Melody Ying-Yu Huang

Comparison of infantile nystagmus syndrome in achiasmatic zebrafish and humans.

Infantile nystagmus syndrome (INS; formerly called congenital nystagmus) is an ocular motor disorder characterized by several typical nystagmus waveforms. To date, restrictions inherent to human research and the absence of a handy animal model have impeded efforts to identify the underlying mechanism of INS. Displaying INS‐like spontaneous eye oscillations, achiasmatic zebrafish belladonna (bel) mutants may provide new insights into the mystery of INS. In this study, we demonstrate that these spontaneous eye oscillations match the diagnostic waveforms of INS. As a result, zebrafish bel mutants can be used as an animal model for the study of INS. In zebrafish bel mutants, visual pathway abnormalities may contribute to the spontaneous nystagmus via an inverted signal to the pretectal area. We hypothesized that human INS may also be linked to visual pathway abnormalities (possibly underdiagnosed in INS patients) in a similar way.

Severity of Infantile Nystagmus Syndrome-Like Ocular Motor Phenotype Is Linked to the Extent of the Underlying Optic Nerve Projection Defect in Zebrafish belladonna Mutant

Infantile nystagmus syndrome (INS), formerly known as congenital nystagmus, is an ocular motor disorder in humans characterized by spontaneous eye oscillations (SOs) and, in several cases, reversed optokinetic response (OKR). Its etiology and pathomechanism is largely unknown, but misrouting of the optic nerve has been observed in some patients. Likewise, optic nerve misrouting, a reversed OKR and SOs with INS-like waveforms are observed in zebrafish belladonna (bel) mutants. We aimed to investigate whether and how misrouting of the optic nerve correlates with the ocular motor behaviors in bel larvae. OKR and SOs were quantified and subsequently the optic nerve fibers were stained with fluorescent lipophilic dyes. Eye velocity during OKR was reduced in larvae with few misprojecting optic nerve fibers and reversed in larvae with a substantial fraction of misprojecting fibers. All larvae with reversed OKR also displayed SOs. A stronger reversed OKR correlated with more frequent SOs. Since we did not find a correlation between additional retinal defects and ocular motor behavior, we suggest that axon misrouting is in fact origin of INS in the zebrafish animal model. Depending on the ratio between misprojecting ipsilateral and correctly projecting contralateral fibers, the negative feedback loop normally regulating OKR can turn into a positive loop, resulting in an increase in retinal slip. Our data not only give new insights into the etiology of INS but may also be of interest for studies on how the brain deals with and adapts to conflicting inputs.

Velocity storage mechanism in zebrafish larvae

•  Five‐day‐old zebrafish larvae already exhibit a velocity storage mechanism (VSM). •  The VSM in zebrafish larvae emerges earlier than a functional horizontal angular vestibular reflex. •  The VSM may be critical to ocular motor control in larval zebrafish.

Positive or Negative Feedback of Optokinetic Signals: Degree of the Misrouted Optic Flow Determines System Dynamics of Human Ocular Motor Behavior

PURPOSE The optokinetic system in healthy humans is a negative-feedback system that stabilizes gaze: slow-phase eye movements (i.e., the output signal) minimize retinal slip (i.e., the error signal). A positive-feedback optokinetic system may exist due to the misrouting of optic fibers. Previous studies have shown that, in a zebrafish mutant with a high degree of the misrouting, the optokinetic response (OKR) is reversed. As a result, slow-phase eye movements amplify retinal slip, forming a positive-feedback optokinetic loop. The positive-feedback optokinetic system cannot stabilize gaze, thus leading to spontaneous eye oscillations (SEOs). Because the misrouting in human patients (e.g., with a condition of albinism or achiasmia) is partial, both positive- and negative-feedback loops co-exist. How this co-existence affects human ocular motor behavior remains unclear. METHODS We presented a visual environment consisting of two stimuli in different parts of the visual field to healthy subjects. One mimicked positive-feedback optokinetic signals and the other preserved negative-feedback optokinetic signals. By changing the ratio and position of the visual field of these visual stimuli, various optic nerve misrouting patterns were simulated. Eye-movement responses to stationary and moving stimuli were measured and compared with computer simulations. The SEOs were correlated with the magnitude of the virtual positive-feedback optokinetic effect. RESULTS We found a correlation among the simulated misrouting, the corresponding OKR, and the SEOs in humans. The proportion of the simulated misrouting needed to be greater than 50% to reverse the OKR and at least greater than or equal to 70% to evoke SEOs. Once the SEOs were evoked, the magnitude positively correlated to the strength of the positive-feedback OKR. CONCLUSIONS This study provides a mechanism of how the misrouting of optic fibers in humans could lead to SEOs, offering a possible explanation for a subtype of infantile nystagmus syndrome (INS).

