80 research outputs found

    Head-Down Tilt Position, but Not the Duration of Bed Rest Affects Resting State Electrocortical Activity

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    Adverse cognitive and behavioral conditions and psychiatric disorders are considered a critical and unmitigated risk during future long-duration space missions (LDSM). Monitoring and mitigating crew health and performance risks during these missions will require tools and technologies that allow to reliably assess cognitive performance and mental well-being. Electroencephalography (EEG) has the potential to meet the technical requirements for the non-invasive and objective monitoring of neurobehavioral conditions during LDSM. Weightlessness is associated with fluid and brain shifts, and these effects could potentially challenge the interpretation of resting state EEG recordings. Head-down tilt bed rest (HDBR) provides a unique spaceflight analog to study these effects on Earth. Here, we present data from two long-duration HDBR experiments, which were used to systematically investigate the time course of resting state electrocortical activity during prolonged HDBR. EEG spectral power significantly reduced within the delta, theta, alpha, and beta frequency bands. Likewise, EEG source localization revealed significantly lower activity in a broad range of centroparietal and occipital areas within the alpha and beta frequency domains. These changes were observed shortly after the onset of HDBR, did not change throughout HDBR, and returned to baseline after the cessation of bed rest. EEG resting state functional connectivity was not affected by HDBR. The results provide evidence for a postural effect on resting state brain activity that persists throughout long-duration HDBR, indicating that immobilization and inactivity per se do not affect resting state electrocortical activity during HDBR. Our findings raise an important issue on the validity of EEG to identify the time course of changes in brain function during prolonged HBDR, and highlight the importance to maintain a consistent body posture during all testing sessions, including data collections at baseline and recovery

    Neurobehavioral changes in response to long-duration bed rest

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    As space-faring nations across the globe are fueling a new race of human space exploration that goes well beyond the Moon, national agencies and private entities across the globe have accelerated the research and development that will promote the safety and success of such missions. Prolonged body unloading and reduced physical activity levels associated with space travel could adversely affect brain and behavior. Long-duration bed rest in –6° head-down tilt (>1 month) is an established spaceflight analog on Earth to simulate the physiological and psychological adaptations of prolonged inactivity and headward fluid shift during space travel. The present work investigated the effects of long-duration bed rest on brain function and cognitive performance. In a series of five studies combining behavioral, electrocortical and magnetic resonance imaging data it was shown that bed rest can induce significant functional brain changes and cognitive impairments including emotion processing, memory formation, and selective attention, and that these effects may not recover quickly. Structured physical activity programs superimposed to bed rest were found to mitigate cognitive impairments. The benefits of antioxidant supplementation and artificial gravity or their combination with exercise remain to be determined. Some caution is warranted when behavioral data are collected in different body positions, i.e., seated vs. head-down tilt, because the neurophysiological reactions associated with postural changes may mask the effects attributed to physical inactivity. Future work in this field should be characterized by an interdisciplinary approach, integrating multimodal brain imaging, psychological and behavioral, neurovestibular, cardiovascular, biochemical, and circadian data. Such an approach could promote a holistic understanding of intellectual frameworks that together exceed individual disciplinary perspectives. The knowledge from such approaches could go beyond their application to spaceflight. It can translate to the prevention and treatment of various clinical conditions associated with cognitive impairments, and for which reduced physical activity levels are a critical risk factor

    Structure-function study of ubiquitin c-terminal hydrolase L1 (UCH-L1) by NMR spectroscopy - insights into UCH-L1 mutation's association with the risk of Parkinson's disease

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    Poster Presentation: P72Protein ubiquitination and deubiquitination, play important roles in many aspects of cellular mechanisms. Its defective regulation results in diseases that range from developmental abnormalities to neurodegenerative diseases and cancer. Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) is a protein of 223 amino acids, which is highly abundant in brain, constituting up to 2% of total brain proteins. Although it was originally characterized as a deubiquitinating enzyme, recent studies indicate that it also functions as a ubiquitin ligase and a mono-Ub stabilizer. Down-regulation and extensive oxidative modifications of UCH-L1 have been observed in the brains of Alzheimer’s disease and Parkinson’s disease (PD) patients. Of importance, I93M and S18Y point mutations in the UCH-L1 gene have been reported to be linked to susceptibility to and protection from PD respectively. Hence, the structure of UCH-L1 and the effects of disease associated mutations on the structure and function are of considerable interest. Our circular dichroism studies suggest that the S18Y point mutation only slightly perturbs the structure while a significant decrease in the α-helical content is observed in the I93M mutant. We have determined the solution structure of S18Y and mapping its interaction with ubiquitin by chemical shift perturbation approach. The electrostatic surface potential analysis reveals that the interaction between ubiquitin and UCH-L1-S18Y is primarily electrostatic in nature, with negatively charged residues on the surface of UCH-L1-S18Y interacting with the positively charged residues on the basic face of ubiquitin. Although the active site and the L8 loop in UCH-L1-S18Y adopts conformations similar to that observed in the crystal structure of UCH-L1-WT, both the altered hydrogen bond network and surface charge distributions have demonstrated that the S18Y substitution could lead to profound structural changes. In particular, the difference in the dimeric interfaces of the wild-type and the S18Y mutant has shown that mutation can significantly affect the distribution of the surface-exposed residues involved in the dimeric interface. Such observed difference might weaken the stability of the UCH-L1 dimer and hence may explain the reduced dimerization-dependent ligase activity of UCH-L1-S18Y in comparison to UCH-L1-WT.postprin

