Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/B978-0-323-98818-6.00021-2.

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3389/fncom.2023.1218707

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Patients with Parkinson's disease (PD) exhibit distinct abnormal postures, including neck-down, stooped postures, and Pisa syndrome, collectively termed “abnormal posture” henceforth. In the previous study, when assuming an upright stance, patients with PD exhibit heightened instability in contrast to healthy individuals with disturbance, implying that abnormal postures serve as compensatory mechanisms to mitigate sway during static standing. However, limited studies have explored the relationship between abnormal posture and sway in the context of static standing. Increased muscle tone (i.e., constant muscle activity against the gravity) has been proposed as an underlying reason for abnormal postures. Therefore, this study aimed to investigate the following hypothesis: abnormal posture with increased muscle tone leads to a smaller sway compared with that in other postures, including normal upright standing, under the sway minimization criterion. To investigate the hypothesis, we assessed the sway in multiple postures, which is determined by joint angles, including cases with bended hip joints. Our approach involved conducting forward dynamics simulations using a computational model comprising a musculoskeletal model and a neural controller model. The neural controller model proposed integrates two types of control mechanisms: feedforward control (representing muscle tone as a vector) and feedback control using proprioceptive and vestibular sensory information. An optimization was performed to determine the posture of the musculoskeletal model and the accompanied parameters of the neural controller model for each of the given muscle tone vector to minimize sway. The optimized postures to minimize sway for the optimal muscle tone vector of patients with PD were compared to the actual postures observed in these patients. The results revealed that on average, the joint-angle differences between these postures was <4°, which was less than one-tenth of the typical joint range of motion. These results suggest that patients with PD exhibit less sway in the abnormal posture than in other postures. Thus, adopting an abnormal posture with increased muscle tone can potentially serve as a valid strategy for minimizing sway in patients with PD.

DOI： 10.3389/fncom.2023.1218707

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Language：English   Publisher：(一社)日本臨床神経生理学会  

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jphs.2023.07.002

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/nmo.14659

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Language：English   Publishing type：Research paper (scientific journal)  

Patients with Parkinson's disease (PD), a neurodegenerative disorder, exhibit a characteristic posture known as a forward flexed posture. Increased muscle tone is suggested as a possible cause of this abnormal posture. For further analysis, it is necessary to measure muscle tone, but the experimental measurement of muscle tone during standing is challenging. The aim of this study was to examine the hypothesis that "In patients with PD, abnormal postures are those with a small sway at increased muscle tones" using a computational model. The muscle tones of various magnitudes were estimated using the computational model and standing data of patients with PD. The postures with small sway at the estimated muscle tones were then calculated through an optimization method. The postures and sway calculated using the computational model were compared to those of patients with PD. The results showed that the differences in posture and sway between the simulation and experimental results were small at higher muscle tones compared to those considered plausible in healthy subjects by the simulations. This simulation result indicates that the reproduced sway at high muscle tones is similar to that of actual patients with PD and that the reproduced postures with small sway locally at high muscle tones in the simulations are similar to those of patients with PD. The result is consistent with the hypothesis, reinforcing the hypothesis.Clinical relevance- This study implies that improving the increased muscle tone in patients with PD may lead to an improved abnormal posture.

DOI： 10.1109/EMBC40787.2023.10341129

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Language：English   Publishing type：Research paper (scientific journal)  

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.expneurol.2021.113708.

Language：English   Publishing type：Research paper (scientific journal)  

The frontal lobe is crucial and contributes to controlling truncal motion, postural responses, and maintaining equilibrium and locomotion. The rich repertoire of frontal gait disorders gives some indication of this complexity. For human walking, it is necessary to simultaneously achieve at least two tasks, such as maintaining a bipedal upright posture and locomotion. Particularly, postural control plays an extremely significant role in enabling the subject to maintain stable gait behaviors to adapt to the environment. To achieve these requirements, the frontal cortex (1) uses cognitive information from the parietal, temporal, and occipital cortices, (2) creates plans and programs of gait behaviors, and (3) acts on the brainstem and spinal cord, where the core posture-gait mechanisms exist. Moreover, the frontal cortex enables one to achieve a variety of gait patterns in response to environmental changes by switching gait patterns from automatic routine to intentionally controlled and learning the new paradigms of gait strategy via networks with the basal ganglia, cerebellum, and limbic structures. This chapter discusses the role of each area of the frontal cortex in behavioral control and attempts to explain how frontal lobe controls walking with special reference to postural control.