Afternystagmus in darkness after suppression of optokinetic nystagmus: an interaction of motion aftereffect and retinal afterimages

The afternystagmus that occurs in the dark after gaze fixation during optokinetic stimulation is directed in the opposite direction relative to the previous optokinetic stimulus. The mechanism responsible for such afternystagmus after suppression of optokinetic nystagmus (ASOKN) is unclear. Several hypotheses have been put forward to explain it, but none is conclusive. We hypothesized that ASOKN is driven by the interaction of two mechanisms: (1) motion-aftereffect (MAE)-induced eye movements and (2) retinal afterimages (RAIs) produced by fixation during the suppression of optokinetic nystagmus (OKN). We examined the correlation among ASOKN, MAE-induced eye movements, and RAIs in healthy subjects. Adapting stimuli consisted of moving random dot patterns and a fixation spot and their brightness was adjusted to induce different RAI durations. Test patterns were a stationary random dot pattern (to test for the presence of a MAE), a dim homogeneous background (to test for MAE driven eye movements), and a black background (to test for ASOKN and RAIs). MAEs were reported by 16 out of 17 subjects, but only 7 out of 17 subjects demonstrated MAE-induced eye movements. Importantly, ASOKN was only found when these seven subjects reported a RAI after suppression of OKN. Moreover, the duration of ASOKN was longer for high-brightness stimuli compared with low-brightness stimuli, just as RAIs persist longer with increasing brightness. We conclude that ASOKN results from the interaction of MAE-induced eye movements and RAIs.

Spontaneous nystagmus in the dark in an infantile nystagmus patient may represent negative optokinetic afternystagmus

Abnormal projection of the optic nerves to the wrong cerebral hemisphere transforms the optokinetic system from its usual negative feedback loop to a positive feedback loop with characteristic ocular motor instabilities including directional reversal of the optokinetic nystagmus (OKN) and spontaneous nystagmus, which are common features of infantile nystagmus syndrome (INS). Visual input plays a critical role in INS linked to an underlying optic nerve misprojection such as that often seen in albinism. However, spontaneous nystagmus often continues in darkness, making the visual, sensory-driven etiology questionable. We propose that sensorimotor adaptation during the constant nystagmus of patients in the light could account for continuing nystagmus in the dark. The OKN is a stereotyped reflexive eye movement in response to motion in the surround and serves to stabilize the visual image on the retina, allowing high resolution vision. Robust negative optokinetic afternystagmus (negative OKAN), referring to the continuous nystagmus in the dark with opposite beating direction of the preceding OKN, has been identified in various non-foveated animals. In humans, a robust afternystagmus in the same direction as previous smooth-pursuit movements (the eye’s continuous tracking and foveation of a moving target) induced by visual stimuli has been known to commonly mask negative OKAN. Some INS patients are often associated with ocular hypopigmentation, foveal hypoplasia, and compromised smooth pursuit. We identified an INS case with negative OKAN in the dark, in contrast to the positive afternystagmus in healthy subjects. We hypothesize that spontaneous nystagmus in the dark in INS patients may be attributable to sensory adaptation in the optokinetic system after a sustained period of spontaneous nystagmus with directional visual input in light.

