen in some cases of RP, and thus these mice may stand as a possible model for studies of therapeutic interventions.
Other genetic manipulations have also been shown to remove rod function, but they have differing consequences for cone function. For example, mice in which the gene for the rod transducin α-subunit and mice in which rod arrestin has been deleted both display changes in rod function. No rod responses can be recorded from the former animals, while in the latter mice rod signals are detectable but strikingly suppressed over extended time periods (a matter of hours) following intense photic stimulation [56]. Unlike the rhodopsin knockout mice, these animals do maintain their cone function and thus might be used to probe the nature of cone function following severe rod loss.
A variety of genetic manipulations have been effected that lead to the opposite photoreceptor outcome in mice—a loss of functional cones. In addition to isolating rods for study, such animals may also serve as models for the human condition congenital achromatopsia. One case targets a cyclic nucleotide-gated (CNG) channel that is found in cone photoreceptors (CNG3) but is absent from rods. ERG signals recorded from mice in which CNG3 has been deleted show normal rod responses, but cone signals are greatly diminished in size by 2 months of age, and they are absent entirely in adult animals [57]. The loss of cones does not apparently have an impact on normal rod function in these animals. Another manipulation impacting mouse cones but leaving rods unscathed involves the production of transgenic animals that have incorporated a DNA segment encoding an attenuated diphtheria toxin under the control of a cone opsin gene promoter [47]. Normal rod signals can be recorded from ganglion cells in such mice,
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but no analogous cone signals are detected, and their absence has allowed an examination of the nature of signaling pathways connecting rods to ganglion cells. Behavioral tests on these so-called coneless mice also allow an examination of the characteristics of rod-based vision at light levels at which cone signals are predominant in animals with normal retinas [8].
A variety of other genetic alterations has been exploited to selectively ablate photoreceptors. On occasion, it has proven useful to be able to remove both rods and cones. For example, in recent years it has been established that a subset of mammalian ganglion cells express the photosensitive pigment melanopsin, and that signals initiated in these cells are important for the photic regulation of circadian cycles [58]. Demonstrations that circadian responses remain intact in the complete absence of photoreceptors (coneless/rodless mice) provided one of the strong pieces of evidence supporting this conclusion [59].
Addition of New Cone Pigments
The examples given all involve deletion of function, and they were mostly designed to mimic some aspect of retinal pathology. At the same time, there are circumstances for which it would be useful to examine consequences that flow not from deletion but from the addition of neural components. Component addition occurs naturally during the evolution of visual systems, and thus such artificial manipulations could allow direct tests of ideas about visual system evolution. For example, the bcl2 gene inhibits naturally occurring cell death, and consequently when that gene is overexpressed in a transgenic mouse the number of neurons in the brain increases [39]. This general change includes an increase in ganglion cell number. Based on the idea that the number of ganglion cells serves to limit visual acuity, one might predict that such animals would show an increase in visual acuity. They do not, perhaps because considerable other neuronal rewiring also occurs as a result of component addition [39].
Examination of the phylogeny of opsins indicates that photopigments have frequently been gained and lost during vertebrate evolution, including a number of well-documented changes that have occurred during the diversification of primates [60]. One central question in the evolution of photopigments and the capacities they provide is whether the mere addition of a new pigment is sufficient to yield a change in visual capacity that increases fitness or whether other significant reorganization must occur in the visual system to support new visual capacities.
Several attempts have been made to use genetically altered mice to examine these possibilities. One case involved the production of a transgenic mouse that had incorporated a human L-cone opsin gene [61]. This new pigment was found to be abundantly expressed in mouse cones. In addition, ERG measurements indicated that the new pigment worked well, changing spectral sensitivity in the manner predicted by the spectral absorption properties of the L-cone pigment. Even more significant, in behavioral tests it was possible to demonstrate that these transgenic mice could utilize information supplied by their new pigment to support visual discrimination [62]. A comparison of the spectral sensitivity functions obtained from transgenic mice and wild-type controls is shown in Fig. 6, which shows that addition of the human L-cone pigment to the mouse retina produces a significant elevation of sensitivity to long-wavelength lights. This result suggests that