DOI： 10.1016/B978-0-323-98818-6.00021-2

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Publishing type：Research paper (scientific journal)   Publisher：Fuji Technology Press Ltd.  

An association is observed between the standing sway posture and falls in patients with stroke; hence, it is important to study their standing balance. Although there are studies on the standing balance in stroke patients, differences in control have not been adequately investigated. This study aims to propose a method to characterize the postural sway in standing stroke patients using a mathematical model. A musculoskeletal model and neural controller model were used to simulate ten stroke patients (five patients with cerebral hemorrhages and five patients with cerebral infarctions) and eight young healthy participants, and their data were monitored during quiet standing. The model parameters were adjusted by focusing on the maximum-minimum difference in sway, which was considered important in a previous study, and sway speed, which is frequently used in the analysis. The adjusted model parameters were subjected to dimension reduction using non-negative matrix factorization. Consequently, the sway characteristics of stroke patients were expressed as the magnitude of gain parameters related to the extension of the entire body. The results of this study demonstrated the possibility of representing the characteristics of postural sway as model parameters in stroke patients using a mathematical model. This characterization could lead to the design of individualized rehabilitation systems in the future.

DOI： 10.20965/jrm.2022.p1451

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Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/ncn3.12683

Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：IEEE  

DOI： 10.1109/bibe55377.2022.00029

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Regulation of posture-gait control by the basal ganglia (BG) plays a critical role in the acquisition of automatically executed context-dependent learned motor acts, technically referred to as habit formation. Patients with Parkinson's disease (PD) show posture-gait disturbances and progressively lose habitual behaviors. Injury to dopamine (DA) neurons in the midbrain is implicated as the primary pathophysiological mechanism underlying PD; therefore, DA actions in the BG play a pivotal role in optimal BG function. In this commentary, we discuss the mechanism underlying BG-modulated regulation of cognitive posture-gait control by the cerebral cortex through the cortico-BG loop and the basic posture-gait mechanisms underlying the actions of the brainstem and spinal cord via the BG-brainstem projection. The BG primarily regulates excitability of the cerebral cortex and brainstem through its DA-mediated inhibitory action. Based on these considerations, we describe the pathophysiological mechanisms that contribute to posture-gait disturbances in PD. Recent clinical studies suggest that posture-gait disturbances may be attributable to functional disconnection between the BG and the cerebral cortex and brainstem. Injury to various neurotransmitter systems in addition to the DA system and significant alpha-synuclein (Lewy body)-induced degeneration of the brainstem neurons may worsen posture-gait control impairment in PD.

DOI： 10.11477/mf.1416202185

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/mds.29049.

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1111/ncn3.12605

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/ncn3.12605

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.npep.2022.102248.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3389/fncom.2022.785099.

Language：English   Publishing type：Research paper (scientific journal)  

Humans are able to control their posture in their daily lives. It is important to understand how this is achieved in order to understand the mechanisms that lead to impaired postural control in various diseases. The descending tracts play an important role in controlling posture, particularly the reticulospinal and the vestibulospinal tracts (VST), and there is evidence that the latter is impaired in various diseases. However, the contribution of the VST to human postural control remains unclear, despite extensive research using neuroscientific methods. One reason for this is that the neuroscientific approach limits our understanding of the relationship between an array of sensory information and the muscle outputs. This limitation can be addressed by carrying out studies using computational models, where it is possible to make and validate hypotheses about postural control. However, previous computational models have not considered the VST. In this study, we present a neural controller model that mimics the VST, which was constructed on the basis of physiological data. The computational model is composed of a musculoskeletal model and a neural controller model. The musculoskeletal model had 18 degrees of freedom and 94 muscles, including those of the neck related to the function of the VST. We used an optimization method to adjust the control parameters for different conditions of muscle tone and with/without the VST. We examined the postural sway for each condition. The validity of the neural controller model was evaluated by comparing the modeled postural control with (1) experimental results in human subjects, and (2) the results of a previous study that used a computational model. It was found that the pattern of results was similar for both. This therefore validated the neural controller model, and we could present the neural controller model that mimics the VST.

DOI： 10.3389/fncom.2022.785099

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1589/jpts.34.103.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/mds.28883.

