Retinoic acid degradation shapes zonal development of vestibular organs and sensitivity to transient linear accelerations

Each vestibular sensory epithelium in the inner ear is divided morphologically and physio- logically into two zones, called the striola and extrastriola in otolith organ maculae, and the central and peripheral zones in semicircular canal cristae. We found that formation of striolar/central zones during embryogenesis requires Cytochrome P450 26b1 (Cyp26b1)- mediated degradation of retinoic acid (RA). In Cyp26b1 conditional knockout mice, formation of striolar/central zones is compromised, such that they resemble extrastriolar/peripheral zones in multiple features. Mutants have deficient vestibular evoked potential (VsEP) responses to jerk stimuli, head tremor and deficits in balance beam tests that are consistent with abnormal vestibular input, but normal vestibulo-ocular reflexes and apparently normal motor performance during swimming. Thus, degradation of RA during embryogenesis is required for formation of highly specialized regions of the vestibular sensory epithelia with specific functions in detecting head motions

Aerospace medicine and biology. A continuing bibliography with indexes, supplement 206, May 1980

This bibliography lists 169 reports, articles, and other documents introduced into the NASA scientific and technical information system in April 1980

Aerospace medicine and biology: A continuing bibliography with indexes, supplement 128, May 1974

This special bibliography lists 282 reports, articles, and other documents introduced into the NASA scientific and technical information system in April 1974

A review on otolith models in human perception

The vestibular system, which consists of semicircular canals and otolith, are the main sensors mammals use to perceive rotational and linear motions. Identifying the most suitable and consistent mathematical model of the vestibular system is important for research related to driving perception. An appropriate vestibular model is essential for implementation of the Motion Cueing Algorithm (MCA) for motion simulation purposes, because the quality of the MCA is directly dependent on the vestibular model used. In this review, the history and development process of otolith models are presented and analyzed. The otolith organs can detect linear acceleration and transmit information about sensed applied specific forces on the human body. The main purpose of this review is to determine the appropriate otolith models that agree with theoretical analyses and experimental results as well as provide reliable estimation for the vestibular system functions. Formulating and selecting the most appropriate mathematical model of the vestibular system is important to ensure successful human perception modelling and simulation when implementing the model into the MCA for motion analysis

Early components of the human vestibulo-ocular response to head rotation: latency and gain

To characterize vestibulo-ocular reflex (VOR) properties in the time window in which contributions by other systems are minimal, eye movements during the first 50-100 ms after the start of transient angular head accelerations ( approximately 1000 degrees /s(2)) imposed by a torque helmet were analyzed in normal human subjects. Orientations of the head and both eyes were recorded with magnetic search coils (resolution, approximately 1 min arc; 1000 samples/s). Typically, the first response to a head perturbation was an anti-compensatory eye movement with zero latency, peak-velocity of several degrees per second, and peak excursion of several tenths of a degree. This was interpreted as a passive mechanical response to linear acceleration of the orbital tissues caused by eccentric rotation of the eye. The response was modeled as a damped oscillation (approximately 13 Hz) of the orbital contents, approaching a constant eye deviation for a sustained linear acceleration. The subsequent compensatory eye movements showed (like the head movements) a linear increase in velocity, which allowed estimates of latency and gain with linear regressions. After appropriate accounting for the preceding passive eye movements, average VOR latency (for pooled eyes, directions, and subjects) was calculated as 8.6 ms. Paired comparisons between the two eyes revealed that the latency for the eye contralateral to the direction of head rotation was, on average, 1.3 ms shorter than for the ipsilateral eye. This highly significant average inter-ocular difference was attributed to the additional internuclear abducens neuron in the pathway to the ipsilateral eye. Average acceleration gain (ratio between slopes of eye and head velocities) over the first 40-50 ms was approximately 1.1. Instantaneous velocity gain, calculated as Veye(t)/Vhead(t-latency), showed a gradual build-up converging toward unity (often after a slight overshoot). Instantaneous acceleration gain also converged toward unity but showed a much steeper build-up and larger oscillations. This behavior of acceleration and velocity gain could be accounted for by modeling the eye movements as the sum of the passive response to the linear acceleration and the active rotational VOR. Due to the latency and the anticompensatory component, gaze stabilization was never complete. The influence of visual targets was limited. The initial VOR was identical with a distant target (continuously visible or interrupted) and in complete darkness. A near visual target caused VOR gain to rise to a higher level, but the time after which the difference between far and near targets emerged varied between individuals

