Orexin-A attenuated motion sickness through modulating neural activity in hypothalamus nuclei.

BACKGROUND AND PURPOSE: We evaluated the hypothesis that central orexin application could counteract motion sickness responses through regulating neural activity in target brain areas. EXPERIMENTAL APPROACH: Thec effects of intracerebroventricular (i.c.v.) injection of orexin-A and SB-334867 (OX1 antagonist) on motion sickness-induced anorexia, nausea-like behaviour (conditioned gaping), hypoactivity and hypothermia were investigated in rats subjected to Ferris wheel-like rotation. Orexin-A responsive brain areas were identified using Fos immunolabelling and were verified via motion sickness responses after intranucleus injection of orexin-A, SB-334867 and TCS-OX2-29 (OX2 antagonist). The efficacy of intranasal application of orexin-A versus scopolamine on motion sickness symptoms in cats was also investigated. KEY RESULTS: Orexin-A (i.c.v.) dose-dependently attenuated motion sickness-related behavioural responses and hypothermia. Fos expression was inhibited in the ventral part of the dorsomedial hypothalamus (DMV) and the paraventricular nucleus (PVN), but was enhanced in the ventral part of the premammillary nucleus ventral part (PMV) by orexin-A (20 µg) in rotated animals. Motion sickness responses were differentially inhibited by orexin-A injection into the DMV (anorexia and hypoactivity), the PVN (conditioned gaping) and the PMV (hypothermia). SB-334867 and TCS-OX2-29 (i.c.v. and intranucleus injection) inhibited behavioural and thermal effects of orexin-A. Orexin-A (60 µg·kg-1) and scopolamine inhibited rotation-induced emesis and non-retching/vomiting symptoms, while orexin-A also attenuated anorexia with mild salivation in motion sickness cats. CONCLUSION AND IMPLICATIONS: Orexin-A might relieve motion sickness through acting on OX1 and OX2 receptors in various hypothalamus nuclei. Intranasal orexin-A could be a potential strategy against motion sickness.

New Role of D-Cycloserine: Shorten Adaptation Process and Extend Maintenance Time of Motion Sickness.

INTRODUCTION: The aim of the study was to investigate the role of D-cycloserine (DCS) in the adaptation process and maintenance of motion sickness (MS). METHODS: In experiment 1, 120 SD rats were used to study the promoting effect of DCS on the adaptation process of MS in rats. They were randomly divided into four groups, DCS-rotation (DCS-Rot), DCS-static, saline-rotation (Sal-Rot), and saline-static, and further divided into three subgroups according to the adaptation time (4 days, 7 days, and 10 days) in each group. After being given DCS (0.5 mg/kg) or 0.9% saline, they were rotated or kept static according to the group. Their fecal granules, total distance, and total activity of spontaneous activity were recorded and analyzed. In experiment 2, other 120 rats were used. The experimental grouping and specific experimental method were the same as experiment 1. According to the grouping of the adaptive maintenance duration, the animals of 14 days, 17 days, and 21 days groups were measured on the corresponding date of the changes in the animals' exploratory behavior. RESULTS: In experiment 1, the fecal granules, total distance, and total activity of spontaneous activity of Sal-Rot returned to the control level on 9 days, and the DCS-Rot group returned to the control level on 6 days, indicating that DCS could shorten the adaptation time of MS rats from 9 days to 6 days. In experiment 2, the Sal-Rot could not maintain the adaptive state after 14 days' absence from the seasickness environment. The fecal granules of DCS-Rot increased significantly, and total distance and total activity of spontaneous activity of DCS-Rot decreased significantly from 17 days. These illustrate that DCS can prolong the adaptive maintenance time from within 14 days to 17 days in MS rats. CONCLUSION: 0.5 mg/kg DCS injected intraperitoneally can shorten the MS adaptation process and extend the maintenance time of adaptation of SD rats.

Stroboscopic lighting with intensity synchronized to rotation velocity alleviates motion sickness gastrointestinal symptoms and motor disorders in rats.

