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Pressure chamber experiments for studying changes in motor, cadiovascular, respiratory, and central nervous systems during oxygen toxicity
The major goal of these studies was to continue investigations into the influence of altered gravitational fields on the development and function of the vertebrate brain and nervous system. Of major focus during the 18-month finding period of this award was the maintenance of the animals used in the experimental mouse and medaka model paradigms. The experiments focused on characterization of stress-sensitive periods in neural development and immediate or delayed effects on gene expression, physiology and behavior. The hypothesis under investigation was that the environment of space will have biologically significant effects on the development and function of the vertebrate nervous system. We have postulated that these effects will be more significant on certain neural compartments, such as the vestibular-motor system, and that these effects will have greater impact at particular stages of embryonic and post-natal development of the animal. Development of the central nervous system is well known for its vulnerability and sensitivity to environmental stimuli, although the effects of gravitational influences are poorly understood. The long-term goals of this research effort, initiated previously and continued in limited capacity during this interim period, were to provide important new information on the effects of altered environments during these critical periods.
Although expression of the small heat shock protein family member Hsp25 has been previously observed in the central nervous system (CNS), both constitutively and upon induction, its function in the CNS remains far from clear. In the present study we have characterized the spatial pattern of expression of Hsp25 in the normal adult mouse brain as well as the changes in expression patterns induced by subjecting mice to experimental hyperthermia or hypoxia. Immunohistochemical analysis revealed a surprisingly restricted pattern of constitutive expression of Hsp25 in the brain, limited to the facial, trigeminal, ambiguus, hypoglossal and vagal motor nuclei of the brainstem. After hyperthermia or hypoxia treatment, significant increases in the levels of Hsp25 were observed in these same areas and also in fibers of the facial and trigeminal nerve tracts. Immunoblot analysis of protein lysates from brainstem also showed the same pattern of induction of Hsp25. Surprisingly, no other area in the brain showed expression of Hsp25, in either control or stressed animals. The highly restricted expression of Hsp25 implies that this protein may have a specific physiological role in the orofacial motor nuclei, which govern precise coordination between muscles of mastication and the pharynx, larynx, and face. Its rapid induction after stress further suggests that Hsp25 may serve as a specific molecular chaperone in the lower cholinergic motor neurons and along their fibers under conditions of stress or injury. Copyright 1998 Elsevier Science B.V.
Vasopressin is synthesized by magnocellular neurons in supraoptic (SON) and paraventricular (PVN) hypothalamic nuclei and released by their axon terminals in the neurohypophysis (NH). With its actions as an antidiuretic hormone and vasoactive agent, vasopressin plays a pivotal role in the control of body fluids and cardiovascular homeostasis. Because of its well-defined neurobiology and functional importance, the SON/PVN-NH system is ideal to establish methods for gene transfer of genetic material into specific pathways in the mouse central nervous system. In these studies, we compared the efficiency of transferring the gene lacZ, encoding for beta-galactosidase (beta-gal), versus a gene encoding for green fluorescent protein by using replication-deficient adenovirus (Ad) vectors in adult mice. Transfection with viral concentrations up to 2 x 10(7) plaque-forming units per coverslip of NH, PVN, and SON in dissociated, cultured cells caused efficient transfection without cytotoxicity. However, over an extended period of time, higher levels (50% to 75% of the cells) of beta-gal expression were detected in comparison with green fluorescent protein (5% to 50% of the cells). With the use of a stereotaxic approach, the pituitary glands of mice were injected with Ad (4 x 10(6) plaque-forming units). In material from these animals, we were able to visualize the expression of the beta-gal gene in the NH and in magnocellular neurons of both the PVN and SON. The results of these experiments indicate that Ad-Rous sarcoma virus promoter-beta-gal is taken up by nerve terminals at the injection site (NH) and retrogradely transported to the soma of the neurons projecting to the NH. We conclude that the application of these experimental approaches will provide powerful tools for physiological studies and potential approaches to deliver therapeutic genes to treat diseases.
