Reconsidering the Role of Neuronal Intrinsic Properties and Neuromodulation in Vestibular Homeostasis

The sensorimotor transformations performed by central vestibular neurons constantly adapt as the animal faces conflicting sensory information or sustains injuries. To ensure the homeostasis of vestibular-related functions, neural changes could in part rely on the regulation of 2° VN intrinsic properties. Here we review evidence that demonstrates modulation and plasticity of central vestibular neurons’ intrinsic properties. We first present the partition of Rodents’ vestibular neurons into distinct subtypes, namely type A and type B. Then, we focus on the respective properties of each type, their putative roles in vestibular functions, fast control by neuromodulators and persistent modifications following a lesion. The intrinsic properties of central vestibular neurons can be swiftly modulated by a wealth of neuromodulators to adapt rapidly to temporary changes of ecophysiological surroundings. To illustrate how intrinsic excitability can be rapidly modified in physiological conditions and therefore be therapeutic targets, we present the modulation of vestibular reflexes in relation to the variations of the neuromodulatory inputs during the sleep/wake cycle. On the other hand, intrinsic properties can also be slowly, yet permanently, modified in response to major perturbations, e.g., after unilateral labyrinthectomy (UL). We revisit the experimental evidence, which demonstrates that drastic alterations of the central vestibular neurons’ intrinsic properties occur following UL, with a slow time course, more on par with the compensation of dynamic deficits than static ones. Data are interpreted in the framework of distributed processes that progress from global, large-scale coping mechanisms (e.g., changes in behavioral strategies) to local, small-scale ones (e.g., changes in intrinsic properties). Within this framework, the compensation of dynamic deficits improves over time as deeper modifications are engraved within the finer parts of the vestibular-related networks. Finally, we offer perspectives and working hypotheses to pave the way for future research aimed at understanding the modulation and plasticity of central vestibular neurons’ intrinsic properties

How Tilting the Head Interferes With Eye-Hand Coordination: The Role of Gravity in Visuo-Proprioceptive, Cross-Modal Sensory Transformations

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.This work was supported by the Centre National d’Etudes Spatiales (DAR 2017/4800000906, DAR 2018/4800000948, 2019/4800001041). JB-E was supported by a Ph.D. fellowship of the École Doctorale Cerveau-Cognition-Comportement (ED3C, n°158, Sorbonne Université and Université de Paris). The research team is supported by the Centre National de la Recherche Scientifique and the Université de Paris. This study contributes to the IdEx Université de Paris ANR-18-IDEX-0001

No Gain No Pain: Relations Between Vestibulo-Ocular Reflexes and Motion Sickness in Mice

Motion sickness occurs when the vestibular system is subjected to conflicting sensory information or overstimulation. Despite the lack of knowledge about the actual underlying mechanisms, several drugs, among which scopolamine, are known to prevent or alleviate the symptoms. Here, we aim at better understanding how motion sickness affects the vestibular system, as well as how scopolamine prevents motion sickness at the behavioral and cellular levels. We induced motion sickness in adult mice and tested the vestibulo-ocular responses to specific stimulations of the semi-circular canals and of the otoliths, with or without scopolamine, as well as the effects of scopolamine and muscarine on central vestibular neurons recorded on brainstem slices. We found that both motion sickness and scopolamine decrease the efficacy of the vestibulo-ocular reflexes and propose that this decrease in efficacy might be a protective mechanism to prevent later occurrences of motion sickness. To test this hypothesis, we used a behavioral paradigm based on visuo-vestibular interactions which reduces the efficacy of the vestibulo-ocular reflexes. This paradigm also offers protection against motion sickness, without requiring any drug. At the cellular level, we find that depending on the neuron, scopolamine can have opposite effects on the polarization level and firing frequency, indicating the presence of at least two types of muscarinic receptors in the medial vestibular nucleus. The present results set the basis for future studies of motion sickness counter-measures in the mouse model and offers translational perspectives for improving the treatment of affected patients

Multisensory gaze stabilization in response to subchronic alteration of vestibular type I hair cells

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

HCN1 channels in cerebellar Purkinje cell promote late stages of learning and constrain synaptic inhibition

Abstract Neural computations rely on ion channels that modify neuronal responses to synaptic inputs. While single cell recordings suggest diverse and neurone type-specific computational functions for HCN1 channels, their behavioural roles in any single neurone type are not clear. Using a battery of behavioural assays, including analysis of motor learning in vestibulo-ocular reflex and rotarod tests, we find that deletion of HCN1 channels from cerebellar Purkinje cells selectively impairs late stages of motor learning. Because deletion of HCN1 modifies only a subset of behaviours involving Purkinje cells, we asked whether the channel also has functional specificity at a cellular level. We find that HCN1 channels in cerebellar Purkinje cells reduce the duration of inhibitory synaptic responses but, in the absence of membrane hyperpolarization, do not affect responses to excitatory inputs. Our results indicate that manipulation of subthreshold computation in a single neurone type causes specific modifications to behaviour. © 2013 The Physiological Society

