Nystagmus in patients with congenital stationary night blindness (CSNB) originates from synchronously firing retinal ganglion cells

Congenital nystagmus, involuntary oscillating small eye movements, is commonly thought to originate from aberrant interactions between brainstem nuclei and foveal cortical pathways. Here, we investigated whether nystagmus associated with congenital stationary night blindness (CSNB) results from primary deficits in the retina. We found that

Motor coding in floccular climbing fibers

The climbing fibers (CFs) that project from the dorsal cap of the inferior olive (IO) to the flocculus of the cerebellar cortex have been reported to be purely sensory, encoding "retinal slip." However, a clear oculomotor projection from the nucleus prepositus hypoglossi (NPH) to the IO has been shown. We therefore studied the sensorimotor information that is present in the CF signal. We presented rabbits with visual motion noise stimuli to break up the tight relation between instantaneous retinal slip and eye movement. Strikingly, the information about the motor behavior in the CF signal more than doubled that of the sensory component and was time-locked more tightly. The contribution of oculomotor signals was independently confirmed by analysis of spontaneous eye movements in the absence of visual input. The motor component of the CF code is essential to distinguish unexpected slip from self-generated slip, which is a prerequisite for proper oculomotor learning. Copyrigh

Three-dimensional optokinetic eye movements in the C57BL/6J mouse

PURPOSE. To study three-dimensional optokinetic eye movements of wild-type C57BL/6J mice, the most commonly used mouse in oculomotor physiology. Optokinetic eye movements are reflexive eye movements that use visual feedback to minimize image motion across the retina. These gaze-stabilizing reflexes are a prominent model system for studying motor control and learning. They are three dimensional and consist of a horizontal, vertical, and torsional component. METHODS. Eye movements were evoked by sinusoidally rotating a virtual sphere of equally spaced dots at six frequencies (0.1-1 Hz), with a fixed amplitude of 5°. Markers were applied to the mouse eye and video oculography was used to record its movements in three dimensions. In addition, marker tracking was compared with conventional pupil tracking of horizontal optokinetic eye movements. RESULTS. Gains recorded with marker and pupil tracking are not significantly different. Optokinetic eye movements in mice are equally well developed in all directions and have a uniform input- output relation for all stimuli, including stimuli that evoke purely torsional eye movements, with gains close to unity and minimal phase differences. CONCLUSIONS. Optokinetic eye movements of C57Bl6 mice largely compensate for image motion over the retina, regardless of stimulus orientation. All responses are frequency-velocity dependent: gains decrease and phase lags increase with increasing stimulus frequency. Mice show strong torsional responses, with high gains at low stimulus frequency

Selective impairment of the cerebellar C1 module involved in rat hind limb control reduces step-dependent modulation of cutaneous reflexes

The cerebellum is divided into multiple parasagittally organized modules, which are thought to represent functional entities. How individual modules participate in cerebellar control of complex movements such as locomotion remains largely unknown. To a large extent, this is caused by the inability to study the contribution of individual modules during locomotion. Because of the architecture of modules, based on narrow, elongated cortical strips that may be discontinuous in the rostrocaudal direction, lesion of a complete module, without affecting neighboring modules, has not been possible. Here, we report on a new method for inducing a selective dysfunction of spatially separated parts of a single module using a small cortical injection of a retrogradely transported neurotoxin, cholera toxin b-subunit-saporin. We show that such a local injection into the C1 module results in climbing fiber and partial mossy fiber deafferentation of functionally related areas of this module, thereby resulting in a severe impairment of the whole module without affecting neighboring modules. A subsequent functional analysis indicates that such an impairment of the hindlimb part of the C1 module did not have a significant impact on skilled walking or overall stepping pattern. However, the modulation of cutaneously induced reflexes during stepping was severely diminished. We propose that the C1 module is specifically involved in the adaptive control of reflexes. Copyrigh

