We have isolated a dominant mutation, night blindness a (nba) , that causes a slow retinal degeneration in zebrafish. Heterozygous nba fish have normal vision through 2–3 months of age but subsequently become night blind. By 9.5 months of age, visual sensitivity of affected fish may be decreased more than two log units, or 100-fold, as measured behaviorally. Electroretinographic (ERG) thresholds of mutant fish are also raised significantly, and the ERG b-wave shows a delayed implicit time. These defects are due primarily to a late-onset photoreceptor cell degeneration involving initially the rods but eventually the cones as well. Homozygous nba fish display an early-onset neuronal degeneration throughout the retina and elsewhere in the central nervous system. As a result, animals develop with small eyes and die by 4–5 days postfertilization (pf). These latter data indicate that the mutation affecting nba fish is not in a photoreceptor cell-specific gene.

We have recently developed a behavioral assay, based on the escape response of fish to a threatening object, to analyze quantitatively the visual sensitivity of zebrafish. During the course of dark adaptation, we measure the threshold light intensity required to evoke an escape response. Under a normal light–dark (LD) cycle, thresholds for both the cone and rod systems are considerably lower in late afternoon hours than in early morning hours. Over a period of 24 h, zebrafish are most sensitive to visual stimuli prior to light off and least sensitive prior to light on. Under conditions of constant illumination, this rhythm of visual sensitivity persists for several days but is gradually lost. In constant light (LL), the rhythm persists 1–2 days; thereafter, visual thresholds at all times of the day converge at a level similar to thresholds measured in late afternoon hours in control animals. In constant darkness (DD), the rhythm persists at least 5 days; thereafter, it dampens to a level about a half-log unit less sensitive to that measured in the late afternoon hours in control animals. These data suggest that visual sensitivity in zebrafish is regulated by an endogenous circadian clock which functions to decrease the visual sensitivity.

The visual sensitivity of zebrafish in which the retinal dopaminergic interplexiform cells (DA-IPCs) were destroyed by 6-hydroxydopamine was measured behaviorally. During the first 6–8 min of dark adaptation, visual thresholds of DA-IPC-depleted animals were similar to those of control animals. Thereafter, their visual thresholds were elevated so that by 14–18 min of dark adaptation, they were 2–3 log units above those of control animals. In DA-IPC-depleted animals, the electroretinogram was normal in terms of light sensitivity and waveform, but the light threshold for eliciting a ganglion cell discharge was raised by 1.8 log units as compared with control animals. No obvious rod system function was detected in DA-IPC-depleted animals as measured behaviorally. Partial rescue of the behavioral visual sensitivity loss in DA-IPC-depleted animals occurred when dopamine or a long-acting dopamine agonist (2-amino-6, 7-dihydroxy-1, 2, 3, 4-tetrahydronaphthalene hydrobromide) were injected intraocularly. Our data suggest that the principal visual defect shown by DA-IPC-depleted animals is attributable to effects occurring in the inner retina, mainly on rod signals. We also show that dopamine is involved in mediating the effect of the circadian clock on visual sensitivity.

We describe here a dominant mutation,night blindness b(nbb), which causes an age-related visual system defect in zebrafish. At 4–5 months of age, dark-adaptednbb^+/−mutants show abnormal visual threshold fluctuations when measured behaviorally. Light sensitizes the animals; thus early dark adaptation ofnbb^+/−fish is normal. After 2 hr of dark adaptation, however, visual thresholds ofnbb^+/−mutants are raised on average 2–3 log units, and rod system function is not detectable. Electroretinograms recorded fromnbb^+/−mutants are normal, but ganglion cell thresholds are raised in prolonged darkness, suggesting an inner retinal defect. The visual defect ofnbb^+/−mutants may be likely caused by an abnormal olfactoretinal centrifugal innervation; innbb^+/−mutants, the olfactoretinal centrifugal projection to the retina is disrupted, and the number of retinal dopaminergic interplexiform cells is reduced. A similar visual defect as shown bynbb^+/−mutants is observed in zebrafish in which the olfactory epithelium and olfactory bulb have been excised. Homozygousnbbfish display an early onset neural degeneration throughout the CNS and die by 7–8 d of age.