    Protective effects of lycium barbarum polysaccharides on cerebral edema and blood-brain barrier disruption after ischemic stroke

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    Young Investigators Symposium I (Y3) - Di YangBACKGROUND: Ischemic stroke is a destructive cerebrovascular disease and one of the leading causes of death worldwide. The long term disability after stroke induces heavy burden both to the patients and the society. Yet, no effective neuroprotective agents are available. The polysaccharides extracted from the fruits of wolfberry, Lycium barbarum (LBP), showed neuroprotective and immune-modulative functions. We aim to evaluate the protective effects of LBP in experimental stroke using a focal cerebral ischemia/reperfusion (I/R) model. METHODS: C57BL/6N mice were subjected to 2 h of middle cerebral artery occlusion (MCAO) followed by 22 h of reperfusion. Prior to ischemia induction, animals were treated with either vehicle (PBS) or LBP daily for 7 days. Mice were evaluated for neurological deficits just before sacrifice. Brains were harvested for infarct size estimation, water content measurement and immunohistochemical analysis as well as Western blot experiments. Evans blue (EB) extravasation experiment was performed to determine blood-brain barrier (BBB) disruption after MCAO. RESULTS: LBP treatment significantly improved neurological scores and decreased infarct size, hemispheric swelling and water content as well as reduced EB extravasation. In addition, fewer apoptotic cells were identified in the LBP-treated brains by TUNEL assay. Immunoreactivity for aquaporin-4 and glial fibrillary acidic protein were also significantly decreased in LBP-treated brains. We further observed a reduction of nuclear factor-ÎşB translocation and IÎşB expression after LBP treatment. CONCLUSION: Seven-day LBP pre-treatment effectively improved neurological deficits, decreased infarct size and cerebral edema as well as protected the brain from BBB disruption, aquaporin water channel up-regulation and glial activation. The protective effects of LBP might partially act through its anti-inflammatory effects. The present study suggests that LBP may be used as a preventive neuroprotectant for ischemic stroke.postprin

    Aldose reductase deficiency protects the retinal neurons in a mouse model of retinopathy of prematurity

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    Poster Presentation: P64PURPOSE: Retinopathy of prematurity (ROP) is a common retinal disease occurred in premature babies. It is found to be related to oxidative stress while dysfunction of the neural retina has also been documented. We previously showed that genetic deletion or pharmacological inhibition of aldose reductase (AR), a rate- limiting enzyme in the polyol pathway, prevented ischemia-induced retinal ganglion cell (RGC) loss and oxidative stress. Here, we assessed the effects of AR deletion on retinal neurons using a mouse model of ROP. METHODS: Seven-day-old mouse pups were exposed to 75% oxygen for five days and returned to room air. The pathological neuronal changes were examined and compared between wild-type (WT) and AR-deficient retinae on P14 and P17 (P, postnatal). Retinal thickness was measured and immunohistochemistry for calbindin, calretinin, PKCα, Tuj1, glial fibrillary acidic protein (GFAP), nitrotyrosine (NT), as well as poly(ADP-ribose) (PAR) was performed. RESULTS: After hyperoxia exposure, significantly reduced inner nuclear layer (INL) and inner plexiform layer (IPL) thickness were found in both genotypes. The intensity of calbindin staining for horizontal cells in INL was reduced in the WT retinae but not in AR-deficient retinae. In addition, significant reduction was found in calretinin-positive amacrine cell bodies in central INL especially in WT retinae. Serious distortion was also observed in the three calretinin-positive strata along IPL in the WT retinae but not AR-deficient retinae on P17. Moreover, increased GFAP intensity across IPL indicating Müller cell processes was observed in AR-deficient retinae on P14 and in WT retinae on P17. Furthermore, increased NT immunoreactivity in INL and nuclear or para-nuclear PAR staining along GCL were observed in WT retina while these changes were not apparent in AR-deficient retina. CONCLUSION: Our observations demonstrated morphological changes of retinal neurons in the mouse model of ROP and indicated that AR deficiency showed neuronal protection in the retina, possibly through modulating glial responses and reducing oxidative stress.postprin

