Zebrafish dscaml1 Deficiency Impairs Retinal Patterning and Oculomotor Function.
ABSTRACT: Down syndrome cell adhesion molecules (dscam and dscaml1) are essential regulators of neural circuit assembly, but their roles in vertebrate neural circuit function are still mostly unexplored. We investigated the functional consequences of dscaml1 deficiency in the larval zebrafish (sexually undifferentiated) oculomotor system, where behavior, circuit function, and neuronal activity can be precisely quantified. Genetic perturbation of dscaml1 resulted in deficits in retinal patterning and light adaptation, consistent with its known roles in mammals. Oculomotor analyses revealed specific deficits related to the dscaml1 mutation, including severe fatigue during gaze stabilization, reduced saccade amplitude and velocity in the light, greater disconjugacy, and impaired fixation. Two-photon calcium imaging of abducens neurons in control and dscaml1 mutant animals confirmed deficits in saccade-command signals (indicative of an impairment in the saccadic premotor pathway), whereas abducens activation by the pretectum-vestibular pathway was not affected. Together, we show that loss of dscaml1 resulted in impairments in specific oculomotor circuits, providing a new animal model to investigate the development of oculomotor premotor pathways and their associated human ocular disorders.SIGNIFICANCE STATEMENT Dscaml1 is a neural developmental gene with unknown behavioral significance. Using the zebrafish model, this study shows that dscaml1 mutants have a host of oculomotor (eye movement) deficits. Notably, the oculomotor phenotypes in dscaml1 mutants are reminiscent of human ocular motor apraxia, a neurodevelopmental disorder characterized by reduced saccade amplitude and gaze stabilization deficits. Population-level recording of neuronal activity further revealed potential subcircuit-specific requirements for dscaml1 during oculomotor behavior. These findings underscore the importance of dscaml1 in the development of visuomotor function and characterize a new model to investigate potential circuit deficits underlying human oculomotor disorders.
Project description:DSCAM and DSCAM-LIKE1 (DSCAML1) serve diverse neurodevelopmental functions, including axon guidance, synaptic adhesion, and self-avoidance, depending on the species, cell type, and gene family member studied. We examined the function of DSCAM and DSCAML1 in the developing mouse retina. In addition to a subset of amacrine cells, Dscam was expressed in most retinal ganglion cells (RGCs). RGCs had fasciculated dendrites and clumped cell bodies in Dscam(-/-) mice, suggesting a role in self-avoidance. Dscaml1 was expressed in the rod circuit, and mice lacking Dscaml1 had fasciculated rod bipolar cell dendrites and clumped AII amacrine cell bodies, also indicating a role in self-avoidance. Neurons in Dscam or Dscaml1 mutant retinas stratified their processes appropriately in synaptic laminae in the inner plexiform layer, and functional synapses formed in the rod circuit in mice lacking Dscaml1. Therefore, DSCAM and DSCAML1 function similarly in self-avoidance, and are not essential for synaptic specificity in the mouse retina.
Project description:To what extent oculomotor and attention systems are linked remains strongly debated. Previous studies suggested that saccadic adaptation, a well-studied model of oculomotor plasticity, and orienting of attention rely on overlapping networks in the parietal cortex and can functionally interact. Using a Posner-like paradigm in healthy human subjects, we demonstrate for the first time that saccadic adaptation boosts endogenous attention orienting. Indeed, the discrimination of perifoveal targets benefits more from central cues after backward adaptation of leftward voluntary saccades than after a control saccade task. We propose that the overlap of underlying neural networks actually consists of neuronal populations co-activated by oculomotor plasticity and endogenous attention deployed perifoveally. The functional coupling demonstrated here plaids for conceptual models not belonging to the framework of the premotor theory of attention as the latter has been rejected precisely for this voluntary/endogenous modality. These results also open new perspective for rehabilitation of visuo-attentional deficits.
