Loss of α-9 Nicotinic Acetylcholine Receptor Subunit Predominantly Results in Impaired Postural Stability Rather Than Gaze Stability

The functional role of the mammalian efferent vestibular system (EVS) is not fully understood. One proposal is that the mammalian EVS plays a role in the long-term calibration of central vestibular pathways, for example during development. Here to test this possibility, we studied vestibular function in mice lacking a functional α9 subunit of the nicotinic acetylcholine receptor (nAChR) gene family, which mediates efferent activation of the vestibular periphery. We focused on an α9 (−/−) model with a deletion in exons 1 and 2. First, we quantified gaze stability by testing vestibulo-ocular reflex (VOR, 0.2–3 Hz) responses of both α9 (−/−) mouse models in dark and light conditions. VOR gains and phases were comparable for both α9 (−/−) mutants and wild-type controls. Second, we confirmed the lack of an effect from the α9 (−/−) mutation on central visuo-motor pathways/eye movement pathways via analyses of the optokinetic reflex (OKR) and quick phases of the VOR. We found no differences between α9 (−/−) mutants and wild-type controls. Third and finally, we investigated postural abilities during instrumented rotarod and balance beam tasks. Head movements were quantified using a 6D microelectromechanical systems (MEMS) module fixed to the mouse’s head. Compared to wild-type controls, we found head movements were strikingly altered in α9 (−/−) mice, most notably in the pitch axis. We confirmed these later results in another α9 (−/−) model, with a deletion in the exon 4 region. Overall, we conclude that the absence of the α9 subunit of nAChRs predominately results in an impairment of posture rather than gaze.

Visually Evoked Postural Responses (VEPRs) in Children with Vestibular Migraine

Vestibular migraine (VM) is the most common cause of episodic vertigo in children. Vertigo, nausea, dizziness and unsteadiness are often complained of by children with migraine, which can precede, follow or be present simultaneously with headache. The aim of this study was to use posturography to investigate the visually evoked postural responses (VEPRs) of children with VM and compare them to data obtained from children with primary headache (M) and controls (C). Twenty children diagnosed as affected by VM, nineteen children with M without aura and twenty healthy subjects were recruited in this cross-sectional study. Posturography was performed by a standardized stabilometric force-platform (Svep-Politecnica) in the following conditions: open eyes (OE), closed eyes (CE) and during full-field horizontal optokinetic stimulation (OKN-S). Electronystagmography was performed simultaneously to analyze optokinetic reflex parameters. In the OE condition, no difference was found between groups with respect to body sway area. In contrast, this parameter increased in the two pathological groups with respect to controls in the CE condition. The optokinetic stimulations also induced a similar increase of body sway area in the M group relative to controls, but a further increase was elicited in the VM group. Electronystagmographic recording also revealed different optokinetic reflex parameters in the latter groups. This study disclosed an abnormal sensitivity of children with M and VM to full-field moving scenes and a consequent destabilization of posture, as documented by the abnormal VEPRs. Children with VM were particularly exposed to this risk. Possible clinical implications of these findings are discussed.

Image motion with color contrast suffices to elicit an optokinetic reflex in Xenopus laevis tadpoles

The optokinetic reflex is a closed-loop gaze-stabilizing ocular motor reaction that minimizes residual retinal image slip during vestibulo-ocular reflexes. In experimental isolation, the reflex is usually activated by motion of an achromatic large-field visual background with strong influence of radiance contrast on visual motion estimation and behavioral performance. The presence of color in natural environments, however, suggests that chromatic cues of visual scenes provide additional parameters for image motion detection. Here, we employed Xenopus laevis tadpoles to study the influence of color cues on the performance of the optokinetic reflex and multi-unit optic nerve discharge during motion of a large-field visual scene. Even though the amplitude of the optokinetic reflex decreases with smaller radiance contrast, considerable residual eye movements persist at the ‘point of equiluminance’ of the colored stimuli. Given the color motion preferences of individual optic nerve fibers, the underlying computation potentially originates in retinal circuits. Differential retinal ganglion cell projections and associated ocular motor signal transformation might further reinforce the color dependency in conceptual correspondence with head/body optomotor signaling. Optokinetic reflex performance under natural light conditions is accordingly influenced by radiance contrast as well as by the color composition of the moving visual scene.