It is well known from numerous space flight studies that exposure to micro-g produces both morphological and neural adaptations in the major postural muscles. However, the characteristics and mechanism of these changes, particularly when it may involve the central nervous system are not defined. Furthermore, it is not known what role unloading of the muscular system may have on central changes in sensorimotor function or if centrifugation along the +Gz direction (long body axis) can mitigate both the peripheral changes in muscle function and modification of the central changes in sensorimotor adaptation to the near weightless environment of space flight. The purpose of this specific effort was, therefore, to investigate the efficacy of artificial gravity (AG) as a method for maintaining sensorimotor function in micro-g. Eight male subjects were exposed to daily 1 hr centrifugation during a 21 day 6 degree head-down bed rest study. Seven controls were placed on the centrifuge without rotation. The radius and angular velocity of the centrifuge were adjusted such that each subject experienced a centripetal acceleration of 2.5g at the feet, and approximately 1.0g at the heart. Both the tendon (MSR) and functional stretch reflexes (FSR) were collected using an 80 lb. ft. servomotor controlled via position feedback to provide a dorsiflexion step input to elicit the MSR, and the same step input with a built in 3 sec hold to evoke the FSR. EMG data were obtained from the triceps surae. Supplementary torque, velocity and position data were collected with the EMG responses. All data were digitized and sampled at 4 kHz. Only the MSR data has been analyzed at this time, and preliminary results suggest that those subjects exposed to active centrifugation (treatment group) show only minor changes in MSR peak latency times, either as a function of time spent in bed rest or exposure to centrifugation, while the control subjects show delays in the MSR peak latencies that are typical of bed rested subjects. There also appears to be a trend in the treatment group where centrifugation results in peak latencies that are shorter than the control group. This trend is supported by the observation that peak reflex amplitudes are larger (up to 40% in magnitude)than those of the control subjects. Furthermore, centrifugation tends, by day 21 of bed rest, to normalize the peak amplitudes to the amplitudes observed prior to bed rest or centrifugation. From a preliminary point of view, centrifugation appears to have a positive effect on the sensorimotor system, and specifically on those muscles that provide anti-gravity and postural support.
The timing of cell generation (onset and duration) in the developing rat vestibular and proprioceptive systems is investigated. The results clearly indicate a defined time-span for generation of all neurons in the central nervous system nuclei studied. This cytogenetic period in both vestibular and proprioceptive sensory nuclei is determined to occur during and immediately after placentation, a potentially critical period for spaceflight exposure due to alterations in maternal physiology.
The phenomenon of involuntary dehydration, the delay in full restoration of a body water deficit by drinking, has been described extensively but relatively little is known about its physiological mechanism. It occurs primarily in humans when they are exposed to various stresses including exercise, environmental heat and cold, altitude, water immersion, dehydration, and perhaps microgravity, singly and in various combinations. The level of involuntary dehydration is approximately proportional to the degree of total stress imposed on the body. Involuntary dehydration appears to be controlled by more than one factor including social customs that influence what is consumed, the capacity and rate of fluid absorption from the gastrointestinal system, the level of cellular hydration involving the osmotic-vasopressin interaction with sensitive cells or structures in the central nervous system, and, to a lesser extent, hypovolemic-angiotensin II stimuli. Since humans drink when there is no apparent physiological stimulus, the psychological component should always be considered when investigating the total mechanisms for drinking.
Scientific literature suggests that tear biomarkers can be used as a guide towards clinical diagnosis of human health (Hagan et al., 2016). This study will investigate whether tear biomarkers represents a research and clinical opportunity to assess human health prior to, during, and after exposure to the spaceflight environment. The focus of this study is to compare biomarkers previously identified as potentially relevant to both ocular and brain health against unique physiological outcomes of exposure to the space flight environment. Study subjects suffering from terrestrial conditions thought to be similar to Spaceflight Associated Neuro-ocular Syndrome (SANS: formerly VIIP), e.g. patients with idiopathic intracranial hypertension (IIH) and optic neuritis may be relevant to conditions associated with spaceflight. This study will review methodologies, tear biomarkers related to state of ocular and brain health, the strengths and weakness of using tear fluid biomarkers versus other body fluid samples, and will survey current tear fluid biomarker knowledge in research and clinical practice. A strength of using tear biomarkers is that sampling is non-invasive and used as a guide in understanding pathologies, including ocular and systemic inflammatory conditions (Cocho et al., 2016)., Salvisberg et al., 2014). Moreover, tear biomarkers may reflect diseases affecting the central nervous system (CNS) (Salvisberg et al., 2014). For example, in multiple sclerosis (MS), the concordance rate between tear biomarkers versus cerebrospinal fluid (CSF) is approximately 83%, indicating that, in the majority of cases, tears are at least as effective as CSF in potentially identifying novel MS biomarkers (Devos et al., 2001).