Project description:Both patients with eye movement disorders and healthy participants whose oculomotor range had been experimentally reduced have been reported to show attentional deficits at locations unreachable by their eyes. Whereas previous studies were mainly based on the evaluation of reaction times, we measured visual sensitivity before saccadic eye movements and during fixation at locations either within or beyond participants' oculomotor range. Participants rotated their heads to prevent them from performing large rightward saccades. In this posture, an attentional cue was presented inside or outside their oculomotor range. Participants either made a saccade to the cue or maintained fixation while they discriminated the orientation of a visual noise patch. In contrast to previous reports, we found that the cue attracted visual attention regardless of whether it was presented within or beyond participants' oculomotor range during both fixation and saccade preparation. Moreover, when participants aimed to look to a cue that they could not reach with their eyes, we observed no benefit at their actual saccade endpoint. This demonstrates that spatial attention is not coupled to the executed oculomotor program but instead can be deployed unrestrictedly also toward locations to which no saccade can be executed. Our results are compatible with the view that covert and overt attentional orienting are guided by feedback projections of visual and visuomotor neurons of the gaze control system, irrespective of oculomotor limitations.
Project description:Objectives:To evaluate the function of the oculomotor and vestibular systems and to correlate these findings with the clinical status of patients with Gaucher disease type 3 (GD3). The goal of this cross-sectional and longitudinal study was to find oculomotor biomarkers for future clinical trials. Methods:Twenty-six patients with GD3 were assessed for eligibility and 21 were able to perform at least one task. Horizontal and vertical reflexive saccades, smooth pursuit, gaze-holding, optokinetic nystagmus, and horizontal vestibulo-ocular reflex (VOR) were examined by video-oculography/video-head impulse test and compared concurrently with 33 healthy controls. The Scale for the Assessment and Rating of Ataxia (SARA), the modified Severity Scoring Tool (mSST), and Grooved Pegboard Test (GPT) were administered to assess overall neurological function. Eleven patients were also re-assessed after 1?year. Results:Nine out of 17 patients exhibited gaze-holding deficits. One patient had upbeat nystagmus. Three patients presented with bilateral abducens palsy in combination with central oculomotor disorders, suggesting a bilateral involvement of the abducens nucleus. Horizontal angular VOR gain was reduced in all patients (0.66?±?0.37) compared with controls (1.1?±?0.11, p?<?0.001). Most strongly correlated with clinical rating scales were peak velocity of downward saccades (SARA: ??=?-0.752, p?<?0.0005; mSST: ??=?-0.611, p?=?0.003; GPT: ??=?-0.649, p?=?0.005) and duration of vertical saccades (SARA: ??=?0.806, p?<?0.001; mSST: ??=?0.700, p?<?0.0005; GPT: ??=?0.558, p?=?0.02) together with the VOR gain (SARA: ??=?-0.63, p?=?0.016; mSST: ??=?-0.725, p?=?0.003; GPT: ??=?-0.666, p?=?0.004). Vertical smooth pursuit gain decreased significantly at follow-up. Interpretation:This study shows neuronal degeneration of the brainstem and cerebellum with combined involvement of both supranuclear and nuclear oculomotor structures and the vestibular system in GD3. We also identified oculomotor parameters that correlate with the neurological status and can be used as biomarkers in future clinical trials.
Project description:Duane retraction syndrome (DRS) is a congenital eye-movement disorder defined by limited outward gaze and retraction of the eye on attempted inward gaze. Here, we report on three heterozygous loss-of-function MAFB mutations causing DRS and a dominant-negative MAFB mutation causing DRS and deafness. Using genotype-phenotype correlations in humans and Mafb-knockout mice, we propose a threshold model for variable loss of MAFB function. Postmortem studies of DRS have reported abducens nerve hypoplasia and aberrant innervation of the lateral rectus muscle by the oculomotor nerve. Our studies in mice now confirm this human DRS pathology. Moreover, we demonstrate that selectively disrupting abducens nerve development is sufficient to cause secondary innervation of the lateral rectus muscle by aberrant oculomotor nerve branches, which form at developmental decision regions close to target extraocular muscles. Thus, we present evidence that the primary cause of DRS is failure of the abducens nerve to fully innervate the lateral rectus muscle in early development.