Discordant phenotypes in twins with infantile nystagmus

Infantile nystagmus (IN) may result from aetiologies including albinism and FRMD7 mutations. IN has low prevalence, and twins with IN are rare. Whilst discordant presentation has been previously reported for IN, we present for the first time the comprehensive assessment of diagnostically discordant monozygotic twins. From a cohort of over 2000 patients, we identified twins and triplets discordant for nystagmus. Using next-generation sequencing, high-resolution infra-red pupil tracking and optical coherence tomography, we characterised differences in genotype and phenotype. Monozygotic twins (n = 1), dizygotic twins (n = 3) and triplets (n = 1) were included. The monozygotic twins had concordant TYR variants. No causative variants were identified in the triplets. Dizygotic twins had discordant variants in TYR, OCA2 and FRMD7. One unaffected co-twin demonstrated sub-clinical nystagmus. Foveal hypoplasia (FH) was noted in four of five probands. Both co-twins of the monozygotic pair and triplets displayed FH. In three families, at least one parent had FH without nystagmus. FH alone may be insufficient to develop nystagmus. Whilst arrested optokinetic reflex pathway development is implicated in IN, discordant twins raise questions regarding where differences in development have arisen. In unaffected monozygotes therefore, genetic variants may predispose to oculomotor instability, with variable expressivity possibly responsible for the discordance observed.

Long term measures of vestibulo-ocular reflex function in high level male gymnasts and its possible role during context specific rotational tasks

In a prior publication, we described a previously unknown eye movement phenomenon during the execution of actively performed multiaxial rotations in high level gymnasts. This phenomenon was consistently observed during the phase of fast free flight rotations and was marked by a prolonged and complete suppression of nystagmus and gaze stabilizing “environment referenced eye movements” (EREM; such as the vestibulo-ocular reflex, optokinetic reflex, smooth pursuit and others). Instead, these eye movements were coupled with intersegmental body movements. We have therefore called it “spinal motor-coupled eye movements” (SCEM) and have interpreted the phenomenon to likely be caused by anti-compensatory functions of more proprioceptive mediated reflexes and perhaps other mechanisms (e.g., top-down regulation as part of a motor plan) to effectively cope with a new-orientation in space, undisturbed by EREM functions. In the phase before landing, the phenomenon was replaced again by the known gaze-stabilizing EREM functions. The present study specifically evaluated long-term measures of vestibulo-ocular reflex functions (VOR) in high level gymnasts and controls during both passively driven monoaxial rotations and context-specific multiaxial somersault simulations in a vestibular lab. This approach provided further insights into the possible roles of adaptive or mental influences concerning the VOR function and how they are associated with the described phenomenon of SCEM. Results showed high inter-individual variability of VOR function in both gymnasts and controls, but no systematic adaptation of the VOR in gymnasts, neither compared to controls nor over a period of three years. This might generally support the hypothesis that the phenomenon of SCEM might indeed be driven more by proprioceptively mediated and situationally dominant eye movement functions than by adaptative processes of the VOR.

Long term visuo-vestibular mismatch in freely behaving mice differentially affects gaze stabilizing reflexes

The vestibulo-ocular reflex (VOR) and the optokinetic reflex (OKR) work synergistically to stabilize gaze in response to head movements. We previously demonstrated that a 14-day visuo-vestibular mismatch (VVM) protocol applied in freely behaving mice decreased the VOR gain. Here, we show for the first time that the OKR gain is also reduced and report on the recovery dynamics of both VOR and OKR after the end of the VVM protocol. Using sinusoidally-modulated stimulations, the decreases in VOR and OKR were found to be frequency-selective with larger reductions for frequencies < 0.5 Hz. Constant-velocity OKR stimulation tests demonstrated that the persistent components of the OKR were not modified while the transient, initial responses were. To identify the signals driving VOR and OKR reductions, we compared the responses of mice exposed to a high-contrast and no-contrast VVM. Despite being more robust in the high-contrast conditions, reductions were largely comparable and recovered with a similar time course. An analysis that directly compared VOR and OKR responses revealed that, alterations in the VOR were of significantly larger amplitude with significantly slower dynamics of recovery. Our findings are evidence for a frequency-selective influence of visual signals in the tuning of gaze stabilizing reflexes in normal mice.