Spontaneous alternation behavior in larval zebrafish

ABSTRACT Spontaneous alternation behavior (SAB) describes the tendency of animals to alternate their turn direction in consecutive turns. SAB, unlike other mnestic tasks, does not require any prior training or reinforcement. Because of its close correlation with the development and function of the hippocampus in mice, it is thought to reflect a type of memory. Adult zebrafish possess a hippocampus-like structure utilizing the same neurotransmitters as in human brains, and have thus been used to study memory. In the current study, we established SAB in zebrafish larvae at 6 days post-fertilization using a custom-made forced-turn maze with a rate of 57%. Our demonstration of the presence of SAB in larval zebrafish at a very early developmental stage not only provides evidence for early cognition in this species but also suggests its future usefulness as a high-throughput model for mnestic studies. Summary: Larval zebrafish show spontaneous alternation behavior, supporting the future use of zebrafish as a high-throughput pharmacological model in mnestic studies.

Effect of Gabapentin/Memantine on the Infantile Nystagmus Syndrome in the Zebrafish Model: Implications for the Therapy of Ocular Motor Diseases

Purpose Infantile nystagmus syndrome (INS) is a disorder characterized by typical horizontal eye oscillations. Due to the uncertain etiology of INS, developing specific treatments remains difficult. Single reports demonstrated, on limited measures, alleviating effects of gabapentin and memantine. In the current study, we employed the zebrafish INS model belladonna (bel) to conduct an in-depth study of how gabapentin and memantine interventions alleviate INS signs, which may further restore visual conditions in affected subjects. Moreover, we described the influence of both medications on ocular motor functions in healthy zebrafish, evaluating possible iatrogenic effects. Methods Ocular motor function and INS characteristics were assessed by eliciting optokinetic response, spontaneous nystagmus, and spontaneous saccades in light and in dark, in 5- to 6-day postfertilization bel larvae and heterozygous siblings. Single larvae were recorded before and after a 1-hour drug treatment (200 mM gabapentin/0.2 mM memantine). Results Both interventions significantly reduced nystagmus intensity (gabapentin: 59.98%, memantine: 39.59%). However, while the application of gabapentin affected all tested ocular motor functions, memantine specifically reduced nystagmus amplitude and intensity, and thus left controls completely unaffected. Finally, both drug treatments resulted in specific changes in nystagmus waveform and velocity. Conclusions Our study provides deeper insight into gabapentin and memantine treatment effect in the zebrafish INS model. Moreover, this study should establish zebrafish as a pharmacologic animal model for treating nystagmus and ocular motor disease, serving as a basis for future large-scale drug screenings.

Saccadic and Postsaccadic Disconjugacy in Zebrafish Larvae Suggests Independent Eye Movement Control

Spontaneous eye movements of zebrafish larvae in the dark consist of centrifugal saccades that move the eyes from a central to an eccentric position and postsaccadic centripetal drifts. In a previous study, we showed that the fitted single-exponential time constants of the postsaccadic drifts are longer in the temporal-to-nasal (T->N) direction than in the nasal-to-temporal (N->T) direction. In the present study, we further report that saccadic peak velocities are higher and saccadic amplitudes are larger in the N->T direction than in the T->N direction. We investigated the underlying mechanism of this ocular disconjugacy in the dark with a top-down approach. A mathematic ocular motor model, including an eye plant, a set of burst neurons and a velocity-to-position neural integrator (VPNI), was built to simulate the typical larval eye movements in the dark. The modeling parameters, such as VPNI time constants, neural impulse signals generated by the burst neurons and time constants of the eye plant, were iteratively adjusted to fit the average saccadic eye movement. These simulations suggest that four pools of burst neurons and four pools of VPNIs are needed to explain the disconjugate eye movements in our results. A premotor mechanism controls the synchronous timing of binocular saccades, but the pools of burst and integrator neurons in zebrafish larvae seem to be different (and maybe separate) for both eyes and horizontal directions, which leads to the observed ocular disconjugacies during saccades and postsaccadic drifts in the dark.