Final Science Reports of the US Experiments Flown on the Russian Biosatellite Cosmos 2229

Cosmos 2229 was launched on December 29, 1992, containing a biological payload including two young male rhesus monkeys, insects, amphibians, and cell cultures. The biosatellite was launched from the Plesetsk Cosmodrome in Russia for a mission duration of 11.5 days. The major research objectives were: (1) Study of adaptive response mechanisms of mammals during flight; and (2) Study of physiological mechanisms underlying vestibular, motor system and brain function in primates during early and later adaptation phases. American scientists and their Russian collaborators conducted 11 experiments on this mission which included extensive preflight and postflight studies with rhesus monkeys. Biosamples and data were subsequently transferred to the United States. The U.S. responsibilities for this flight included the development of experiment protocols, the fabrication of some flight instrumentation and experiment-specific ground-based hardware, the conducting of preflight and postflight testing and the analysis of biospecimens and data for the U.S. experiments. A description of the Cosmos 2229 mission is presented in this report including preflight, on-orbit and postflight activities. The flight and ground-based bioinstrumentation which was developed by the U.S. and Russia is also described, along with the associated preflight testing ot the U.S. hardware. Final Science Reports for the experiments are also included

The dynamic characteristics of the mouse horizontal vestibulo-ocular and optokinetic response

In the present study the optokinetic reflex, vestibulo-ocular reflex and their interaction were investigated in the mouse, using a modified subconjunctival search coil technique. Gain of the ocular response to sinusoidal optokinetic stimulation was relatively constant for peak velocities lower than 8°/s, ranging from 0.7 to 0.8. Gain decreased proportionally to velocity for faster stimuli. The vestibulo-ocular reflex acted to produce a sinusoidal compensatory eye movement in response to sinusoidal stimuli. The phase of the eye movement with respect to head movement advanced as stimulus frequency decreased, the familiar signature of the torsion pendulum behavior of the semicircular canals. The first-order time constant of the vestibulo-ocular reflex, as measured from the eye velocity decay after a vestibular velocity step, was 660 ms. The response of the vestibulo-ocular reflex changed with stimulus amplitude, having a higher gain and smaller phase lead when stimulus amplitude was increased. As a result of this nonlinear behavior, reflex gain correlated strongly with stimulus acceleration over the 0.1-1.6 Hz frequency range. When whole body rotation was performed in the light the optokinetic and vestibular system combined to generate nearly constant response gain (approximately 0.8) and phase (approximately 0°) over the tested frequency range of 0.1-1.6 Hz. We conclude that the compensatory eye movements of the mouse are similar to those found in other afoveate mammals, but there are also significant differences, namely shorter apparent time constants of the angular VOR and stronger nonlinearities

The Intrinsic Plasticity Of Medial Vestibular Nucleus Neurons During Vestibular Compensation: A Systematic Review And Meta-Analysis

