Stéphane Besnard

Bone remodeling is regulated by inner ear vestibular signals

Bone remodeling allows the conservation of normal bone mass despite constant changes in internal and external environments. The adaptation of the skeleton to these various stimuli leads credence to the notion that bone remodeling is a true homeostatic function, and as such is under the control of specific centers in the central nervous system (CNS). Hypothalamic and brainstem centers, as well as the sympathetic nervous system (SNS), have been identified as regulators of bone remodeling. However, the nature of the afferent CNS stimuli that may modulate CNS centers involved in the control of bone remodeling, with the exception of leptin, remains unclear. Based on the partial efficacy of exercise and mechanical stimulation regimens to prevent microgravity‐induced bone loss and the known alterations in vestibular functions associated with space flights, we hypothesized that inner ear vestibular signals may contribute to the regulation of bone remodeling. Using an established model of bilateral vestibular lesions and microtomographic and histomorphometric bone analyses, we show here that induction of bilateral vestibular lesion in rats generates significant bone loss, which is restricted to weight‐bearing bones and associated with a significant reduction in bone formation, as observed in rats under microgravity conditions. Importantly, this bone loss was not associated with reduced locomotor activity or metabolic abnormalities, was accompanied with molecular signs of increased sympathetic outflow, and could be prevented by the β‐blocker propranolol. Collectively, these data suggest that the homeostatic process of bone remodeling has a vestibulosympathetic regulatory component and that vestibular system pathologies might be accompanied by bone fragility.

Influence of anxiety in spatial memory impairments related to the loss of vestibular function in rat

It is now well established that vestibular information plays an important role in spatial memory processes. Although vestibular lesions induce anxiety in humans, this finding remains controversial in rodents. However, it is possible that anxiety-related behavior is associated with spatial memory impairments after vestibular lesions. We aimed to evaluate anxiety-like behavior and the effect of an anxiolytic treatment during a complex spatial memory task in a rat model of compensated bilateral vestibular lesions. Adult rats were divided into four groups, with or without vestibular lesions and, treated or untreated by diazepam. The vestibular lesion was performed by transtympanic injection of arsanilate and compared to transtympanic saline injection. Diazepam or saline was administered 1h before each test or learning session. Vestibular-lesioned rats exhibited anxiety-like behavior which was decreased with diazepam. Spatial memory performance was similar in control-treated and untreated groups, suggesting no effect on memory at the dose of diazepam used. Spatial memory performances were not modified by anxiolytic drug treatment in vestibular-lesioned rats compared to vestibular-lesioned rats without drug treatment. We conclude that bilateral vestibular lesions in rats induced anxiety-like behavior which was unrelated to spatial memory impairment and was probably specifically related to the loss of vestibular information.

Stimulation of the rat medullary raphe nuclei induces differential responses in respiratory muscle activity

Neural control circuits that coordinate the motor activity of the diaphragm (DIA) and the geniohyoid muscle (GH) are potentially involved in pathological conditions such as various forms of sleep apnea. Here we investigated a differential role of the raphe magnus (RMg), pallidus (RPa) and the obscurus (ROb) nuclei in the neural control of DIA and GH muscle activity in rats under volatile anesthesia. In order to characterize a topographical organization of the raphe nuclei we analyzed changes in DIA and GH during high-frequency stimulation (HFS, 10-130 Hz, 60 micros pulse width, 40-160 microA, 30s). HFS of the RMg and the ROb induced apnea, in the latter case apnea was associated with massive tonic discharge in the GH. By contrast, HFS of the RPa induced tachypnea. At caudal stimulation sites the tachypnea was accompanied by tonic DIA activity and cessation of GH. These data suggest a differential distribution of inhibitory and excitatory drives of DIA and GH muscles within distinct raphe nuclei.

Vestibular loss promotes procedural response during a spatial task in rats

Declarative memory refers to a spatial strategy using numerous sources of sensory input information in which visual and vestibular inputs are assimilated in the hippocampus. In contrast, procedural memory refers to a response strategy based on motor skills and familiar gestures and involves the striatum. Even if vestibular loss impairs hippocampal activity and spatial memory, vestibular‐lesioned rats remain able to find food rewards during complex spatial memory task. Since hippocampal lesions induce a switch from declarative memory to procedural memory, we hypothesize that vestibular‐lesioned rats use a strategy other than that of hippocampal spatial response to complete the task and to counterbalance the loss of vestibular information. We test, in a reverse T‐maze paradigm, the types of strategy vestibular‐lesioned rats preferentially uses in a spatial task. We clearly demonstrate that all vestibular‐lesioned rats shift to a response strategy to solve the spatial task, while control rats use spatial and response strategies equally. We conclude that the loss of vestibular informations leading to spatial learning impairments is not offset at the hippocampus level by integration process of other sense mainly visual informations; but favors a response strategy through procedural memory most likely involving the striatum, cerebellum, and motor learning.