It has been postulated that alpha 2-adrenergic receptors play a modulatory role in the regulation of blood pressure. Activation of alpha 2-receptors located in the central nervous system results in inhibition of sympathetic tone and decrease of blood pressure. This indeed may be the mechanism of action of central sympatholytic antihypertensives such as alpha-methyldopa. Presynaptic alpha 2-receptors also are found in adrenergic nerve terminals. These receptors act as a negative feedback mechanism by inhibiting the release of norepinephrine. The relevance of alpha 2-adrenergic receptors for blood pressure regulation can be explored with yohimbine, a selective antagonist of these receptors. Yohimbine increases blood pressure in resting normal volunteers. This effect is associated with an increase in both sympathetic nerve activity, reflecting an increase in central sympathetic outflow, and in norepinephrine spillover, reflecting potentiation of the release of norepinephrine from adrenergic nerve terminals. These actions, therefore, underscore the importance of alpha 2-adrenergic receptors for blood pressure regulation even under resting conditions. Patients with autonomic failure, even those with severe sympathetic deprivation, are hypersensitive to the pressor effects of yohimbine. This increased responsiveness can be explained by sensitization of adrenergic receptors, analogous to denervation supersensitivity, and by the lack of autonomic reflexes that would normally buffer any increase in blood pressure. Preliminary studies suggest that the effectiveness of yohimbine in autonomic failure can be enhanced with monoamine oxidase inhibitors. Used in combination, yohimbine increases norepinephrine release, whereas monoamine oxidase inhibitors inhibit its degradation. Therefore, yohimbine is not only a useful tool in the study of blood pressure regulation, but may offer a therapeutic option in autonomic dysfunction.
The control of a multifingered hand slave in order to accurately exert arbitrary forces and impart small movements to a grasped object is, at present, a knotty problem in teleoperation. Although a number of articulated robotic hands have been proposed in the recent past for dexterous manipulation in autonomous robots, the possible use of such hands as slaves in teleoperated manipulation is hindered by the present lack of sensors in those hands, and (even if those sensors were available) by the inherent difficulty of transmitting to the master operator the complex sensations elicited by such sensors at the slave level. An analysis of different problems related to sensor-based telemanipulation is presented. The general sensory systems requirements for dexterous slave manipulators are pointed out and the description of a practical sensory system set-up for the developed robotic system is presented. The problem of feeding back to the human master operator stimuli that can be interpreted by his central nervous system as originated during real dexterous manipulation is then considered. Finally, some preliminary work aimed at developing an instrumented glove designed purposely for commanding the master operation and incorporating Kevlar tendons and tension sensors, is discussed.
Based on preliminary suggestions that individual differences in susceptibility to stressful motion might be related to physiological differences in responses of the hypothalamic-pituitary-adrenal axis, the efficacy of dexamethasone and metyrapone is tested in subjects exposed to cross-coupled accelerative semicircular canal stimulation on a rotating chair. Subjects given 0.5 mg of dexamethasone every 6 h for 48 h could endure 80 percent more stressful motion (P = 0.03) in a within-subjects design study, whereas, no improvement followed treatment with 750 mg of metryapone every 4 h for 24 h. The efficacy of dexamethasone might be explained in terms of its neurochemical actions on several neurotransmitter systems which are also modulated by such classical antimotion sickness drugs as amphetamine and scopolamine. Because dexamethasone induces adaptive changes within the central nervous system it may prove superior to scopolamine and amphetamine which possess significant side effects, are short acting, and rapidly tolerated.
