Ординатура / Офтальмология / Английские материалы / Eye, Retina, and Visual System of the Mouse_Chalupa, Williams_2008

2006) on a task requiring mice to swim to a hidden platform, the location of which is predicted by a visual cue displayed on a computer screen (see figure 2.1B). Mice were trained for eight trials per day to discriminate between a low spatial frequency (0.17 c/deg) sinusoidal vertical grating (S+), and a gray screen (S−). The percentage of correct choices on each day was used as a measure of visual ability, with 70% correct set as the learning criterion. Using this procedure, Wong and Brown (2006) tested 14 strains of mice with different visual abilities as predicted by the physiology of their visual system (figure 2.2). Mice with reportedly normal vision at 3–4 months of age (129S1/SvImJ, C57BL/6J, DBA/2J) performed very well on this task, and mice with poor visual abilities due to albinism (AKR/J, A/J, BALB/cByJ, BALB/ cJ) performed worse than mice with normal vision except AKR/J, which performed as well as mice with normal vision. Mice with retinal degeneration (C3H/HeJ, FVB/NJ, MOLF/EiJ, SJL/J) performed at chance levels, as did mice with uncharacterized visual abilities (CAST/EiJ, SM/J, SPRET/EiJ).

Pattern Discrimination Behavioral tasks have also been used to study pattern discrimination in mice. Using a modified version of the eight-arm radial maze, AmmassariTeule and de Marsanich (1996) trained mice to collect food from four baited arms displaying distinctive visual patterns. CD-1 mice adopted a 45-degree angle turn strategy to locate the food instead of associating the visual patterns with the presence of food; however, C57BL/6NCrlBR and DBA/ 2NCrlBR mice successfully learned this pattern discrimination task, and there was no difference in performance between these strains (Passino and Ammassauri-Teule, 1999). The results of these experiments indicate there are strain differences in visual pattern discrimination ability, but discrimination ability could have been masked by the complexity of the task.

Using escape from an eight-arm water maze modified into a T-maze, Hyde and Denenberg (1999) found that BXSB mice could learn to discriminate between different pairs of visual patterns and could reach a criterion of 80% correct after 5 days of training with 10 trials per day with each of the nine pattern discrimination tasks (see figure 2.1C). On a probe trial in which all six patterns were available in the eight-arm maze, the mice showed a preference for the S+ over the S− patterns, indicating they were capable of complex pattern discrimination. The modified radial arm maze pro-

tocol employed by Hyde and Denenberg (1999) exploited the natural inclination for the mouse to escape from water, and the results on this task suggest that escape from water is a more successful motivation than food reward as used by Passino and Ammassauri-Teule (1999) for visual discrimination tasks in mice.

Balogh et al. (1998, 1999) found that C57BL/6J, ectopic BXSB mice, which have neocortical malformations and are used as a model of developmental learning difficulties, nonectopic BXSB mice, and 129/SvEvTac mice, which have the pink-eyed dilution allele, could be trained to discriminate between horizontal and vertical patterns in a water-escape T maze (see figure 2.1D). The 129/SvEvTac mice, however, did not perform as well as the BXSB and C57BL/6J strains, presumably because of deficits in visual acuity.

Using the visual water box, Wong and Brown (2006) trained mice of 14 strains to discriminate between vertical and horizontal gratings. Mice with reportedly normal vision (129S1/SvImJ, C57BL/6J, DBA/2J) were capable of pattern discrimination as they reached the criterion of 70% correct within the 8 days of testing. Albino mice (AKR/J, A/J, BALB/cByJ, and BALB/cJ) performed worse than mice with normal vision, taking longer to reach criterion, while mice with retinal degeneration (C3H/HeJ, FVB/NJ, MOLF/EiJ and SJL/J) and mice with uncharacterized visual abilities (CAST/EiJ, SM/J and SPRET/EiJ) performed at chance levels, a finding indicating they could not differentiate between the vertical and horizontal grating patterns (see figure 2.2).

Visual Acuity Visual acuity is the ability to detect small distances separating two points, and the threshold for visual acuity is reached when the observer can no longer determine a separation between the two points. Spatial frequency is defined by how rapidly a stimulus changes across space and is measured in term of cycles per degree (c/deg). For a grating stimulus, spatial frequency refers to the frequency with which the grating repeats itself per degree of visual angle (Goldstein, 1999).

One procedure for determining the visual acuity of mice is a two-alternative forced choice apparatus (see figure 2.1E) consisting of a start box that leads to a choice area with two parallel alleys, each with a food cup and a stimulus card at the end (Wiesenfeld and Branchek, 1976). Food-deprived mice were trained for 80 trials per day to discriminate

Figure 2.2 Mean (± SEM) percent correct for each of the 14 mouse strains on each of the eight days of testing in the visual detection task (left column) and the pattern discrimination task (middle column) and calculation of visual acuity threshold from mean (± SEM) percent correct for each strain on each of the eight spatial

frequencies that were tested in the visual acuity task (right column). For clarity, mice were grouped into those with normal vision (A), albinos (B), those with retinal degeneration (C), and those of unknown visual abilities (D). (From Wong and Brown, 2006, p. 394.)

