Chihiro Iwata

Vestibular-mediated increase in central serotonin plays an important role in hypergravity-induced hypophagia in rats

Exposure to a hypergravity environment induces acute transient hypophagia, which is partially restored by a vestibular lesion (VL), suggesting that the vestibular system is involved in the afferent pathway of hypergravity-induced hypophagia. When rats were placed in a 3-G environment for 14 days, Fos-containing cells increased in the paraventricular hypothalamic nucleus, the central nucleus of the amygdala, the medial vestibular nucleus, the raphe nucleus, the nucleus of the solitary tract, and the area postrema. The increase in Fos expression was completely abolished or significantly suppressed by VL. Therefore, these regions may be critical for the initiation and integration of hypophagia. Because the vestibular nucleus contains serotonergic neurons and because serotonin (5-HT) is a key neurotransmitter in hypophagia, with possible involvement in motion sickness, we hypothesized that central 5-HT increases during hypergravity and induces hypophagia. To examine this proposition, the 5-HT concentrations in the cerebrospinal fluid were measured when rats were reared in a 3-G environment for 14 days. The 5-HT concentrations increased in the hypergravity environment, and these increases were completely abolished in rats with VL. Furthermore, a 5-HT(2A) antagonist (ketanserin) significantly reduced 3-G (120 min) load-induced Fos expression in the medial vestibular nucleus, and chronically administered ketanserin ameliorated hypergravity-induced hypophagia. These results indicate that hypergravity induces an increase in central 5-HT via the vestibular input and that this increase plays a significant role in hypergravity-induced hypophagia. The 5-HT(2A) receptor is involved in the signal transduction of hypergravity stress in the vestibular nucleus.

Arterial pressure oscillation and muscle sympathetic nerve activity after 20 days of head-down bed rest

Both spectral power within the low-frequency component, i.e., 0.04 to 0.15 Hz, of systolic pressure and muscle sympathetic nerve activity are increased during head-up tilt. The nerve activity during tilt is altered after space flight and exposure to simulated microgravity. In the present study, correlations of the low-frequency component and the nerve activity were analyzed before and after 20 days of -6° of head-down bed rest. Measurements were performed at -6° head-down bed rest, 0° (flat), and 30° and 60° head-up tilt (HUT). Mean arterial pressure during HUT was not different between pre- and post-bed rest, but muscle sympathetic nerve activity in post-bed rest significantly increased at tilt angles of -6°, 0°, 30°, and 60° compared with those during pre-bed rest. The low-frequency component of systolic pressure also significantly increased during post-bed rest compared with pre-bed rest at tilts of 0°, 30°, and 60°. The nerve activity and the frequency component were linearly correlated for individual (r(2) = 0.51-0.88) and averaged (r(2) = 0.60) values when the values included both pre- and post-bed rest. Thus, the low-frequency component of systolic pressure could be an index of the muscle sympathetic nerve activity during tilt during pre- and post-bed rest.

Effect of daily linear acceleration training on the hypergravity-induced vomiting response in house musk shrew (Suncus murinus)

The effects of repeated linear acceleration training and the antimotion sickness drug, promethazine, on hypergravity-induced motion sickness were examined in musk shrew (Suncus murinus), which is known to show a vomiting response to motion stimulation. Animals were assigned into five groups: vestibular intact, untreated animals (Sham), vestibular lesioned (VL) animals, vestibular intact animals with promethazine hydrochloride administered as daily drinking water (Prom), vestibular intact animals who underwent horizontal linear accelerator motion training (Train), and vestibular intact animals treated with both promethazine hydrochloride and linear acceleration training (Prom+Train). In Sham animals, the number of vomiting episodes was 14±2 during 2 G exposure for 10min, and was accompanied by intense Fos expression in the medial vestibular nucleus (MVe), the nucleus of the solitary tract (NTS), the area postrema (AP), and the paraventricular hypothalamic nucleus (PVN). The vomiting response and Fos expression were completely abolished in VL animals, indicating that these responses are mediated via the vestibular system. Although Train and Prom animals experienced a significantly reduced number of hypergravity-induced vomiting episodes compared with Sham animals, the effect was significantly greater in Train animals than in Prom animals. Fos expression in the NTS, AP, and PVN were significantly more reduced in Train animals than in Prom animals. Higher dose of bolus injection of promethazine (50mg/kg, i.p.) completely abolished the vomiting episodes, although the animals were drowsy and sedated due to side effects. In conclusion, daily linear acceleration training and promethazine could prevent the hypergravity-induced vomiting episodes.