Project description:Schizophrenia is associated with diverse cognitive deficits, including disorders of attention-related oculomotor behavior. At the structural level, schizophrenia is associated with abnormal inhibitory control in the circuit linking cortex and thalamus. We developed a spiking neural network model that demonstrates how dysfunctional inhibition can degrade attentive gaze control. Our model revealed that perturbations of two functionally distinct classes of cortical inhibitory neurons, or of the inhibitory thalamic reticular nucleus, disrupted processing vital for sustained attention to a stimulus, leading to distractibility. Because perturbation at each circuit node led to comparable but qualitatively distinct disruptions in attentive tracking or fixation, our findings support the search for new eye movement metrics that may index distinct underlying neural defects. Moreover, because the cortico-thalamic circuit is a common motif across sensory, association, and motor systems, the model and extensions can be broadly applied to study normal function and the neural bases of other cognitive deficits in schizophrenia.
Project description:Much evidence indicates that humans and other species process large-scale visual information before fine spatial detail. Neurophysiological data obtained with paralyzed eyes suggest that this coarse-to-fine sequence results from spatiotemporal filtering by neurons in the early visual pathway. However, the eyes are normally never stationary: rapid gaze shifts (saccades) incessantly alternate with slow fixational movements. To investigate the consequences of this oculomotor cycle on the dynamics of perception, we combined spectral analysis of visual input signals, neural modeling, and gaze-contingent control of retinal stimulation in humans. We show that the saccade/fixation cycle reformats the flow impinging on the retina in a way that initiates coarse-to-fine processing at each fixation. This finding reveals that the visual system uses oculomotor-induced temporal modulations to sequentially encode different spatial components and suggests that, rather than initiating coarse-to-fine processing, spatiotemporal coupling in the early visual pathway builds on the information dynamics of the oculomotor cycle.
Project description:Monocular organization of the goldfish horizontal neural integrator was studied during spontaneous scanning saccadic and fixation behaviors. Analysis of neuronal firing rates revealed a population of ipsilateral (37%), conjugate (59%), and contralateral (4%) eye position neurons. When monocular optokinetic stimuli were employed to maximize disjunctive horizontal eye movements, the sampled population changed to 57, 39, and 4%. Monocular eye tracking could be elicited at different gain and phase with the integrator time constant independently modified for each eye by either centripetal (leak) or centrifugal (instability) drifting visual stimuli. Acute midline separation between the hindbrain oculomotor integrators did not affect either monocularity or time constant tuning, corroborating that left and right eye positions are independently encoded within each integrator. Together these findings suggest that the "ipsilateral" and "conjugate/contralateral" integrator neurons primarily target abducens motoneurons and internuclear neurons, respectively. The commissural pathway is proposed to select the conjugate/contralateral eye position neurons and act as a feedforward inhibition affecting null eye position, oculomotor range, and saccade pattern.