129S1/SvImJ

C57BL/6J

DBA/2J

spatial frequency (c/deg)

spatial frequency (c/deg)

CAST/Ei

SM/J

SPRET/Ei

between pairs of vertical and horizontal stripes of the same spatial frequency (0.15 c/deg) using a food reward. During testing, the spatial frequencies were increased or decreased by 0.1 c/deg until the mouse reached a criterion of 90% correct choices. Using this protocol, Gianfranceschi et al. (1999) determined that the visual acuity of C57BL/6J mice was between 0.5 and 0.6 c/deg.

Using their visual water box, Prusky, West, and Douglas (2000a) trained mice as young as 40 days of age to swim to an escape platform signaled by a sinusoidal wave grating (S+) versus a homogeneous gray screen (S−). During testing, the spatial frequency of the grating was increased by one cycle at a time until the mouse made an incorrect response. A visual acuity threshold was obtained when the mouse performed below 70% correct at a particular spatial frequency. With this protocol, it was determined that C57BL/6J mice had a visual acuity of 0.51 c/deg.

Different test procedures, however, result in different visual acuity thresholds in the same strains of mice. Wong and Brown (2006) modified the procedure of Prusky et al. (2000a) by employing a standard set of eight spatial frequencies that were tested daily for 8 days. Using this procedure, mice with no known visual defects (129S1/SvImJ, C57BL/6J, DBA/2J) and two albino strains (AKR/J and BALB/cByJ) had defined visual acuity thresholds of 0.375, 0.245, 0.375, 0.375, and 0.320 c/deg, respectively. The other albino strains (A/J, BALB/cByJ, BALB/cJ) did not reach the criterion of 70% correct and so had thresholds below 0.17 c/ deg (the largest stimulus used), whereas mice with retinal degeneration (C3H/HeJ, FVB/NJ, MOLF/EiJ, SJL/J) and mice with uncharacterized visual abilities (CAST/EiJ, SM/J, SPRET/EiJ) performed at chance levels. Using the same apparatus and procedure, however, Wong and Brown (2007) determined the visual acuity of 6-month-old C57BL/6J mice as 0.48 c/deg and that of DBA/2J mice as 0.54 c/deg.

There are also age-related differences in visual acuity within strains. As DBA/2J mice age, they develop glaucomalike visual defects, and after 12 months of age they perform at chance, and no visual acuity threshold can be measured. C57BL/6J mice, on the other hand, retain their visual ability to at least 24 months of age, when it was measured at 0.38 c/ deg (Wong and Brown, 2007) (figure 2.3). Because BALB/ cByJ albino mice also show age-related retinal degeneration (Danciger et al., 2000, 2003), measurements of visual acuity obtained in young mice (3–6 months) may change as these mice age (see discussion in Wong and Brown, 2007).

Using the virtual optokinetic system, which records head movements in response to the “movement” of computergenerated vertical gratings in an optical cylinder (see figure 2.1F), Prusky et al. (2004) determined that C57BL/6J mice had a visual acuity threshold of 0.39 c/deg. The virtual optokinetic system is much less time-consuming than the visual

water box, as it can provide reliable, consistent visual acuity thresholds in a single 25to 40-minute test. Because it measures a reflex response and does not rely on swimming ability or involve the stress of immersion in water, as occurs with the visual water box, it seems to be a better way of measuring visual acuity, but this method is less sensitive than the visual water box in determining visual acuity thresholds in mice. Using an optokinetic drum, Abdeljalil et al. (2005) determined the visual acuity of C57BL/6J mice as 0.26 c/deg under scotopic conditions and 0.52 c/deg under photopic conditions, while 129/SvPas mice had a visual acuity threshold of 0.52 c/deg under both conditions. These measures are only crude estimates, because the steps were 0.26, 0.52, and 1.25 c/deg. CD-1 albino mice and C3HeB/FeJ mice, which have retinal degeneration, had no observable optomotor responses; thus their visual acuity was not measurable.

In general, behavioral tests indicate that mice without visual defects (C57BL/6J) have a visual acuity between 0.5 and 0.6 c/deg and albino mice have reduced visual acuity thresholds of 0.17–0.38 c/deg (Gianfranceschi et al., 1999; Prusky et al., 2000a; Sinex et al., 1979; Wong and Brown, 2006). This is relatively low compared to the visual acuity of 0.92 c/deg for the rat (Prusky et al., 2000a), 6–7 c/deg for cats (Blake et al., 1974; Smith, 1936), and 60 c/deg for humans (Oyster, 1999).

Hearing

The most sensitive and objective measure of hearing ability in mice is the measurement of the auditory evoked brainstem response (ABR), which is an evoked potential measurement of activity in the auditory nerve, fiber tracts, and nuclei within the auditory brainstem pathways. The ABR is a useful measure for determining hearing sensitivity in mice (Zhou et al., 2006), because analysis of ABR threshold, amplitude, and latency provides important information regarding the peripheral hearing status and the integrity of the brainstem pathways. The ABR is elicited using clicks and tones of varying frequency and intensity that are channeled through the ear canals of the mouse. Measurement of the ABR requires mice to be deeply anesthetized and subcutaneously implanted with a recording electrode below the pinna, superficial to the auditory nerve. Various clicks and tones ranging from 8 to 32 kHz are presented through earphones on both ears and the loudness of each tone is varied in 5-dB steps. Auditory nerve responses are filtered through a preamplifier and amplified 25,000–100,000 fold. The ABR is presented as a waveform for each stimulus, and an auditory threshold is defined as the lowest stimulus intensity that will evoke a normal ABR wave.

In a survey of 80 inbred mouse strains, Zheng et al. (1999) found that 61 strains had normal ABR thresholds and 19