Hippocampal and striatal M1‐muscarinic acetylcholine receptors are down‐regulated following bilateral vestibular loss in rats

Permanent vestibular loss has detrimental effects on the hippocampus, resulting in a disruption to spatial learning and memory, hippocampal theta rhythm and place cell field spatial coherence. Little is known about the vestibular system‐related hippocampal cholinergic transmission. Since the pharmacological blockade of muscarinic acetylcholine (ACh) receptors within the hippocampus produces deficits in learning and memory, we hypothesized that ACh receptors may at least partly support the integration of vestibular input. Consequently, we examined the expression of M1 muscarinic ACh receptors in the hippocampus at 7 and 30 days following bilateral vestibular lesions (BVL) in rats using autoradiography. Animals were divided into sham (n = 12) and BVL (n = 11) groups. BVL animals received intratympanic injections of sodium arsanilate (30 mg/0.1 ml) under isoflurane anesthesia and sham animals received the same volume of saline. Analysis of the brain tissue revealed a significant reduction in the number of M1 receptors throughout the hippocampus and striatum at 30 days (P ≤ 0.0001), but not at 7 days following BVL. This suggests that the changes in learning and memory seen following vestibular damage may be in part due to the loss of M1 muscarinic receptors in the hippocampus and striatum.

Increased myofiber remodelling and NFATc1-myonuclear translocation in rat postural skeletal muscle after experimental vestibular deafferentation

BACKGROUND The vestibular system undergoes considerable modification during spaceflight [5]. This is paralleled by microgravity-induced muscle atrophy [6]. However, the possibility of vestibulo-autonomic regulatory mechanisms affecting skeletal muscle structure and function have not yet been addressed. OBJECTIVE We hypothesise that the vestibular system affects anti-gravitational skeletal muscle phenotype composition, size and the transcriptional factor called nuclear factor of activated T cells (NFATc1). METHODS In a laboratory study, we examined the morphological and histochemical properties including intramyocellular NFATc1 changes in slow-type soleus muscle of chemically labyrinthectomized rats (VLx; n=8) compared to a control group (Sham; n=6) after a period of one month. RESULTS AND CONCLUSION Neurochemical vestibular deafferentation resulted in smaller myofibre sizes, altered myofibre phenotype composition, high yields of hybrid fibre formation, and reduced myonuclear NFATc1 accumulation as signs of slow-type myofibre atrophy, myofibre type remodelling, and altered nuclear transcriptional activity in the postural soleus muscle of rats. We propose that vestibulo-autonomic modification of skeletal muscles occurs during prolonged microgravity. Our findings are likely to have implications for vestibular rehabilitation in clinical settings.

Differential respiratory control of the upper airway and diaphragm muscles induced by 5-HT1A receptor ligands

BackgroundSerotonin (5-HT) has a role in respiratory function and dysfunction. Although 5-HT affects respiratory drive to both phrenic and cranial motoneurons, relatively little is known about the role of 5-HT receptor subtypes in the control of upper airway muscle (UAM) respiratory activity.Materials and methodsHere, we performed central injections of 5-HT1A agonist (8-OHDPAT) or antagonist (WAY100635) in anesthetized rats and analyzed changes in the electromyographic activity of several UAM and other cardiorespiratory parameters. We also compared the pattern of Fos expression induced after central injection of a control solution or 8-OHDPAT.ResultsResults showed that 8-OHDPAT induced a robust increase in UAM activity, associated with either tachypnea under volatile anesthesia or bradypnea under liquid anesthesia. Injection of WAY100635 switched off UAM respiratory activity and led to bradypnea, suggesting a tonic excitatory role of endogenous 5-HT1A receptor activation. Co-injection of the agonist and the antagonist blocked the effects produced by each drug alone. Besides drug-induced changes in respiratory frequency, only slight increases in surface of diaphragm bursts were observed. Significant increases in Fos expression after 5-HT1A receptor activation were seen in the nucleus tractus solitarius, nucleus raphe pallidus, parapyramidal region, retrotrapezoid nucleus, lateral parabrachial, and Kölliker-Fuse nuclei. This restricted pattern of Fos expression likely identified the neural substrate responsible for the enhancement of UAM respiratory activity observed after 8-OHDPAT injection.ConclusionsThese findings suggest an important role for the 5-HT1A receptors in the neural control of upper airway patency and may be relevant to counteract pharyngeal atonia during obstructive sleep apneas.