Motion sickness (MS) is caused by mismatch between conflicted motion perception produced by motion challenges and expected "internal model" of integrated motion sensory pattern formed under normal condition in the brain. Stroboscopic light could reduce MS nausea symptom via increasing fixation ability for gaze stabilization to reduce visuo-vestibular confliction triggered by distorted vision during locomotion. This study tried to clarify whether MS induced by passive motion could be alleviated by stroboscopic light with emitting rate and intensity synchronized to acceleration-deceleration phase of motion. We observed synchronized and unsynchronized stroboscopic light (SSL: 6 cycle/min; uSSL: 2, 4, and 8 cycle/min) on MS-related gastrointestinal symptoms (conditioned gaping and defecation responses), motor disorders (hypoactivity and balance disturbance), and central Fos protein expression in rats receiving Ferris wheel-like rotation (6 cycle/min). The effects of color temperature and peak light intensity were also examined. We found that SSL (6 cycle/min) significantly reduced rotation-induced conditioned gaping and defecation responses and alleviated rotation-induced decline in spontaneous locomotion activity and disruption in balance beam performance. The efficacy of SSL against MS behavioral responses was affected by peak light intensity but not color temperature. The uSSL (4 and 8 cycle/min) only released defecation but less efficiently than SSL, while uSSL (2 cycle/min) showed no beneficial effect in MS animals. SSL but not uSSL inhibited Fos protein expression in the caudal vestibular nucleus, the nucleus of solitary tract, the parabrachial nucleus, the central nucleus of amygdala, and the paraventricular nucleus of hypothalamus, while uSSL (4 and 8 cycle/min) only decreased Fos expression in the paraventricular nucleus of hypothalamus. These results suggested that stroboscopic light synchronized to motion pattern might alleviate MS gastrointestinal symptoms and motor disorders and inhibit vestibular-autonomic pathways. Our study supports the utilization of motion-synchronous stroboscopic light as a potential countermeasure against MS under abnormal motion condition in future.

Rapid responses of adipocytes to iron overload increase serum TG level by decreasing adiponectin.

Iron overload is tightly connected with metabolic disorders. Excess iron in the adipose and its roles in dyslipidemia are of interest to be identified. In acute iron overload mice receiving intraperitoneal injection of 100 mg/kg/day dextran-iron for 5 days, the epididymis adipose showed a remarkable increase in iron. Serum triglyceride and low-density lipoprotein cholesterol (LDL-C) levels were increased and high-density lipoprotein cholesterol (HDL-C) level was decreased, while serum alkaline phosphatase, aspartate aminotransferase, glucose, and insulin were not affected. The serum-cytokine-microarray showed that adipocytokines, including adiponectin, leptin, and resistin were significantly decreased. Other serum cytokines, including pro-insulin cytokines, inflammatory cytokines, chemokines, and growth factors were not changed, except that ghrelin and chemokine RANTES were increased. Iron overload decreased expressions of adiponectin and leptin both in vivo and in vitro. Intraperitoneal injection of recombinant leptin at 1 µg/g in acute iron overload mice had no significant effects on serum levels of TC, TG, HDL-C, and LDL-C, while intraperitoneal injection of recombinant adiponectin at 3 µg/g partially restored serum TG level through improving activities of lipoprotein lipase and hepatic lipase, but abnormal serum LDL-C and HDL-C were not redressed, suggesting other mechanisms also existed. In conclusion, the adipose responds to iron overload at an early stage to interfere with lipid metabolism by secreting adipocytokines, which may further affect glucose metabolism, inflammation, and other iron overload-induced effects on the body.

Pyruvate accumulation may contribute to acceleration-induced impairment of physical and cognitive abilities: an experimental study.

BACKGROUND: Fatigue can be induced after acceleration exposure, however its mechanism is still unclear. The aim of the present study was to examine whether metabolites' changes can decrease cognitive and physical function after acceleration. METHODS: Graybiel scale and Fatigue Self-rating scale were used to assess the seasickness and fatigue degrees of 87 male seafarers respectively after sailing. To test the effect of pyruvate on cognitive and physical functions, five different doses of pyruvate were administrated into rats. Insulin can reduce the accumulation of pyruvate. To observe the insulin effect on pyruvate, cognitive and physical functions after acceleration, insulin administration or treatment of promoting insulin secretion was used. Physical and cognitive functions were assessed using open field test (OFT), morris water maze (MWM) and loaded swimming test (LST) in animals. RESULTS: Physical and cognitive abilities were decreased obviously, and serum pyruvate increased mostly in human and rats after acceleration. Compared with vehicle group, physical and cognitive abilities were significantly decreased after pyruvate administration. Besides, we found a significant decline in adenosine triphosphate (ATP) concentration and pyruvate dehydrogenase (PDH) activity in the hippocampus, prefrontal cortex, liver, and muscle of rats treated with acceleration or pyruvate injection, while insulin administration or treatment of promoting insulin secretion markedly alleviated this decline and the impairment of physical and cognitive abilities, compared with the control group. CONCLUSION: Our results indicate that pyruvate has a negative effect on physical and cognitive abilities after acceleration. Insulin can inhibit pyruvate accumulation and cognitive and physical function after acceleration exposure.