Long-Lasting Visuo-Vestibular Mismatch in Freely-Behaving Mice Reduces the Vestibulo-Ocular Reflex and Leads to Neural Changes in the Direct Vestibular Pathway

International audienceCalibration of the vestibulo-ocular reflex (VOR) depends on the presence of visual feedback. However, the cellular mechanisms associated with VOR modifications at the level of the brainstem remain largely unknown. A new protocol was designed to expose freely behaving mice to a visuo-vestibular mismatch during a 2-week period. This protocol induced a 50% reduction of the VOR. In vivo pharmacological experiments demonstrated that the VOR reduction depends on changes located outside the flocculus/paraflocculus complex. The cellular mechanisms associated with the VOR reduction were then studied in vitro on brainstem slices through a combination of vestibular afferent stimulation and patch-clamp recordings of central vestibular neurons. The evoked synaptic activity demonstrated that the efficacy of the synapses between vestibular afferents and central vestibular neurons was decreased. In addition, a long-term depression protocol failed to further decrease the synapse efficacy, suggesting that the VOR reduction might have occurred through depression-like mechanisms. Analysis of the intrinsic membrane properties of central vestibular neurons revealed that the synaptic changes were supplemented by a decrease in the spontaneous discharge and excitability of a subpopulation of neurons. Our results provide evidence that a long-lasting visuo-vestibular mismatch leads to changes in synaptic transmission and intrinsic properties of central vestibular neurons in the direct VOR pathway. Overall, these results open new avenues for future studies on visual and vestibular interactions conducted in vivo and in vitro

Curr Biol

Efference copies are neural replicas of motor outputs used to anticipate the sensory consequences of a self-generated motor action or to coordinate neural networks involved in distinct motor behaviors. An established example of this motor-to-motor coupling is the efference copy of the propulsive motor command, which supplements classical visuo-vestibular reflexes to ensure gaze stabilization during amphibian larval locomotion. Such feedforward replica of spinal pattern-generating circuits produces a spino-extraocular motor coupled activity that evokes eye movements, spatiotemporally coordinated to tail undulation independently of any sensory signal. Exploiting the developmental stages of the frog, studies in metamorphing Xenopus demonstrated the persistence of this spino-extraocular motor command in adults and its developmental adaptation to tetrapodal locomotion. Here, we demonstrate for the first time the existence of a comparable locomotor-to-ocular motor coupling in the mouse. In neonates, ex vivo nerve recordings of brainstem-spinal cord preparations reveal a spino-extraocular motor coupled activity similar to the one described in Xenopus. In adult mice, trans-synaptic rabies virus injections in lateral rectus eye muscle label cervical spinal cord neurons closely connected to abducens motor neurons. Finally, treadmill-elicited locomotion in decerebrated preparations evokes rhythmic eye movements in synchrony with the limb gait pattern. Overall, our data are evidence for the conservation of locomotor-induced eye movements in vertebrate lineages. Thus, in mammals as in amphibians, CPG-efference copy feedforward signals might interact with sensory feedback to ensure efficient gaze control during locomotion.Corrélats neurophysiologiques de l'évolution et du développement des stratégies de stabilisation du regard pendant la locomotion chez les vertébrésUniversité de Pari

Soft tissue involvement, mediastinal pseudotumor, and venous thrombosis in pustulotic arthro-osteitis

A syndrome of hyperostosis of the thoracic wall, nonspecific signs of inflammatory disease, and palmar and plantar pustulosis is described in eight patients (Table 1). Seven had intersternocostoclavicular ossification [12], and one had chromic recurrent multifocal osteomyelitis [2]. This complex of findings has been called “pustulotic arthro-osteitis” [5, 12]. This report emphasizes the periosseous soft tissue inflammation and the unexplained subclavian and mediastinal vein thrombosis seen in two patients [8]. Inflammatory periosseous and mediastinal lesions were seen on plain films in all eight patients and on computed tomographic (CT) scans in seven. Radiographs of the spine showed a spondyloarthropathy in three patients. This was characterized by ossification of the vertebral ligaments and sclerosis of the vertebral bodies. Awareness of the radiologic features of pustulotic arthro-osteitis is important because the clinical, biochemical and pathologic findings are often nonspecific and misleading [5, 8, 12].Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46791/1/256_2004_Article_BF00366761.pd