Hyperbaric oxygen increases tissue-plasminogen activator-induced thrombolysis in vitro, and reduces ischemic brain damage and edema in rats subjected to thromboembolic brain ischemia

Recent data have shown that normobaric oxygen (NBO) increases the catalytic and thrombolytic efficiency of recombinant tissue plasminogen activator (rtPA) in vitro, and is as efficient as rtPA at restoring cerebral blood flow in rats subjected to thromboembolic brain ischemia. Therefore, in the present study, we studied the effects of hyperbaric oxygen (HBO) (i) on rtPA-induced thrombolysis in vitro and (ii) in rats subjected to thromboembolic middle cerebral artery occlusion-induced brain ischemia. HBO increases rtPA-induced thrombolysis in vitro to a greater extent than NBO; in addition, HBO treatment of 5-minute duration, but not of 25-minute duration, reduces brain damage and edema in vivo. In line with the facilitating effect of NBO on cerebral blood flow, our findings suggest that 5-minute HBO could have provided neuroprotection by promoting thrombolysis. The lack of effect of HBO exposure of longer duration is discussed.

Prevalence, predictors and prevention of motion sickness in zero-G parabolic flights.

INTRODUCTION Zero-G parabolic flight reproduces the weightlessness of space for short periods. However, motion sickness may affect some fliers. The aim was to assess the extent of this problem and to find possible predictors and modifying factors. METHODS Airbus zero-G flights consist of 31 parabolas performed in blocks. Each parabola consisted of 20 s of 0 g sandwiched by 20 s of hypergravity of 1.5-1.8 g. The survey covered N = 246 person-flights (193 men, 53 women), ages (M ± SD) 36.0 ± 11.3 yr. An anonymous questionnaire included motion sickness rating (1 = OK to 6 = vomiting), Motion Sickness Susceptibility Questionnaire (MSSQ), antimotion sickness medication, prior zero-G experience, anxiety level, and other characteristics. RESULTS Participants had lower MSSQ percentile scores (27.4 ± 28.0) than the population norm of 50. Motion sickness was experienced by 33% and 12% vomited. Less motion sickness was predicted by older age, greater prior zero-G flight experience, medication with scopolamine, lower MSSQ scores, but not gender or anxiety. Sickness ratings in fliers pretreated with scopolamine (1.81 ± 1.58) were lower than for nonmedicated fliers (2.93 ± 2.16), and incidence of vomiting in fliers using scopolamine treatment was reduced by half to a third. Possible confounding factors including age, sex, flight experience, and MSSQ could not account for this. CONCLUSION Motion sickness affected one-third of zero-G fliers despite being intrinsically less motion sickness susceptible compared to the general population. Susceptible individuals probably try to avoid such a provocative environment. Risk factors for motion sickness included younger age and higher MSSQ scores. Protective factors included prior zero-G flight experience (habituation) and antimotion sickness medication.Golding JF, Paillard AC, Normand H, Besnard S, Denise P. Prevalence, predictors, and prevention of motion sickness in zero-G parabolic flights. Aerosp Med Hum Perform. 2017; 88(1):3-9.

The underestimated effect of normobaric hyperoxia on cerebral blood flow and its relationship to neuroprotection

Sir, Neurons in the ischaemic penumbra are at risk from ischaemia-induced constrained oxygen delivery. Therefore, increasing arterial oxygen content by normobaric oxygen therapy (NBO) has been thought a logical strategy, and as expected further shown to increase markedly and rapidly the very low tissue oxygen pressure that prevails in the ischaemic penumbra (Shin et al. , 2007; Baskerville et al. , 2011). However, due to controversial results in rodent stroke models, there is still no clear consensus on the benefits of NBO. By demonstrating in a recent issue of Brain that NBO prevents behavioural deficits and almost suppresses neuronal loss in a rat model of transient ischaemic attack, the work of Ejaz et al. (2016) brings renewed interest as for the benefits of NBO in brain ischaemia. One caveat when critically assessing the effects and mechanisms by which NBO, alone or in combination with tissue plasminogen activator (tPA), provides benefits on brain ischaemia is that little attention is paid to the facilitating action of NBO on cerebral blood flow (Shin et al. , 2007; Baskerville et al. , 2011; David et al. , 2012) and to the use of transient rather than permanent, and thromboembolic rather than mechanical models of ischaemic stroke. Doubtlessly, this is due to the fact that the ability of NBO to improve the very low tissue oxygen pressure that prevails in the ischaemic penumbra is generally believed to occur through passive-mediated oxygen transport (i.e. oxygen diffusion). However, contrary to this straightforward reasoning, and to hyperbaric oxygen therapy, NBO has been shown to fail reducing cell injury in acute brain slices exposed to oxygen and glucose deprivation …