Sea Voyage Training and Motion Sickness Effects on Working Ability and Life Quality After Landing.

BACKGROUND: The effects of seasickness on working performance during motion exposure have been reported, while the aftereffects on working ability and life quality decline (WLD) still remain unclarified.METHODS: Two cohorts of healthy male Chinese subjects received either a single (SSV) or repeated (RSV) sea voyage training program on different vessels. A seasickness incidence (SSI) questionnaire was administered to assess the prevalence of seasickness symptoms (vomiting, nausea, other, or no symptoms). A WLD questionnaire was used to survey the general feeling of WLD (severe, moderate, slight, and none) by a 4-point score as well as the incidence rate (IR) of specific WLD items within 24 h after landing.RESULTS: The RSV cohort had lower overall IR of WLD than the SSV cohort (54.64% vs. 63.78%, N 657 for both cohorts). The landing ship trainees in both cohorts showed higher general WLD score and higher IRs of physical fatigue, sleep disorder, and spontaneous locomotion decrement than those trained on the small vessels. Subjects with vomiting or nausea had higher general WLD score and higher IRs of concentration distraction, physical fatigue, anorexia, and spontaneous locomotion decrement than those with no symptoms. Higher IRs of firing accuracy decline (SSV: 21.35% vs. 7.13%, 9.14%; RSV: 22.11% vs. 9.28%, 5.27%), equipment operation disturbance (SSV: 16.85% vs. 3.57%, 6.85%; RSV: 20.47% vs. 7.85%, 7.03%) were also observed in the vomiting subjects than those with other symptoms and no symptoms.DISCUSSION: Significant WLD after landing was associated with transportation types, seasickness severity, and habituation during sea voyage training.Qi R-R, Xiao S-F, Su Y, Mao Y-Q, Pan L-L, Li C-H, Lu Y-L, Wang J-Q, Cai Y-L. Sea voyage training and motion sickness effects on working ability and life quality after landing. Aerosp Med Hum Perform. 2021; 92(2):9298.

Profiling of cybersickness and balance disturbance induced by virtual ship motion immersion combined with galvanic vestibular stimulation.

Profile of cybersickness and balance disturbance induced by virtual ship motion alone and in combination with galvanic vestibular stimulation (GVS) remained unclear. Subjects were exposed to a ship deck vision scene under simulated Degree 5 or 3 sea condition using a head-mounted virtual reality display with or without GVS. Virtual ship motion at Degree 5 induced significant cybersickness with symptom profile: nausea syndrome > central (headache and dizziness) > peripheral (cold sweating) > increased salivation. During a single session of virtual ship motion exposure, GVS aggravated balance disturbance but did not affect most cybersickness symptoms except cold sweating. Repeated exposure induced cybersickness habituation which was delayed by GVS, while the temporal change of balance disturbance was unaffected. These results suggested that vestibular inputs play different roles in cybersickness and balance disturbance during virtual reality exposure. GVS might not serve as a potential countermeasure against cybersickness induced by virtual ship motion.

Reduction of hemoglobin, not iron, inhibited maturation of red blood cells in male rats exposed to high intensity endurance exercises.

The existence of sports anemia, induced by strenuous or long-term exercise and characterized by decreases of red blood cells (RBCs), hemoglobin and iron content, remains to be doubtful. To observe the effects of endurance exercise on RBCs and explain the underlying reason, we designed this study by observing RBCs parameters and iron metabolism in 8-weeks training rats and effects of iron supplement or protein supplement on RBCs. Results showed that erythrocyte counts, hematocrit, mean corpuscular volume and hemoglobin content decreased while RBC distribution width increased in exercised rats at later stage during 8 weeks training. But the contents of serum iron and ferritin decreased only at 1-week and 2-week and returned to normal at 4-week and 8-week. Same as iron content, apparent iron absorption rate was declined at early stage but restored to normal level at 8-week, as well as serum adrenaline, cortisol and insulin levels. Instead, the contents of total protein and albumin in serum were decreased at later stage during 8-weeks training. Furthermore, we observed that protein supplement ameliorated RBCs parameters in rats exposed to 8 weeks swimming exercise, but iron supplement had no effects on RBCs, though it obviously increased iron content of serum and the liver. Based on these results, we drew a conclusion that transient changes of iron metabolism, which may be induced by stress hormone changes, was not the reason for RBCs decrease in endurance exercises but hemoglobin reduction, induced by defects in protein supplement, impeded development of RBCs.