A "sensory conflict" model of spatial orientation was developed. This mathematical model was based on concepts derived from observer theory, optimal observer theory, and the mathematical properties of coordinate rotations. The primary hypothesis is that the central nervous system of the squirrel monkey incorporates information about body dynamics and sensory dynamics to develop an internal model. The output of this central model (expected sensory afference) is compared to the actual sensory afference, with the difference defined as "sensory conflict." The sensory conflict information is, in turn, used to drive central estimates of angular velocity ("velocity storage"), gravity ("gravity storage"), and linear acceleration ("acceleration storage") toward more accurate values. The model successfully predicts "velocity storage" during rotation about an earth-vertical axis. The model also successfully predicts that the time constant of the horizontal vestibulo-ocular reflex is reduced and that the axis of eye rotation shifts toward alignment with gravity following postrotatory tilt. Finally, the model predicts the bias, modulation, and decay components that have been observed during off-vertical axis rotations (OVAR).
Radiation is considered to be one of three or four major hazards for personnel in space and has emerged as the most critical issue to be resolved for long-term missions, both orbital and interplanetary. Space habitats are stressful and dangerous environments. Health and medical consequences arising from microgravity, stress, and trauma include weakened immune systems, increased viral activity, and loss of bone mass. The greatest risks from radiation are generally assumed to be cancers and possibly damage to the central nervous system. Synergistic effects arising from the other environmental hazards along with abscopal and exogenic factors are likely. Space programs represent an exceptional opportunity for examining the biological consequences of low-dose exposures of humans to radiation at every level of progression. Although astronauts are a relatively small population, they are healthy, physically active volunteers who undergo extensive testing and medical examinations before, during, and after protracted exposures with periodic follow-up examinations. The radiation environments along with other hazards are likewise monitored and documented. Extensive international research programs are in progress. Seven years ago the U.S. National Aeronautics and Space Administration established the National Space Biomedical Research Institute through a cooperative agreement with a consortium of research and academic institutions in order to address radiation issues through a concerted, programmatic effort. Advanced technologies are rapidly being incorporated into these programs to determine the significance of new biological data and to evaluate the interplay among the different medical hazards. Programmatic in vivo and in vitro studies of the processes leading to carcinogenesis are in progress. Drugs and dietary supplements are being examined at the cellular and in vivo levels to assess their potential as dose-modifying agents. The infrastructure of this new approach, recent results, and research in progress are reviewed and discussed.
This paper reports on a theoretical investigation into the effects of vasomotion on blood through the human cardiovascular system. The finite element method has been used to analyse the model. Vasoconstriction and vasodilation may be effected either through the action of the central nervous system or autoregulation. One of the conditions responsible for vasomotion is exercise. The proposed model has been solved and quantitative results of flows and pressures due to changing the conductances of specific networks of arterioles, capillaries and venules comprising the arms, legs, stomach and their combinations have been obtained.
The many known health risks currently associated with space travel include increased risk of cardiovascular disease, cancer, central nervous system related diseases, muscle degeneration, and changes with host-gut microbiome interactions that can have profound impact with these and other health risks. The majority of the risk from space travel stem of the two components of the space environment which are microgravity and radiation. Two specific systemic effects have been uncovered by us to impact the body as a whole due to the space environment. One factor is related from our earlier work (Beheshti et al, PLOS One, 2018), we predicted that there is a systemic component of the host that causes general increased health risks due to spaceflight driven by a circulating microRNA (miRNA) signature consisting of 13 miRNAs that directly regulates both p53 and TGF1. MiRNAs are small non-coding RNA molecules with a negative and post-transcriptional regulation on gene expression) are increasingly recognized as major systemic regulators of responses to stressors, including microgravity, oxidative stress, and DNA damage. In addition, due to the size and stability of miRNAs, it is known that miRNAs can circulate throughout the body and have been found in the majority of the bodily fluids including blood, urine, saliva, and tears. Here, we start to dissect the actual impact of this miRNA signature on both the radiation and microgravity components and prove that this miRNA signature actually exists in the circulation of a host. The other systemic factor we uncovered was the impact the mitochondria on the whole body due to spaceflight. We hypothesize that spaceflight may promote a physiologic response driven by systemic mitochondria pathways leading to metabolic disorder stemming from the liver and directly impacting other organs and tissues. A systems biology method was implemented utilizing GeneLab datasets that involved in vitro experiments performed at the low Earth orbit, in vivo experiments involving mice flown to space, and finally human physiological data from astronauts. A comprehensive multi-omics approach was implemented which involved correlating transcriptomic analysis with proteomics, metabolomics, and methylation analysis. This approach led us to confirm our hypothesis that a systemic mitochondrial driven response is responsible for increasing potential health risk and is conserved from the in vitro studies, to the in vivo studies, and finally confirmed in astronauts.