The diversity of activity displayed by neurons of the central nervous system is unmatched by any other cell in the body. Each neuron displays a characteristic, stereotypic pattern of firing which often defines its functional role (Llinas, 1988). Some neurons are spontaneously active at rest, displaying pacemaker-like properties, while others are very quiescent until stimulated by synaptic inputs. Some neurons fire rapid, regular action potential trains which show little deterioration in frequency over time. Others fire only short bursts of action potentials and reduce their rate of firing quickly, producing very little response to even large inputs (Bean, 2007). These discharge characteristics are fundamentally determined by two main features: the intrinsic membrane properties of the neuron and the nature of the synaptic inputs the neuron receives. Intrinsic properties are those relating to the architecture of the neuronal membrane, intracellular ionic buffers that regular electrolyte concentrations and the types of ion channels expressed on the membrane and their pattern of distribution (Wijesinghe & Camp, 2011). Meanwhile, synaptic properties are determined by the types of transmitters arriving at the neuronal surface, the distribution of these synapses and their density over various functionally specialised regions of the neuron (Spruston, 2008). From the various permutations of these different properties emerges the vast array of different firing characteristics observed of individual neurons from different regions of the brain (Llinas, 2014). Despite the prevalent stereotypy observed across different subtypes of neurons, alterations in the local environment and external stimuli can induce changes in these basic properties. This phenomenon, known as neuronal plasticity, has been observed in normal physiological states and is believed to underlie experience-dependent changes in neural activity such as learning and memory (Mayford, Siegelbaum & Kandel, 2012; Sweatt, 2016). It has also been observed in various disease states and may act as a homeostatic mechanism to downregulate excitotoxicity or restore lost functional capacities (Beck & Yaari, 2008; Camp, 2012; Vitureira, Letellier & Goda, 2012; Yin & Yuan, 2014). These changes were first observed to occur in synapses, where high intensity stimuli induced changes that altered the likelihood of signal transmission at a particular synapse. Since then, the stimuli that induce synaptic plasticity and the cellular mechanisms that maintain these changes have been widely investigated (Bailey, Kandel & Harris, 2015; Kandel, 2001). However, it has now been recognised that intrinsic neuronal properties themselves are plastic and may contribute to some of the processes previously attributed to synaptic mechanisms alone (Desai, 2003; Hanse, 2008; Mozzachiodi & Byrne, 2010; Titley, Brunel & Hansel, 2017). A number of studies in the past 30 years have demonstrated important activity-dependent changes in firing dynamics that appear to be act along multiple timescales and influence network activity in a variety of ways. These changes, termed intrinsic plasticity, are manifest in the patterns and frequency of action potential discharge of individual neurons. This dynamism is primarily driven by alterations in ion channel expression, excitatory neurotransmitter receptor expression and intracellular buffering protein concentrations (Beraneck & Idoux, 2012; Camp & Wijesinghe, 2009). I am interested in the studying the basic intrinsic properties of individual neurons, how they determine discharge dynamics in networks, and the conditions that modulate these properties (for example see previous work in Camp & Wijesinghe, 2009; Wijesinghe & Camp, 2011; Wijesinghe, Solomon & Camp, 2013; Wijesinghe et al., 2015). In particular, I am interested in how pathological changes might influence the firing properties of downstream neurons. Typically, animal models with a simple neuronal circuit, an easily lesioned peripheral sensory organ and observable behaviours have been chosen for such studies. One such model system is the vestibular system, which maintains our sense of equilibrium. It is composed of an easily accessible neuronal circuit within the brainstem which is homologous between a number of species (Goldberg et al., 2012). It mediates basic reflexes that maintain gaze stability during head movement and stabilises dynamic posture (Bronstein, Patel & Arshad, 2015). This sensory modality also has a unique property of near immediate recovery following damage to the components that mediate it, a process known as vestibular compensation (Curthoys & Halmagyi, 1995). This process occurs in humans and can be reliably reproduced experimentally, making it a convenient model to bridge in vitro findings to clinical observations (Straka, Zwergal & Cullen, 2016). Recent studies have suggested that vestibular compensation may be behavioural correlate of a form of experience-dependent plasticity occurring within the vestibular nuclei of the brainstem (Dutia, 2010; Lacour & Tighilet, 2010; Macdougall & Curthoys, 2012). More interestingly, part of the recovery may be mediated by changes in the intrinsic properties of vestibular nucleus neurons in a way that is necessary for the process to occur. In the thesis that follows, I present the first comprehensive systematic review of the scientific literature searching for evidence to investigate the following hypothesis: intrinsic plasticity mediates changes observed during the acute phase of vestibular compensation. To determine the methodological quality of studies discovered through searches of electronic databases, I independently developed tools to assess the precision, validity and bias of each study. Based on a total of 17 studies which met pre-determined inclusion and exclusion criteria, I conclude that there is