Anti-cholinergics mecamylamine and scopolamine alleviate motion sickness-induced gastrointestinal symptoms through both peripheral and central actions.

Enhanced cholinergic activity contributes to the production of complex autonomic manifestations of motion sickness (MS). However, whether anti-cholinergics exert their anti-MS effects through central or peripheral actions remained unclarified. In the present study, we investigated the effects of mecamylamine (MEC) and scopolamine (SCOP) on rotation-induced gastrointestinal symptoms (conditioned gaping and defecation), locomotion disturbances (hypoactivity and impaired balance performance), hypothermia as well as Fos expression in vestibulo-autonomic regions in rats. We also observed the effects of hexamethonium (HEX) and methyl scopolamine (MSCP) on those MS behavioral responses. The efficacy of all these drugs on rotation-induced emesis and other MS symptoms in cats was also examined. We found that intragastric administration of MEC and SCOP inhibited rotation-induced gaping and defecation in rats, but only MEC showed a dose-dependent manner. MEC aggravated rotation-induced balance disorder and failed to attenuate rotation-induced hypothermia as the SCOP did. MEC was more effective for inhibiting Fos expression in the caudal vestibular nucleus and nucleus of solitary tract than SCOP. Intraperitoneal injection of HEX and MSCP also significantly alleviated rotation-induced gastrointestinal symptoms, and showed benefit to balance performance in rats. In cats, MEC, SCOP and HEX had prophylactic effects against rotation-induced emesis and salivation, and deceased non-retching/vomiting symptoms, but MSCP only attenuated emesis. It suggested that MEC and SCOP might alleviate gastrointestinal symptoms of MS via inhibiting peripheral autonomic nervous system and central vestibulo-autonomic pathways. The nicotinic acetylcholine receptor inhibitors like MEC might be new candidates against gastrointestinal symptoms induced by MS or other vestibular disorders.

CCL2 is Upregulated by Decreased miR-122 Expression in Iron-Overload-Induced Hepatic Inflammation.

BACKGROUND/AIMS: Iron overload (IO) is accompanied by hepatic inflammation. The chemokine (C-C motif) ligand 2 (CCL2) mediates inflammation, and its overexpression is associated with IO. However, whether IO results in CCL2 overexpression in the liver and the underlying mechanisms are unclear. METHODS: We subjected mice to IO by administering intraperitoneal injections of dextran-iron or by feeding mice a 3% dextran-iron diet to observe the effects of IO on miR-122/CCL2 expression through real-time qPCR and Western blot analysis. We also used indicators, including the expression of the inflammatory cytokine, the inflammation score based on H&E staining and the serum content of ALT and AST to evaluate the effects of IO on hepatic inflammation. Meanwhile, we observed the effects of vitamin E on IO-induced hepatic inflammation. In cells, we used 100 µΜ FeSO4 or 30 µΜ Holo-Tf to produce IO and observed the roles of miR-122 in regulating CCL2 expression by using miR-122 mimics or inhibitors to overexpress or inhibit miR-122. Then, we used a dual-luciferase reporter assay to prove that miR-122 regulates CCL2 expression through direct binding to its complementary sequence in the CCL2 mRNA 3'UTR. RESULTS: IO induces the downregulation of miR-122 and the upregulation of CCL2, as well as inflammatory responses both in vitro and in vivo. Although IO-induced oxidative stress is eliminated by the antioxidant vitamin E, IO-induced hepatic inflammation still exists, which probably can be explained by the fact that vitamin E has no effects on the miR-122/CCL2 pathway. In in vitro experiments, the overexpression and inhibition of miR-122 significantly reduced and increased CCL2 expression, respectively. The dual-luciferase reporter assay indicates that miR-122 binds CCL2 mRNA 3'UTR. CONCLUSION: We propose the roles of miR-122/CCL2 in IO-induced hepatic inflammation. Our studies should provide a new clue for developing clinical strategies for patients with IO.