Size does not always matter: Ts65Dn down syndrome mice show cerebellum-dependent motor learning deficits that cannot be rescued by postnatal SAG treatment

Humans with Down syndrome (DS) and Ts65Dn mice both show a reduced volume of the cerebellum due to a significant reduction in the density of granule neurons. Recently, cerebellar hypoplasia in Ts65Dn mice was rescued by a single treatment with SAG, an agonist of the Sonic hedgehog pathway, administered on the day of birth. In addition to normalizing cerebellar morphology, this treatment restored the ability to learn a spatial navigation task, which is associated with hippocampal function. It is not clear to what extent this improved performance results from restoration of the cerebellar architecture or a yet undefined role of Sonic hedgehog (Shh) in perinatal hippocampal development. The absence of a clearly demonstrated deficit in cerebellar function in trisomic mice exacerbates the problem of discerning how SAG acts to improve learning and memory. Here we show that phase reversal adaptation and consolidation of the vestibulo-ocular reflex is significantly impaired in Ts65Dn mice, providing for the first time a precise characterization of cerebellar functional deficits in this murine model of DS. However, these deficits do not benefit from the normalization of cerebellar morphology following treatment with SAG. Together with the previous observation that the synaptic properties of Purkinje cells are also unchanged by SAG treatment, this lack of improvement in a region-specific behavioral assay supports the possibility that a direct effect of Shh pathway stimulation on the hippocampus might explain the benefits of this potential approach to the improvement of cognition in DS

Vestibular role of KCNQ4 and KCNQ5 K+ channels revealed by mouse models

The function of sensory hair cells of the cochlea and vestibular organs depends on an influx of K+ through apical mechanosensitive ion channels and its subsequent removal over their basolateral membrane. The KCNQ4 (Kv7.4) K+ channel, which is mutated in DFNA2 human hearing loss, is expressed in the basal membrane of cochlear outer hair cells where it may mediate K+ efflux. Like the related K+ channel KCNQ5 (Kv7.5), KCNQ4 is also found at calyx terminals ensheathing type I vestibular hair cells where it may be localized pre- or postsynaptically. Making use of Kcnq4-/- mice lacking KCNQ4, as well as Kcnq4dn/dn and Kcnq5dn/dn mice expressing dominant negative channel mutants, we now show unambiguously that in adult mice both channels reside in postsynaptic calyx-forming neurons, but cannot be detected in the innervated hair cells. Accordingly, whole cell currents of vestibular hair cells did not differ between genotypes. Neither Kcnq4-/-, Kcnq5 dn/dn nor Kcnq4-/-/ Kcnq5dn/dn double mutant mice displayed circling behavior found with severe vestibular impairment. However, a milder form of vestibular dysfunction was apparent from altered vestibulo- ocular reflexes in Kcnq4-/-/Kcnq5dn/dn and Kcnq4-/- mice. The larger impact of KCNQ4 may result from its preferential expression in central zon

Loss of Gap Junction Delta-2 (GJD2) gene orthologs leads to refractive error in zebrafish

Myopia is the most common developmental disorder of juvenile eyes, and it has become an increasing cause of severe visual impairment. The GJD2 locus has been consistently associated with myopia in multiple independent genome-wide association studies. However, despite the strong genetic evidence, little is known about the functional role of GJD2 in refractive error development. Here, we find that depletion of gjd2a (Cx35.5) or gjd2b (Cx35.1) orthologs in zebrafish, cause changes in the biometry and refractive status of the eye. Our immunohistological and scRNA sequencing studies show that Cx35.5 (gjd2a) is a retinal connexin and its depletion leads to hyperopia and electrophysiological changes in the retina. These findings support a role for Cx35.5 (gjd2a) in the regulation of ocular biometry. Cx35.1 (gjd2b) has previously been identified in the retina, however, we found an additional lenticular role. Lack of Cx35.1 (gjd2b) led to a nuclear cataract that triggered axial elongation. Our results provide functional evidence of a link between gjd2 and refractive error.</p