Water drinking-related muscle contraction induces the pressor response via mechanoreceptors in conscious rats

Water drinking is known to induce the pressor response. The efferent pathway in this response involves sympathoexcitation, because the pressor response was completely abolished by ganglionic blockade or an α(1)-adrenergic antagonist. However, the afferent pathway in this response has not been identified. In the present study, we hypothesized that water itself stimulates the upper digestive tract to induce the pressor response, and/or drinking-related muscle contraction induces the pressor response via mechanoreceptors. To examine this hypothesis, we evaluated the pressor response induced by spontaneous or passive water drinking in conscious rats. Since the baroreflex modulates and obscures the pressor response, the experiments were conducted using rats with sinoaortic denervation. The pressor response was not suppressed by 1) transient oral surface anesthesia using lidocaine, 2) bilateral denervation of the glossopharyngeal nerve and sensory branch of the superior laryngeal nerve, or 3) denervation of the tunica adventitia in the esophagus. However, the pressor response was significantly suppressed (by -52%) by intravenous gadolinium chloride administration. Electrical stimulation of the hypoglossal nerve induced the pressor response, which was significantly suppressed (by -57%) by intravenous gadolinium chloride administration and completely abolished by severing the distal end of this nerve. These results indicate that afferent signals from mechanoreceptors in drinking-related muscles are involved in the water drinking-induced pressor response.

Subsensory galvanic vestibular stimulation augments arterial pressure control upon head-up tilt in human subjects

The vestibular system plays an important role in control of arterial pressure (AP) upon head-up tilt (HUT). To examine this role in human subjects, we previously compared changes in AP with and without high-amplitude galvanic vestibular stimulation (GVS), which is considered to obscure vestibular input. In contrast, regarding sensory function in skin and muscle, it has been documented that low-amplitude electrical stimulation improves both sensitivity and response. In the present study, we examined whether GVS of smaller amplitude improves AP control upon HUT. GVS was applied at the amplitude of the somatosensory threshold (0.3-0.8 mA), 0.1 mA over the threshold, and 0.1 and 0.2 mA below the threshold during HUT. AP decreased at the onset of HUT compared with that in the supine position in 15 of 25 subjects without GVS (-12±2 mmHg), but applying GVS at 0.1 mA below the somatosensory threshold diminished the decrease (0.3±0.7 mmHg). The APs of another 10 subjects were maintained or decreased by less than 5 mmHg without GVS at the onset of HUT (4±2 mmHg), but applying GVS at the amplitude of 0.1 mA below the somatosensory threshold further increased the AP (12±2 mmHg). GVS at the other amplitudes did not result in AP changes in either group. Thus, subsensory weak GVS enhances AP control at the onset of HUT.

Role of the vestibular system in the arterial pressure response to parabolic-flight-induced gravitational changes in human subjects

Arterial pressure (AP) is known to fluctuate during parabolic-flight-induced gravitational changes in human subjects, increasing during hypergravity and decreasing during microgravity. In this study, we examined whether the vestibular system participates in the AP response to the gravitational changes induced by parabolic flight in human subjects. Eight subjects performed parabolic flights in a supine position as their AP was measured. Their vestibular inputs during the gravitational changes were reversibly masked by artificial electrical stimulation (galvanic vestibular stimulation, GVS). The AP responses during the parabolas were then compared between the GVS-off and GVS-on conditions. AP increased during hypergravity and decreased during microgravity. The AP responses at the onset of hypergravity and microgravity were abolished by GVS. These results indicate that the vestibular system elicits pressor and depressor responses during parabolic-flight-induced hypergravity and microgravity, respectively.

Hypergravity exposure for 14 days increases the effects of propofol in rats.