The hepatocyte-specific HNF4α/miR-122 pathway contributes to iron overload-mediated hepatic inflammation.

Hepatic iron overload (IO) is a major complication of transfusional therapy. It was generally thought that IO triggers substantial inflammatory responses by producing reactive oxygen species in hepatic macrophages. Recently, a decrease in microRNA-122 (miR-122) expression was observed in a genetic knockout (Hfe-/-) mouse model of IO. Because hepatocyte-enriched miR-122 is a key regulator of multiple hepatic pathways, including inflammation, it is of interest whether hepatocyte directly contributes to IO-mediated hepatic inflammation. Here, we report that IO induced similar inflammatory responses in human primary hepatocytes and Thp-1-derived macrophages. In the mouse liver, IO resulted in altered expression of not only inflammatory genes but also >230 genes that are known targets of miR-122. In addition, both iron-dextran injection and a 3% carbonyl iron-containing diet led to upregulation of hepatic inflammation, which was associated with a significant reduction in HNF4α expression and its downstream target, miR-122. Interestingly, the same signaling pathway was changed in macrophage-deficient mice, suggesting that macrophages are not the only target of IO. Most importantly, hepatocyte-specific overexpression of miR-122 rescued IO-mediated hepatic inflammation. Our findings indicate the direct involvement of hepatocytes in IO-induced hepatic inflammation and are informative for developing new molecular targets and preventative therapies for patients with major hemoglobinopathy.

Sex and Age Differences in Motion Sickness in Rats: The Correlation with Blood Hormone Responses and Neuronal Activation in the Vestibular and Autonomic Nuclei.

Many studies have demonstrated sex and age differences in motion sickness, but the underlying physiological basis is still in controversy. In the present study, we tried to investigate the potential correlates of endocrine and/or neuronal activity with sex and age differences in rats with motion sickness. LiCl-induced nausea symptom was evaluated by conditioned gaping. Motion sickness was assessed by measurement of autonomic responses (i.e., conditioned gaping and defecation responses), motor impairments (i.e., hypoactivity and balance disturbance) after Ferris wheel-like rotation, and blood hormone levels and central Fos protein expression was also observed. We found that rotation-induced conditioned gaping, defecation responses and motor disorders were significantly attenuated in middle-aged animals (13- and 14-month-age) compared with adolescents (1- and 2-month-age) and young-adults (4- and/or 5-month-age). LiCl-induced conditioned gapings were also decreased with age, but was less pronounced than rotation-induced ones. Females showed greater responses in defecation and spontaneous locomotor activity during adolescents and/or young-adult period. Blood adrenocorticotropic hormone and corticosterone significantly increased in 4-month-old males after rotation compared with static controls. No significant effect of rotation was observed in norepinephrine, epinephrine, ß-endorphin and arginine-vasopressin levels. The middle-aged animals (13-month-age) also had higher number of rotation-induced Fos-labeled neurons in the spinal vestibular nucleus, the parabrachial nucleus (PBN), the central and medial nucleus of amygdala (CeA and MeA) compared with adolescents (1-month-age) and young-adults (4-month-age) and in the nucleus of solitary tract (NTS) compared with adolescents (1-month-age). Sex difference in rotation-induced Fos-labeling was observed in the PBN, the NTS, the locus ceruleus and the paraventricular hypothalamus nucleus at 4 and/or 13 months of age. These results suggested that the sex and age differences in motion sickness may not correlate with stress hormone responses and habituation. The age-dependent decline in motion sickness susceptibility might be mainly attributed to the neuronal activity changes in vestibulo-autonomic pathways contributing to homeostasis regulation during motion sickness.

Storage of passive motion pattern in hippocampal CA1 region depends on CaMKII/CREB signaling pathway in a motion sickness rodent model.

Sensory mismatch between actual motion information and anticipated sensory patterns (internal model) is the etiology of motion sickness (MS). Some evidence supports that hippocampus might involve the neural storage of the "internal model". This study established an "internal model" acquisition-retention behavioral model using a repeated habituation rotation training protocol. We tried to identify the hippocampal subregion involved in "internal model" retention using chemical lesion methods. Hippocampal kinases (CaMK, CaMKIV, CREB and ERK1/2) phosphorylation in the target subregion was assayed and the effects of kinase inhibitors (KN93 or U0126) on "internal model" retention were investigated. The activities of potential kinases (CaMKII and CREB) were also examined in otoliths deficit het/het mice. In habituated rats, CA1 lesion reproduced MS-related behavioral responses on "internal model" retention day. Habituation training increased CaMKII and CREB activity but had no effect on CaMKIV and ERK1/2 activity in the CA1, while inhibition of CaMKII but not ERK1/2 impaired "internal model" retention. In het/het mice, CaMKII and CREB were not activated in the CA1 on the retention day. These results suggested that CaMKII/CREB pathway might potentially contribute to the storage of the "internal model" in the hippocampal CA1 after motion sickness induced by vestibular stimulation.