Cadherins regulate nuclear topography and function of developing ocular motor circuitry

In the vertebrate central nervous system, groups of functionally related neurons, including cranial motor neurons of the brainstem, are frequently organised as nuclei. The molecular mechanisms governing the emergence of nuclear topography and circuit function are poorly understood. Here we investigate the role of cadherin-mediated adhesion in the development of zebrafish ocular motor (sub)nuclei. We find that developing ocular motor (sub)nuclei differentially express classical cadherins. Perturbing cadherin function in these neurons results in distinct defects in neuronal positioning, including scattering of dorsal cells and defective contralateral migration of ventral subnuclei. In addition, we show that cadherin-mediated interactions between adjacent subnuclei are critical for subnucleus position. We also find that disrupting cadherin adhesivity in dorsal oculomotor neurons impairs the larval optokinetic reflex, suggesting that neuronal clustering is important for co-ordinating circuit function. Our findings reveal that cadherins regulate distinct aspects of cranial motor neuron positioning and establish subnuclear topography and motor function.

Characterization of the Frmd7 Knock-Out Mice Generated by the EUCOMM/COMP Repository as a Model for Idiopathic Infantile Nystagmus (IIN)

In this study, we seek to exclude other pathophysiological mechanisms by which Frmd7 knock-down may cause Idiopathic Infantile Nystagmus (IIN) using the Frmd7.tm1a and Frmd7.tm1b murine models. We used a combination of genetic, histological and visual function techniques to characterize the role of Frmd7 gene in IIN using a novel murine model for the disease. We demonstrate that the Frmd7.tm1b allele represents a more robust model of Frmd7 knock-out at the mRNA level. The expression of Frmd7 was investigated using both antibody staining and X-gal staining confirming previous reports that Frmd7 expression in the retina is restricted to starburst amacrine cells and demonstrating that X-gal staining recapitulates the expression pattern in this model. Thus, it offers a useful tool for further expression studies. We also show that gross retinal morphology and electrophysiology are unchanged in these Frmd7 mutant models when compared with wild-type mice. High-speed eye-tracking recordings of Frmd7 mutant mice confirm a specific horizontal optokinetic reflex defect. In summary, our study confirms the likely role for Frmd7 in the optokinetic reflex in mice mediated by starburst amacrine cells. We show that the Frmd7.tm1b model provides a more robust knock-out than the Frmd7.tm1a model at the mRNA level, although the functional consequence is unchanged. Finally, we establish a robust eye-tracking technique in mice that can be used in a variety of future studies using this model and others. Although our data highlight a deficit in the optiokinetic reflex as a result of the starburst amacrine cells in the retina, this does not rule out the involvement of other cells, in the brain or the retina where Frmd7 is expressed, in the pathophysiology of IIN.

Cadherins regulate nuclear topography and function of developing ocular motor circuitry

In the vertebrate central nervous system, groups of functionally-related neurons, including cranial motor neurons of the brainstem, are frequently organised as nuclei. The molecular mechanisms governing the emergence of nuclear topography and circuit function are poorly understood. Here we investigate the role of cadherin-mediated adhesion in the development of zebrafish ocular motor (sub)nuclei. We find that developing ocular motor (sub)nuclei differentially express classical cadherins. Perturbing cadherin function in these neurons results in distinct defects in neuronal positioning, including scattering of dorsal cells and defective contralateral migration of ventral subnuclei. In addition, we show that cadherin-mediated interactions between adjacent subnuclei are critical for subnucleus position. We also find that disrupting cadherin adhesivity in dorsal oculomotor neurons impairs the larval optokinetic reflex, suggesting that neuronal clustering is important for co-ordinating circuit function. Our findings reveal that cadherins regulate distinct aspects of cranial motor neuron positioning and establish subnuclear topography and motor function.