Language：English   Publishing type：Research paper (scientific journal)  

[Purpose] Patellar tendinopathy is a common sports injury. The risk factors for this injury can be categorized as intrinsic, extrinsic, and dynamic. We examined the dynamic factors in this study. [Participants and Methods] The participants were volleyball players who were assigned to a patient group (n=6) if they had medial patellar tendinopathy in the left knee or to a control group (n=7) otherwise. The participants performed spike jumps, and their ground reaction force and three-dimensional kinematic data were recorded. Knee angle and moment data were extracted at the peak extension moment of take-off and landing. [Results] The two groups showed no differences in knee angles. A tendency for abduction/external rotation moments at take-off and landing on both sides was observed in the control group, while the patient group showed adduction and internal rotation moments at take-off and adduction moment at landing in the left (injured) knee. [Conclusion] The observed knee joint moments in the left (injured) knee of the patient group may have been involved in the pathophysiological mechanism underlying the development of patellar tendinopathy.

DOI： 10.1589/jpts.34.103

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 0.3389/fnsys.2021.792665.

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Postural control precedes the goal-directed movement to maintain body equilibrium during the action. Because the environment continuously changes due to one’s activity, postural control requires a higher-order brain function that predicts the interaction between the body and the environment. Here, we tried to elucidate to what extent such a preceding postural control (PPC) predictively offered a posture that ensured the entire process of the goal-directed movement before starting the action. For this purpose, we employed three cats, which we trained to maintain a four-leg standing posture on force transducers to reach the target by either forelimb. Each cat performed the task under nine target locations in front with different directions and distances. As an index of posture, we employed the center of pressure (CVP) and examined CVP positions when the cat started postural alteration, began to lift its paw, and reached the target. After gazing at the target, each cat started PPC where postural alteration was accompanied by a 20–35 mm CVP shift to the opposite side of the forelimb to be lifted. Then, the cat lifted its paw at the predicted CVP position and reached the forelimb to the target with a CVP shift of only several mm. Moreover, each cat had an optimal target location where the relationship between the cat and target minimized the difference in the CVP positions between the predicted and the final. In this condition, more than 80% of the predicted CVP positions matched the final CVP positions, and the time requiring the reaching movement was the shortest. By contrast, the forelimb reaching movement required a greater CVP shift and longer time when the target was far from the cat. In addition, the time during forelimb reaching showed a negative correlation with the speed of the CVP shift during the PPC. These results suggest that the visuospatial information, such as the body-environment interaction, contributes to the motor programming of the PPC. We conclude that the PPC ensures postural stability throughout the action to optimize the subsequent goal-directed movements. Impairments in these processes may disturb postural stability during movements, resulting in falling.

DOI： 10.3389/fnsys.2021.792665

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Language：Japanese   Publisher：(一社)日本定位・機能神経外科学会  

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3389/fnhum.2021.731677.

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Post-stroke complications are the second most frequent cause of death and the third leading cause of disability worldwide. The motor function of post-stroke patients is often assessed by measuring the postural sway in the patients during quiet standing, based on sway measures, such as sway area and velocity, which are obtained from temporal variations of the center of pressure. However, such approaches to establish a relationship between the sway measures and patients' demographic factors have hardly been successful (e.g., days after onset). This study instead evaluates the postural sway features of post-stroke patients using the clustering method of machine learning. First, we collected the stroke patients' multi-variable motion-capture standing-posture data and processed them into <italic>t</italic> s long data slots. Then, we clustered the <italic>t</italic>-s data slots into <italic>K</italic> cluster groups using the dynamic-time-warping partition-around-medoid (DTW-PAM) method. The DTW measures the similarity between two temporal sequences that may vary in speed, whereas PAM identifies the centroids for the DTW clustering method. Finally, we used a <italic>post-hoc</italic> test and found that the sway amplitudes of markers in the shoulder, hip, knee, and center-of-mass are more important than their sway frequencies. We separately plotted the marker amplitudes and frequencies in the medial-lateral direction during a 5-s data slot and found that the post-stroke patients' postural sway frequency lay within the bandwidth of 0.5–1.5 Hz. Additionally, with an increase in the onset days, the cluster index of cerebral hemorrhage patients gradually transits in a four-cluster solution. However, the cerebral infarction patients did not exhibit such pronounced transitions over time. Moreover, we found that the postural-sway amplitude increased in clusters 1, 3, and 4. However, the amplitude of cluster 2 did not follow this pattern, owing to age effects related to the postural sway changes with age. A rehabilitation doctor can utilize these findings as guidelines to direct the post-stroke patient training.

DOI： 10.3389/fnhum.2021.731677

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.gaitpost.2021.08.003.