Project description:Congenital facial weakness is present in a heterogeneous group of conditions. Among them is Moebius syndrome, which has been defined as a disorder with congenital, non-progressive facial weakness and limited abduction of one or both eyes. It is typically attributed to agenesis of the abducens and facial cranial nerves. This paper details ocular motor findings of 40 subjects (23 months to 64 years; 24 females, 16 males) with congenital facial weakness: 38 presented at a Moebius Syndrome Conference and two were clinic patients. A new classification scheme of patterns based on ocular motor phenotype is presented. Of 40 subjects, 37 had bilateral and three had unilateral facial weakness. The most common ocular motor pattern (Pattern 1, n=17, 43%) was bilateral horizontal gaze palsy with intact vertical range. Pattern 2 (n=10, 26%) was bilateral horizontal gaze palsy with variable vertical limitations. Pattern 3, which was rare, was isolated abduction deficits (n=2, 5%). Others had full motility range and did not meet minimal criteria for the diagnosis of Moebius syndrome (Pattern 4, n=10, 26%). One subject was too severely affected to characterize. Abnormal vertical smooth pursuit was present in 17 (57%) of 30 subjects: nine with Pattern 1, five with Pattern 2, and three with Pattern 4. Abnormal vertical saccades were present in 10 (34%) of 29 subjects. Vertical saccades appeared slow in nine: six with Pattern 1 and three with Pattern 2. Vertical saccades were absent in one subject with Pattern 2. Abnormal vertical optokinetic nystagmus was present in 19 (68%) of 28 subjects: 10 with Pattern 1, six with Pattern 2, one with Pattern 3, and two with Pattern 4. Reduced convergence was present in 19 (66%) of 29 subjects: nine with Pattern 1, six with Pattern 2, one with Pattern 3, and three with Pattern 4. The most common pattern of ocular motor deficit in Moebius syndrome is bilateral horizontal gaze palsy from pontine abducens nuclear defects, rather than abducens nerve involvement. Defects in the range or dynamic properties of vertical movements in subjects with congenital facial weakness may suggest involvement of ocular motor structures in the midbrain, including oculomotor nerves or nuclei, vertical supranuclear saccadic centres, and convergence neurons. Such deficits were found even in subjects with full vertical motility range. Classification of patterns of ocular motor deficits in congenital facial weakness may assist with further delineation of anatomic localization and identification of genetic deficits underlying these disorders.
Project description:<h4>Key points</h4>Oculomotor behaviours are commonly used to evaluate sensorimotor disruption due to ethanol (EtOH). The current study demonstrates the dose-dependent impairment in oculomotor and ocular behaviours across a range of ultra-low BACs (<0.035%). Processing of target speed and direction, as well as pursuit eye movements, are significantly impaired at 0.015% BAC, suggesting impaired neural activity within brain regions associated with the visual processing of motion. Catch-up saccades during steady visual tracking of the moving target compensate for the reduced vigour of smooth eye movements that occurs with the ingestion of low-dose alcohol. Saccade dynamics start to become 'sluggish' at as low as 0.035% BAC. Pupillary light responses appear unaffected at BAC levels up to 0.065%.<h4>Abstract</h4>Changes in oculomotor behaviours are often used as metrics of sensorimotor disruption due to ethanol (EtOH); however, previous studies have focused on deficits at blood-alcohol concentrations (BACs) above about 0.04%. We investigated the dose dependence of the impairment in oculomotor and ocular behaviours caused by EtOH administration across a range of ultra-low BACs (?0.035%). We took repeated measures of oculomotor and ocular performance from sixteen participants, both pre- and post-EtOH administration. To assess the neurological impacts across a wide range of brain areas and pathways, our protocol measured 21 largely independent performance metrics extracted from a range of behavioural responses ranging from ocular tracking of radial step-ramp stimuli, to eccentric gaze holding, to pupillary responses evoked by light flashes. Our results show significant impairment of pursuit and visual motion processing at 0.015% BAC, reflecting degraded neural processing within extrastriate cortical pathways. However, catch-up saccades largely compensate for the tracking displacement shortfall caused by low pursuit gain, although there still is significant residual retinal slip and thus degraded dynamic acuity. Furthermore, although saccades are more frequent, their dynamics are more sluggish (i.e. show lower peak velocities) starting at BAC levels as low as 0.035%. Small effects in eccentric gaze holding and no effect in pupillary response dynamics were observed at levels below 0.07%, showing the higher sensitivity of the pursuit response to very low levels of blood alcohol, under the conditions of our study.