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Objective Unilateral labyrinthectomy (UL) and unilateral vestibular neurectomy (UVN) are two surgical methods to produce vestibular lesions in the mouse. The objective of this study was to describe the surgical technique of both methods, and compare functional compensation using vestibulo-ocular reflex-based tests. Methods UL and UVN were each performed on groups of seven and ten mice, respectively. Main surgical landmarks were the facial nerve, the external auditory canal and the sternomastoid and digastric muscles. For UL, the sternomastoid muscle was elevated to expose the mastoid, which was drilled to destroy the labyrinth. For UVN, the bulla was drilled opened and a transcochlear approach enabled the identification of the vestibulo-cochlear nerve exiting the brainstem, which was sectioned and the ganglion of Scarpa suctioned. Behaviour and vestibular function were analysed before surgery and at 1, 4, 7 days and at 1 month postlesion using sinusoidal rotation, off-vertical axis rotation, static head tilts and angular velocity steps. Results UL is a faster and safer procedure than UVN (operative time 16.3 vs 20.5 min, p  = 0.19; survival rate 86% vs 60%, p  = 0.25). UVN was more severe with significantly worse behavioural scores at day 4 and day 7 ( p  < 0.001). Vestibular compensation was overall similar during the first week and at 1 month (non-statistically significant difference). Conclusion Both UL and UVN procedures can routinely be performed in the mouse with similar post-operative recovery and behavioural compensation. The operative risk of vascular or neurological damage is smaller in UL compared to UVN. UVN may be required for specific research protocols studying central cellular process specifically related to the destruction of the ganglion of Scarpa and following vestibular nerve degeneration.

The functional complementarity of the vestibulo-ocular reflex (VOR) and optokinetic reflex (OKR) allows for optimal combined gaze stabilization responses (CGR) in light. While sensory substitution has been reported following complete vestibular loss, the capacity of the central vestibular system to compensate for partial peripheral vestibular loss remains to be determined. Here, we first demonstrate the efficacy of a 6-week subchronic ototoxic protocol in inducing transient and partial vestibular loss which equally affects the canal- and otolith-dependent VORs. Immunostaining of hair cells in the vestibular sensory epithelia revealed that organ-specific alteration of type I, but not type II, hair cells correlates with functional impairments. The decrease in VOR performance is paralleled with an increase in the gain of the OKR occurring in a specific range of frequencies where VOR normally dominates gaze stabilization, compatible with a sensory substitution process. Comparison of unimodal OKR or VOR versus bimodal CGR revealed that visuo-vestibular interactions remain reduced despite a significant recovery in the VOR. Modeling and sweep-based analysis revealed that the differential capacity to optimally combine OKR and VOR correlates with the reproducibility of the VOR responses. Overall, these results shed light on the multisensory reweighting occurring in pathologies with fluctuating peripheral vestibular malfunction.

For reaching and grasping, as well as for manipulating objects, optimal hand motor control arises from the integration of multiple sources of sensory information, such as proprioception and vision. For this reason, proprioceptive deficits often observed in stroke patients have a significant impact on the integrity of motor functions. The present targeted review attempts to reanalyze previous findings about proprioceptive upper-limb deficits in stroke patients, as well as their ability to compensate for these deficits using vision. Our theoretical approach is based on two concepts: first, the description of multi-sensory integration using statistical optimization models; second, on the insight that sensory information is not only encoded in the reference frame of origin (e.g., retinal and joint space for vision and proprioception, respectively), but also in higher-order sensory spaces. Combining these two concepts within a single framework appears to account for the heterogeneity of experimental findings reported in the literature. The present analysis suggests that functional upper limb post-stroke deficits could not only be due to an impairment of the proprioceptive system per se, but also due to deficiencies of cross-references processing; that is of the ability to encode proprioceptive information in a non-joint space. The distinction between purely proprioceptive or cross-reference-related deficits can account for two experimental observations: first, one and the same patient can perform differently depending on specific proprioceptive assessments; and a given behavioral assessment results in large variability across patients. The distinction between sensory and cross-reference deficits is also supported by a targeted literature review on the relation between cerebral structure and proprioceptive function. This theoretical framework has the potential to lead to a new stratification of patients with proprioceptive deficits, and may offer a novel approach to post-stroke rehabilitation.