Evidence for a Role of Orexin/Hypocretin System in Vestibular Lesion-Induced Locomotor Abnormalities in Rats.

Vestibular damage can induce locomotor abnormalities in both animals and humans. Rodents with bilateral vestibular loss showed vestibular deficits syndrome such as circling, opisthotonus as well as locomotor and exploratory hyperactivity. Previous studies have investigated the changes in the dopamine system after vestibular loss, but the results are inconsistent and inconclusive. Numerous evidences indicate that the orexin system is implicated in central motor control. We hypothesized that orexin may be potentially involved in vestibular loss-induced motor disorders. In this study, we examined the effects of arsanilate- or 3,3'-iminodipropionitrile (IDPN)-induced vestibular lesion (AVL or IVL) on the orexin-A (OXA) labeling in rat hypothalamus using immunohistochemistry. The vestibular lesion-induced locomotor abnormalities were recorded and verified using a histamine H4 receptor antagonist JNJ7777120 (20 mg/kg, i.p.). The effects of the orexin receptor type 1 antagonist SB334867 (16 µg, i.c.v.) on these behavior responses were also investigated. At 72 h post-AVL and IVL, animals exhibited vestibular deficit syndrome and locomotor hyperactivity in the home cages. These responses were significantly alleviated by JNJ7777120 which also eliminated AVL-induced increases in exploratory behavior in an open field. The numbers of OXA-labeled neurons in the hypothalamus were significantly increased in the AVL animals at 72 h post-AVL and in the IVL animals at 24, 48, and 72 h post-IVL. SB334867 significantly attenuated the vestibular deficit syndrome and locomotor hyperactivity at 72 h post-AVL and IVL. It also decreased exploratory behavior in the AVL animals. These results suggested that the alteration of OXA expression might contribute to locomotor abnormalities after acute vestibular lesion. The orexin receptors might be the potential therapeutic targets for vestibular disorders.

Motion Sickness and Resting Energy Expenditure in Chinese Male Adults.

BACKGROUND: Motion sickness can influence energy homeostasis by enhancing thermolysis. This study tested the hypothesis that resting energy expenditure (REE), as the major component of thermogenesis, might also play a role during motion sickness. METHODS: The effect of seasickness on REE at sea was examined in 71 healthy Chinese male volunteers. Change in REE, heart rate variability (HRV), blood ghrelin levels, and leptin levels were observed across baseline, voyage, and recovery stages. Seasickness severity was assessed using the Graybiel motion sickness questionnaire (GMSQ), and the nausea syndrome rating (NSR) of each participant was also evaluated. REE was examined by indirect calorimetry. HRV was derived from the electrocardiogram to analyze cardiac sympathovagal activity. Blood ghrelin and leptin levels were tested by radioimmunoassay. RESULTS: In subjects with severe seasickness during the voyage, the GMSQ and NSR scores were higher than in subjects with slight and moderate seasickness. The REE declined significantly compared to baseline and recovery levels and was lower than in subjects with slight and moderate seasickness. Cardiac sympathetic activity was significantly decreased, while vagal activity was increased. Plasma ghrelin levels were also significantly increased and were negatively correlated with the measured REE levels and positively correlated with NSR as well as change of HRV LF/HF ratio from baseline. DISCUSSION: Severe motion sickness induces REE suppression, which may be attributed to dramatic alteration of sympathovagal activity and plasma ghrelin levels in humans.

Motion Sickness: Current Knowledge and Recent Advance.