    Regulatory role of proheparanase with peri-synaptic heparan sulfate proteoglycan and AMPA-type glutamate receptor in synaptic plasticity

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    Poster Presentation: P59AMPA-type glutamate receptors (AMPAR) govern excitatory synaptic transmission. Perineuronal heparan sulfates (HS) have been implicated in controlling the open-state of AMPAR. Our finding of neuronal heparanase expression in adult rats led us to test (1) if neuronal heparanase is secreted and (2) if the secreted form acts on perineuronal HS to modulate synaptic plasticity. Neuronal secretion of heparanase was triggered by phorbol ester of rat hippocampal neurons in culture. Western blot analysis of the secreted product revealed enzymatically inactive proheparanase, but not the enzymatically active heparanase. Synaptosomes prepared from phorbol ester-treated rat cortexslices showed enrichment in proheparanase; co-immunoprecipitation studies further showed association of AMPAR subunits (GluA1 and GluA2/3) with both syndecan-3 (a transmembrane HS-proteoglycan) and proheparanase, suggesting their partnership in the peri-synaptic environment. Treatment of hippocampal neurons in culture with recombinant proheparanase triggered internalization of proheparanase, perineuronal HS-proteoglycans and AMPARs, suggesting their clustering as a functional complex. Heparitinase pre-treatment of hippocampal neuron cultures reduced proheparanase-induced internalization of AMPARs, suggesting that the HS moiety is critical for effecting the partnership. Treatment of hippocampal slices with recombinant proheparanase resulted in down-regulation of both basal synaptic strength and LTP at Schaffer collateral synapses. These results reveal a novel role of neuronal proheparanase in resetting AMPAR and perineuronal HS levels at the synapse and thus the modulation of synaptic plasticity.postprin

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    Effect of Psycho-Pharmacological Modulation of the Autonomic Nervous System on Human Oesophageal Pain Hypersensitivity

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    Background: Altered autonomic nervous system (ANS) function has been proposed as a mechanism in the development of central sensitisation (CS) and visceral pain hypersensitivity (VPH). The contribution of the parasympathetic nervous system (PNS) and the factors that mediate differences in sensitisation to acid are unclear and their study will clarify risk factors for oesophageal pain hypersensitivity (OPH) in gastrooesophageal reflux disease. Aims: To investigate psychophysiological and pharmacological manipulation of PNS tone in the development of OPH, and to determine factors which predict the development of OPH to acid infusion in healthy volunteers in a validated model of acid induced OPH. Methods: Pain thresholds to electrical stimulation in the proximal oesophagus were determined before and after a 30-minute distal oesophageal infusion of 0.15 mol/L hydrochloric acid in subjects. Sympathetic (SNS) and PNS parameters were measured at baseline and continuously thereafter. Subjects underwent psychological profiling for anxiety, depression, attachment vulnerability and personality type. Using this model, five studies were undertaken: Study 1 a pilot study to trail modulation suitability for further study used. In Study 2, subjects who demonstrated secondary hyperalgesia in the proximal non-acid-exposed oesophagus performed deep or sham breathing. Study 3 subjects, who did not sensitise to acid, underwent a validated stress test to induce OPH. With Study 4, deep breathing with IV saline (placebo) or atropine (PNS antagonist) was used to evaluate deep breathing’s induced PNS tone in OPH reduction. Study 5, a genetic pilot study, exploring the role of the GCH-1 haplotype in VPH. Results: ANS control’s key role in CS was clarified. Deep breathing increased PNS tone and prevented acid-induced OPH in comparison to sham breathing and confirmed increased PNS tone’s reversal of OPH. Psychological factors of anxiety, alexithymia and attachment status influence ANS modulation of CS. Individuals’ predisposition to VPH due to psychogenetic profiles were clarified and their biopsychosocial role illustrated. Conclusions and Inferences: A mechanistic explanation for the analgesic effect of deep breathing is provided with potential therapeutic implications in the treatment of VPH syndromes. Further clinical study is warranted to develop cost-effective treatments for chronic VPH syndromes

    Aerospace Medicine and Biology: A continuing bibliography with indexes (supplement 238)

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    This bibliography lists 583 reports, articles and other documents introduced into the NASA scientific and technical information system in October 1982
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