Locomotion in vertebrates is accompanied by retinal image-stabilizing eye movements that derive from sensory-motor transformations and predictive locomotor efference copies. During development, concurrent maturation of locomotor and ocular motor proficiency depends on the structural and neuronal capacity of the motion detection systems, the propulsive elements and the computational capability for signal integration. In developing Xenopus larvae, we demonstrate an interactive plasticity of predictive locomotor efference copies and multi-sensory motion signals to constantly elicit dynamically adequate eye movements during swimming. During ontogeny, the neuronal integration of vestibulo- and spino-ocular reflex components progressively alters as locomotion parameters change. In young larvae, spino-ocular motor coupling attenuates concurrent angular vestibulo-ocular reflexes, while older larvae express eye movements that derive from a combination of the two components. This integrative switch depends on the locomotor pattern generator frequency, represents a stage-independent gating mechanism, and appears during ontogeny when the swim frequency naturally declines with larval age. Visual perception works best when eye movement counteracts the effects of body movement. This study describes how such coordination first emerges and matures during development in frog larvae.

Introduction: Vestibular sensory hair cells are precisely orientated according to planar cell polarity (PCP) and are key to enable mechanic-electrical transduction and normal vestibular function. PCP is found on different scales in the vestibular organs, ranging from correct hair bundle orientation, coordination of hair cell orientation with neighboring hair cells, and orientation around the striola in otolithic organs. Celsr1 is a PCP protein and a Celsr1 KO mouse model showed hair cell disorganization in all vestibular organs, especially in the canalar ampullae. The objective of this work was to assess to what extent the different vestibulo-ocular reflexes were impaired in Celsr1 KO mice. Methods: Vestibular function was analyzed using non-invasive video-oculography. Semicircular canal function was assessed during sinusoidal rotation and during angular velocity steps. Otolithic function (mainly utricular) was assessed during off-vertical axis rotation (OVAR) and during static and dynamic head tilts. Results: The vestibulo-ocular reflex of 10 Celsr1 KO and 10 control littermates was analyzed. All KO mice presented with spontaneous nystagmus or gaze instability in dark. Canalar function was reduced almost by half in KO mice. Compared to control mice, KO mice had reduced angular VOR gain in all tested frequencies (0.2–1.5 Hz), and abnormal phase at 0.2 and 0.5 Hz. Concerning horizontal steps, KO mice had reduced responses. Otolithic function was reduced by about a third in KO mice. Static ocular-counter roll gain and OVAR bias were both significantly reduced. These results demonstrate that canal- and otolith-dependent vestibulo-ocular reflexes are impaired in KO mice. Conclusion: The major ampullar disorganization led to an important reduction but not to a complete loss of angular coding capacities. Mildly disorganized otolithic hair cells were associated with a significant loss of otolith-dependent function. These results suggest that the highly organized polarization of otolithic hair cells is a critical factor for the accurate encoding of the head movement and that the loss of a small fraction of the otolithic hair cells in pathological conditions is likely to have major functional consequences. Altogether, these results shed light on how partial loss of vestibular information encoding, as often encountered in pathological situations, translates into functional deficits.