BACKGROUND:It is thought that the gravitational environment of space exploration alters the effects of anesthetics; however, no evidence has as yet been reported. In the present study, we sought to provide direct evidence showing that hypergravity exposure for 14 days increases anesthetic effects and to examine the possible causes. METHODS:Sprague-Dawley rats were raised in a 3g environment for 14 days. On the day of the experiment, rats were brought out of 3g and rested at 1g for 1 to 2 hours before IV propofol infusion (20 mg/kg, for 5 minutes). Control rats were continuously raised in a 1g environment. The effects of propofol were compared between rats raised in 1g and 3g environment by measuring time taken to induce the burst suppression in an electroencephalogram, nadir of arterial blood pressure, and time taken for the appearance of the righting response to noxious electrical stimulations. The time course of plasma propofol concentrations was also examined. Experiments were also conducted on rats with vestibular lesions to examine whether the vestibular system participated in the observed results. All values were expressed as mean ± SD. RESULTS:In rats raised in 3g environment, the mean time to induce burst suppression in the electroencephalogram was earlier (195.7 ± 15.1 seconds, P = 0.00037), the nadir of mean arterial blood pressure was lower (75.0 ± 15.5 mm Hg, P = 0.019), and mean time for the righting response to appear was later (39.0 ± 8.4 minutes, P < 0.0001) than in rats raised in 1g environment (267.3 ± 29.4 seconds, 100.6 ± 9.1 mm Hg, and 22.0 ± 3.1 minutes, respectively). However, mean time to induce burst suppression and for the righting response to appear did not change in rats with vestibular lesions raised in 3g environment (275 ± 29.4 seconds, 108.7 ± 14.6 mm Hg, and 20.8 ± 2.8 minutes, P = 0.95, 0.73, and 0.98 vs sham-treated rats continuously raised in a 1g environment, respectively). There was no difference between groups in the time course assessment of plasma propofol concentrations. CONCLUSION:The results provide evidence that hypergravity exposure for 14 days increases the effects of propofol. It is suggested that the results were not caused by differences in plasma propofol concentrations but by increased sensitivity, which was mediated via the vestibular system.

Development and evaluation of gas-pressurized elastic sleeves for extravehicular activity.

INTRODUCTION In space, mobility of the current extravehicular activity space suit is limited due to the pressure differential between the inside and outside of the suit. We have previously demonstrated that an elastic glove increased mobility when compared with a non-elastic glove such as that found in the current suit. Extending this work, we hypothesized that an elastic sleeve would also have more mobility compared to a non-elastic sleeve, but a partially elastic sleeve, consisting of elastic joints sewn to non-elastic parts in low mobility areas, might generate similar mobility to a wholly elastic sleeve. METHODS The right arms of 10 volunteers were studied with wholly elastic, partially elastic, and non-elastic sleeves in a chamber pressure of -220 mmHg. Range of motion (ROM) of the wrist and electromyography (EMG) of the flexor carpi radialis muscle and the biceps brachii muscle during wrist and elbow flexion were measured. RESULTS ROM of the wrist was similar among all the sleeves. However, EMG amplitudes during wrist flexion with both elastic sleeves were significantly smaller than that with the non-elastic sleeve. EMG amplitudes during 90 degrees of elbow flexion were also significantly smaller in both elastic sleeves. However, no significant difference in EMG amplitudes was observed between the two elastic sleeves (0.53 +/- 0.06, 0.56 +/- 0.07, 1.14 +/- 0.10 V for wholly elastic, partially elastic, and non-elastic sleeves, respectively). DISCUSSION The mobility of elastic sleeves is better than that of a non-elastic sleeve. Elasticity over the joints is important; however the elasticity of the other parts does not appear to affect mobility.

Restriction of rear-up-behavior-induced attenuation of vestibulo-cardiovascular reflex in rats

Previously, we have demonstrated that the vestibulo-cardiovascular reflex was attenuated in rats reared in a 3G environment for 14 days. Because continuous galvanic vestibular stimulation preserved the vestibulo-cardiovascular reflex in rats at 3G, this attenuation might be attributable to a reduction in the phasic input to the vestibular system. The present study shows that the head movements of rats were significantly suppressed in the 3G environment. Therefore, we hypothesized that the attenuation of the vestibulo-cardiovascular reflex is induced by the reduced vestibular phasic input caused by the restriction of rear-up behavior. To examine this hypothesis, the pressor responses to linear acceleration were measured in rats reared in a low-roof cage. The linear-acceleration-induced pressor response was significantly suppressed in these rats. The suppressive effect of the low-roof cage was similar to that of 3G. There was no difference in the air-jet-induced pressor response among three groups (rats reared in a usual 1G environment, rats reared in the low-roof cage, and rats reared in the 3G environment), suggesting that the sensitivity of the vestibulo-cardiovascular reflex was selectively suppressed. These results indicate that a reduction in the vestibular phasic input acts to attenuate the vestibulo-cardiovascular reflex.