Motion sickness (MS) is a common physiological response to real or virtual motion. Numerous studies have investigated the neurobiological mechanism and the control measures of MS. This review summarizes the current knowledge about pathogenesis and pathophysiology, prediction, evaluation, and countermeasures of MS. The sensory conflict hypothesis is the most widely accepted theory for MS. Both the hippocampus and vestibular cortex might play a role in forming internal model. The pathophysiology focuses on the visceral afference, thermoregulation and MS-related neuroendocrine. Single-nucleotide polymorphisms (SNPs) in some genes and epigenetic modulation might contribute to MS susceptibility and habituation. Questionnaires, heart rate variability (HRV) and electrogastrogram (EGG) are useful for diagnosing and evaluating MS. We also list MS medications to guide clinical practice. Repeated real motion exposure and combined visual-vestibular interaction training accelerate the progress of habituation. Behavioral and dietary countermeasures, as well as physiotherapy, are also effective in alleviating MS symptoms.

Differential Gene Expression Profile in the Rat Caudal Vestibular Nucleus is Associated with Individual Differences in Motion Sickness Susceptibility.

OBJECTIVE: To identify differentially expressed genes associated with motion sickness (MS) susceptibility in the rat caudal vestibular nucleus. METHODS: We identified MS susceptible (MSS) and insusceptible (inMSS) rats by quantifying rotation-induced MS symptoms: defecation and spontaneous locomotion activity. Microarray analysis was used to screen differentially expressed genes in the caudal vestibular nucleus (CVN) after rotation. Plasma stress hormones were identified by radioimmunoassay. Candidate genes were selected by bioinformatics analysis and the microarray results were verified by real-time quantitative-PCR (RT-qPCR) methods. By using Elvax implantation, receptor antagonists or recombinant adenovirus targeting the candidate genes were applied to the CVN to evaluate their contribution to MS susceptibility variability. Validity of gene expression manipulation was verified by RT-qPCR and western blot analysis. RESULTS: A total of 304 transcripts were differentially expressed in the MSS group compared with the inMSS group. RT-qPCR analysis verified the expression pattern of candidate genes, including nicotinic cholinergic receptor (nAchR) α3 subunit, 5-hydroxytryptamine receptor 4 (5-HT4R), tachykinin neurokinin-1 (NK1R), γ-aminobutyric acid A receptor (GABAAR) α6 subunit, olfactory receptor 81 (Olr81) and homology 2 domain-containing transforming protein 1 (Shc1). In MSS animals, the nAchR antagonist mecamylamine significantly alleviated rotation-induced MS symptoms and the plasma ß-endorphin response. The NK1R antagonist CP99994 and Olr81 knock-down were effective for the defecation response, while the 5-HT4R antagonist RS39604 and Shc1 over-expression showed no therapeutic effect. In inMSS animals, rotation-induced changes in spontaneous locomotion activity and the plasma ß-endorphin level occurred in the presence of the GABAAR antagonist gabazine. CONCLUSION: Our findings suggested that the variability of the CVN gene expression profile after motion stimulation might be a putative molecular basis for individual differences in MS susceptibility and provide information for the development of new therapeutic strategies for MSS individuals.

Temporal change in NMDA receptor signaling and GABAA receptor expression in rat caudal vestibular nucleus during motion sickness habituation.

Repeated exposure to a provocative motion stimulus leads to motion sickness habituation indicative of the existence of central processes to counteract the disturbing properties of the imposed motion. In the present study, we attempt to investigate whether NMDA and GABA(A) receptors in rat caudal vestibular nucleus neurons are involved in motion sickness habituation induced by repeated Ferris-wheel like rotation in daily session (2h/d). We showed that defecation response increased and spontaneous locomotion decreased within 4 sessions (sickness phase). They recovered back to the control level after 7 sessions (habituation phase). Western blot analysis found that NMDA receptor signal molecules: calmodulin protein kinase II and cAMP response element-binding protein (CREB) were both activated during sickness phase, while a prolonged CREB activation was also observed during habituation phase. Real-time quantitative PCR revealed an increase in c-fos and a decrease in Arc mRNA level during sickness phase. We also found an increase in GABA(A) receptor α1 subunit (GABA(A) α1) protein level in this stage. These results suggested that altered NMDA receptor signaling and GABA(A) receptor expression level in caudal vestibular nucleus were associated with motion sickness habituation. Furthermore, immunofluorescence and confocal laser scanning microscopy showed that the number of GABA(A) α1 immunolabeled neurons in caudal vestibular nucleus increased while the number of GABA(A) α1/Arc double labeled neurons and the average amount of Arc particle in soma of these neurons decreased during sickness phase. It suggested that GABA(A) receptor level might be negatively regulated by Arc protein in caudal vestibular nucleus neurons.