To correctly position the hand with respect to the spatial location and orientation of an object to be reached/grasped, visual information about the target and proprioceptive information from the hand must be compared. Since visual and proprioceptive sensory modalities are inherently encoded in a retinal and musculo-skeletal reference frame, respectively, this comparison requires cross-modal sensory transformations. Previous studies have shown that lateral tilts of the head interfere with the visuo-proprioceptive transformations. It is unclear however, whether this phenomenon is related to the neck flexion or to the head-gravity misalignment. To answer to this question, we performed three virtual reality experiments in which we compared a grasping-like movement with lateral neck flexions executed in an upright seated position and while lying supine. In the main experiment, the task requires cross-modal transformations, because the target information is visually acquired, and the hand is sensed through proprioception only. In the other two control experiments, the task is unimodal, because both target and hand are sensed through one, and the same, sensory channel (vision and proprioception respectively), and, hence, cross-modal processing is unnecessary. The results show that lateral neck flexions have considerably different effects in the seated and supine posture, but only for the cross-modal task. More precisely, the subjects’ response variability and the importance associated to the visual encoding of the information significantly increased when supine. We show that these findings are consistent with the idea that head-gravity misalignment interferes with the visuo-proprioceptive cross-modal processing. Indeed, the principle of statistical optimality in multisensory integration predicts the observed results if the noise associated to the visuo-proprioceptive transformations is assumed to be affected by gravitational signals, and not by neck proprioceptive signals per se. This finding is also consistent with the observation of otolithic projections in the posterior parietal cortex, which is involved in the visuo-proprioceptive processing. Altogether these findings represent a clear evidence of the theorized central role of gravity in spatial perception. More precisely, otolithic signals would contribute to reciprocally align the reference frames in which the available sensory information can be encoded.

ObjectiveTo examine SARS-CoV-2 vaccine confidence, attitudes and intentions in Australian adults as part of the iCARE Study.Design and settingCross-sectional online survey conducted when free COVID-19 vaccinations first became available in Australia in February 2021.ParticipantsTotal of 1166 Australians from general population aged 18–90 years (mean 52, SD of 19).Main outcome measuresPrimary outcome: responses to question ‘If a vaccine for COVID-19 were available today, what is the likelihood that you would get vaccinated?’.Secondary outcome: analyses of putative drivers of uptake, including vaccine confidence, socioeconomic status and sources of trust, derived from multiple survey questions.ResultsSeventy-eight per cent reported being likely to receive a SARS-CoV-2 vaccine. Higher SARS-CoV-2 vaccine intentions were associated with: increasing age (OR: 2.01 (95% CI 1.77 to 2.77)), being male (1.37 (95% CI 1.08 to 1.72)), residing in least disadvantaged area quintile (2.27 (95% CI 1.53 to 3.37)) and a self-perceived high risk of getting COVID-19 (1.52 (95% CI 1.08 to 2.14)). However, 72% did not believe they were at a high risk of getting COVID-19. Findings regarding vaccines in general were similar except there were no sex differences. For both the SARS-CoV-2 vaccine and vaccines in general, there were no differences in intentions to vaccinate as a function of education level, perceived income level and rurality. Knowing that the vaccine is safe and effective and that getting vaccinated will protect others, trusting the company that made it and vaccination recommended by a doctor were reported to influence a large proportion of the study cohort to uptake the SARS-CoV-2 vaccine. Seventy-eight per cent reported the intent to continue engaging in virus-protecting behaviours (mask wearing, social distancing, etc) postvaccine.ConclusionsMost Australians are likely to receive a SARS-CoV-2 vaccine. Key influencing factors identified (eg, knowing vaccine is safe and effective, and doctor’s recommendation to get vaccinated) can inform public health messaging to enhance vaccination rates.

Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor involved in xenobiotic metabolism. Plexiform neurofibromas (PNFs) can transform into malignant peripheral nerve sheath tumors (MPNSTs) that are resistant to existing therapies. These tumors are primarily composed of Schwann cells. In addition to neurofibromatosis type 1 (NF1) gene inactivation, further genetic lesions are required for malignant transformation. We have quantified the mRNA expression levels of AHR and its associated genes in 38 human samples. We report that AHR and the biosynthetic enzymes of its endogenous ligand are overexpressed in human biopsies of PNFs and MPNSTs. We also detect a strong nuclear AHR staining in MPNSTs. The inhibition of AHR by siRNA or antagonists, CH-223191 and trimethoxyflavone, induces apoptosis in human MPNST cells. Since AHR dysregulation is observed in these tumors, we investigate AHR involvement in Schwann cell physiology. Hence, we studied the role of AHR in myelin structure and myelin gene regulation in Ahr −/− mice during myelin development. AHR ablation leads to locomotion defects and provokes thinner myelin sheaths around the axons. We observe a dysregulation of myelin gene expression and myelin developmental markers in Ahr −/− mice. Interestingly, AHR does not directly bind to myelin gene promoters. The inhibition of AHR in vitro and in vivo increased β-catenin levels and stimulated the binding of β-catenin on myelin gene promoters. Taken together, our findings reveal an endogenous role of AHR in peripheral myelination and in peripheral nerve sheath tumors. Finally, we suggest a potential therapeutic approach by targeting AHR in nerve tumors.

Modifications of gravity levels induce generalized adaptation of mammalian physiology, including vascular, brain, muscle, bone and immunity functions. As a crucial interface between the vascular system and the brain, the blood–brain barrier (BBB) acts as a filter to protect neurons from pathogens and inflammation. Here we compare the effects of several protocols of hypergravity induced by centrifugation and whole-body vibrations (WBV) on BBB integrity. The immunohistochemistry revealed immunoglobulin G (IgG) extravasation from blood to hippocampal parenchyma of mice centrifuged at 2 × g during 1 or 50 days, whereas short exposures to higher hypergravity mimicking the profiles of spaceflight landing and take-off (short exposures to 5 × g) had no effects. These results suggest prolonged centrifugation (>1 days) at 2 × g induced a BBB leakage. Moreover, WBV were similarly tested. The short exposure to +2 × g vibrations (900 s/day at 90 Hz) repeated for 63 days induced IgG extravasation in hippocampal parenchyma, whereas the progressive increase of vibrations from +0.5 to +2 × g for 63 days was not able to affect the IgG crossing through the BBB. Overall, these results suggest that the BBB permeability is sensitive to prolonged external accelerations. In conclusion, we advise that the protocols of WBV and centrifugation, proposed as countermeasure to spaceflight, should be designed with progressively increasing exposure to reduce potential side effects on the BBB.

The Aryl hydrocarbon Receptor or AhR, a ligand-activated transcription factor, is known to mediate the toxic and carcinogenic effects of various environmental pollutants such as 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD). Recent studies in Caenorhabditis elegans and Drosophila melanogaster show that the orthologs of the AhR are expressed exclusively in certain types of neurons and are implicated in the development and the homeostasis of the central nervous system. While physiological roles of the AhR were demonstrated in the mammalian heart, liver and gametogenesis, its ontogenic expression and putative neural functions remain elusive. Here, we report that the constitutive absence of the AhR in adult mice (AhR-/-) leads to abnormal eye movements in the form of a spontaneous pendular horizontal nystagmus. To determine if the nystagmus is of vestibular, visual, or cerebellar origin, gaze stabilizing reflexes, namely vestibulo-ocular and optokinetic reflexes (VOR and OKR), were investigated. The OKR is less effective in the AhR-/- mice suggesting a deficit in the visuo-motor circuitry, while the VOR is mildly affected. Furthermore, the AhR is expressed in the retinal ganglion cells during the development, however electroretinograms revealed no impairment of retinal cell function. The structure of the cerebellum of the AhR-/- mice is normal which is compatible with the preserved VOR adaptation, a plastic process dependent on cerebellar integrity. Finally, intoxication with TCDD of control adults did not lead to any abnormality of the oculomotor control. These results demonstrate that the absence of the AhR leads to acquired central nervous system deficits in the adults. Given the many common features between both AhR mouse and human infantile nystagmus syndromes, the AhR-/- mice might give insights into the developmental mechanisms which lead to congenital eye disorders.