This article summarizes a variety of newly published findings obtained by the Neuroscience Laboratory, Johnson Space Center, and attempts to place this work within a historical framework of previous results on posture, locomotion, motion sickness, and perceptual responses that have been observed in conjunction with space flight. In this context, we have taken the view that correct transduction and integration of signals from all sensory systems is essential to maintaining stable vision, postural and locomotor control, and eye-hand coordination as components of spatial orientation. The plasticity of the human central nervous system allows individuals to adapt to altered stimulus conditions encountered in a microgravity environment. However, until some level of adaptation is achieved, astronauts and cosmonauts often experience space motion sickness, disturbances in motion control and eye-hand coordination, unstable vision, and illusory motion of the self, the visual scene, or both. Many of the same types of disturbances encountered in space flight reappear immediately after crew members return to earth. The magnitude of these neurosensory, sensory-motor and perceptual disturbances, and the time needed to recover from them, tend to vary as a function of mission duration and the space travelers prior experience with the stimulus rearrangement of space flight. To adequately chart the development of neurosensory changes associated with space flight, we recommend development of enhanced eye movement systems and body position measurement. We also advocate the use of a human small radius centrifuge as both a research tool and as a means of providing on-orbit countermeasures that will lessen the impact of living for long periods of time with out exposure to altering gravito-inertial forces. Copyright 1998 Elsevier Science B.V.
Human balance control is known to be transiently disrupted after spaceflight; however, the mechanisms responsible for postflight postural ataxia are still under investigation. In this report, we propose a conceptual model of vestibulospinal adaptation based on theoretical adaptive control concepts and supported by the results from a comprehensive study of balance control recovery after spaceflight. The conceptual model predicts that immediately after spaceflight the balance control system of a returning astronaut does not expect to receive gravity-induced afferent inputs and that descending vestibulospinal control of balance is disrupted until the central nervous system is able to cope with the newly available vestibular otolith information. Predictions of the model are tested using data from a study of the neurosensory control of balance in astronauts immediately after landing. In that study, the mechanisms of sensorimotor balance control were assessed under normal, reduced, and/or altered (sway-referenced) visual and somatosensory input conditions. We conclude that the adaptive control model accurately describes the neurobehavioral responses to spaceflight and that similar models of altered sensory, motor, or environmental constraints are needed clinically to predict responses that patients with sensorimotor pathologies may have to various visual-vestibular or changing stimulus environments.
Astronauts experience perceptual and sensory-motor disturbances during spaceflight and immediately after return to the 1-g environment of Earth. During spaceflight, sensory information from the eyes, limbs and vestibular organs is reinterpreted by the central nervous system so that astronauts can produce appropriate body movements in microgravity. Alterations in sensory-motor function may affect eye-head-hand coordination and, thus, the crewmember's ability to manually locate objects in extrapersonal space. Previous reports have demonstrated that crewmembers have difficulty in estimating joint and limb position and in pointing to memorized target positions on orbit and immediately postflight. One set of internal cues that may assist in the manual localization of objects is information from the vestibular system. This system contributes to our sense of the body's position in space by providing information on head position and movement and the orientation of the body with respect to gravity. Research on the vestibular system has concentrated on its role in oculo-motor control. Little is known about the role that vestibular information plays in manual motor control, such as reaching and pointing movements. Since central interpretation of vestibular information is altered in microgravity, it is important to determine its role in this process. This summer, we determined the importance of vestibular information in a subject's ability to point accurately toward a target in extrapersonal space. Subjects were passively rotated across the earth-vertical axis and then asked to point back to a previously-seen target. In the first paradigm, the subjects used both visual and vestibular cues for the pointing response, while, in the second paradigm, subjects used only vestibular information. Subjects were able to point with 85 percent accuracy to a target using vestibular information alone. We infer from this result that vestibular input plays a role in the spatial programming of manual responses.