evidence in favour of the hypothesis. Then, pooling quantitative data from this evidence, I performed a meta-analysis which demonstrates a moderate, statistically significant increase in the intrinsic excitability of medial vestibular nucleus neurons following unilateral vestibular deafferentation. Specifically, their spontaneous discharge rate increases by 4 spikes/sec on average and their sensitivity (or gain) in response to current stimuli increases. Using this novel approach, I demonstrate that the methodology of systematic review and meta-analysis is a useful tool in the summation of data across experimental studies with similar aims. I also identify a number of areas in which the reporting of experimentation in field of vestibular research can be improved to strengthen the quality and validity of future work. Despite the prevalent stereotypy observed different subtypes of neurons, alterations in the local environment and external stimuli can induce changes in these basic properties. This phenomenon, known as neuronal plasticity, has been observed in normal physiological states and is believed to underlie experience-dependent changes in neural activity such as learning and memory (Mayford, Siegelbaum et al. 2012, Sweatt 2016). It has also been observed in various disease states and may act as a homeostatic mechanism to downregulate excitotoxicity or restore lost functional capacities (Beck and Yaari 2008, Camp 2012, Vitureira, Letellier et al. 2012, Yin and Yuan 2014). These changes were first observed to occur in synapses, where high intensity stimuli induced changes that altered the likelihood of signal transmission at a particular synapse. Since then, the stimuli that induce synaptic plasticity and the cellular mechanisms that maintain these changes have been widely investigated (Kandel 2001, Bailey, Kandel et al. 2015). However, it has now been recognised that intrinsic neuronal properties themselves are plastic and may contribute to some of the processes previously solely attributed to synaptic mechanisms (Desai 2003, Hanse 2008, Mozzachiodi and Byrne 2010, Titley, Brunel et al. 2017). A number of studies in the past 20 years have demonstrated important activity dependent changes in firing dynamics that appear to be act along multiple timescales and influence network activity in a variety of ways. These changes, termed intrinsic plasticity, are manifest in the patterns and frequency of action potential discharge of individual neurons. This dynamism is primarily driven by alterations in ion channel expression, excitatory neurotransmitter receptor expression and intracellular buffering protein concentrations (Camp and Wijesinghe 2009, Beraneck and Idoux 2012). I am interested in the studying the basic intrinsic properties of individual neurons, how they determine discharge dynamics in networks, and the conditions that modulate these properties. In particular, I am interested in how pathological changes might influence the firing properties of downstream neurons. Typically, animal models with a simple neuronal circuit, an easily lesioned peripheral sensory organ and observable behaviours have been chosen for such studies. One such model system is the vestibular system, which maintains an animal’s sense of equilibrium. It is composed of an easily accessible neuronal circuit within the brainstem which is homologous between a number of species (Goldberg, Wilson et al. 2012). It mediates basic reflexes that maintain gaze stability during head movement (vestibuloocular reflex) and stabilises posture (vestibulospinal reflex) (Bronstein, Patel et al. 2015). This sensory modality also has a unique property of near immediate and complete recovery following damage to the components that mediate it, a process known as vestibular compensation (Curthoys and Halmagyi 1995). For example, following unilateral peripheral vestibular lesions, the acute symptom of vertigo and its behavioural effects abate spontaneously within days (Fetter 2016). This process occurs in humans and can be reliably reproduced experimentally, making it a convenient and ideal model to bridge in vitro findings to clinical observations (Straka, Zwergal et al. 2016). Recent studies have suggested that vestibular compensation may be a form of experience dependent plasticity which occurs within the brainstem vestibular reflex arc, most clearly in the vestibular nuclei (Dutia 2010, Lacour and Tighilet 2010, Macdougall and Curthoys 2012). More interestingly, part of the recovery may be mediated by changes in the intrinsic properties of vestibular nucleus neurons. Many of these changes are of the firing patterns and sensitivity to external stimuli, reflecting changes in the intrinsic properties of these. In the thesis that follows, I present a systematic review of the scientific literature looking for evidence to investigate the following hypothesis: intrinsic plasticity mediates changes observed during vestibular compensation. To determine the quality of studies revealed through searches of electronic databases, I independently developed tools to assess the precision, validity and bias of each study. Based on a total of 16 studies which met pre-determined inclusion and exclusion criteria, I conclude that there is moderate amount of moderate quality evidence, and a small amount of high quality evidence, in favour of the hypothesis. Further, using quantitative data from rodent models of compensation, I performed a meta-analysis which demonstrates strong, statistically significant evidence in favour of the hypothesis. In summary, published evidence to date supports the notion that unilateral vestibular lesions induce changes in the intrinsic membrane properties of medial vestibular nucleus neurons such that their spontaneous discharge rate increases and their sensitivity (or gain) in response to current stimuli increases