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

Background: To maintain an upright standing posture against external disturbances, the human body mainly employs two types of postural control strategies: “ankle strategy” and “hip strategy.” While it has been reported that the magnitude of the disturbance alters the use of postural control strategies, it has not been elucidated how the level of muscle tone, one of the crucial parameters of bodily function, determines the use of each strategy. We have previously confirmed using forward dynamics simulations of human musculoskeletal models that an increased muscle tone promotes the use of ankle strategies. The objective of the present study was to experimentally evaluate a hypothesis: an increased muscle tone promotes the use of ankle strategies. Research question: Do changes in the muscle tone affect the use of ankle strategies? Methods: Participants were asked to maintain their standing posture on a movable platform sliding horizontally at several accelerations. Postural reactions for support surface translations were examined under three instructions with or without handgrips: relax state, squeezing a handgrip, and an increased muscle tone of the whole body. Surface-electromyography and marker locations of joints were measured to calculate the index of muscle tone and postural control strategies. The relationship of the indexes was evaluated based on correlation coefficients. Results: In half of the conditions, weak negative correlations were noted between the muscle tone index and postural control strategy index. In other words, an increased muscle tone rather promoted the use of the ankle strategy than the hip strategy. These findings are consistent with our previous simulation results. Significance: The results recognized a positive response to the research question. This suggests that it is crucial to take muscle tone into account to understand postural control strategies.

DOI： 10.1016/j.gaitpost.2021.08.003

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jphs.2021.04.001.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1080/01691864.2021.1893218

Publishing type：Research paper (scientific journal)   Publisher：Informa UK Limited  

Strokes are the third leading cause of disability worldwide. Currently, several types of performance assessment, such as the Fugl–Meyer index, are used to explore the overall difference between cerebral infarction (CI) and cerebral hemorrhage (CH) post-stroke patients. However, these performance assessments ignore subtle differences in the limbs of patients, which could be helpful for rehabilitation training. This study was designed to determine and evaluate the differences between the limbs of CI and CH patients. First, we collected the kinematic data of patients and extracted the spatio-temporal features. Then, we developed four different models to classify the CI and CH patients, in which a linear support vector machine (LSVM) classifier method achieved an 80.1% classification accuracy. Finally, we calculated the decision boundary of the shoulder and ankle marker position features separately based on the LSVM model. From the decision boundary, we determined that the CI patients' shoulder position appeared to be anterior to that of the CH patients, and the CH patients had a wider stance width compared to the CI patients. Such findings can serve as guidance for doctors and help provide professional rehabilitation courses for post-stroke patients.

DOI： 10.1080/01691864.2021.1893218

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Publishing type：Research paper (international conference proceedings)  

In an aging society, it is increasingly important to solve problems related to human gait. One of these issues is the relationship between gait and muscle tone. In this study, we propose a neuromusculoskeletal model that can be used to represent and evaluate the movement changes generated by changes in muscle tone in human gait using computational simulations. The model is based using a musculoskeletal model with 70 muscles and a neurological controller model that can represent muscle tone. As a hypothesis to judge the validity of the model, a high muscle tone makes it difficult to maintain gait and makes the stride length narrow. A total of 1470 parameters were optimized for 3 days for each trial with varying muscle tone. As a result under the condition of high muscle tone, the gait maintenance time became shorter, and the stride length became narrow compared with the experimental value. Therefore, the hypothesis used to judge the validity of the model that gait maintenance becomes difficult and stride length becomes narrow under high muscle tone was proved. In addition, the tendency for changes in the angle of the knee joint, the distance traveled by the center of the foot pressure, the number of times the foot touched the ground, the distance the foot swung forward, the regularity and periodicity of each gait, and the bimodality of foot pressure were evaluated and confirmed to be natural. From these results, we conclude that the neuromusculoskeletal model for gait proposed in this study was proper.

DOI： 10.1109/SMC52423.2021.9658889

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ejphar.2020

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Lipopolysaccharide (LPS) or repeated water avoidance stress (WAS) induces visceral allodynia and colonic hyperpermeability via corticotropin-releasing factor (CRF) and proinflammatory cytokines, which is considered to be a rat irritable bowel syndrome (IBS) model. As losartan is known to inhibit proinflammatory cytokine release, we hypothesized that it improves these visceral changes. METHODS: The threshold of visceromotor response (VMR), that is, abdominal muscle contractions induced by colonic balloon distention was electrophysiologically measured in rats. Colonic permeability was determined in vivo by quantifying the absorbed Evans blue in colonic tissue for 15 minutes spectrophotometrically. KEY RESULTS: Lipopolysaccharide (1 mg kg-1 ) subcutaneously (s.c.) reduced the threshold of VMR and increased colonic permeability. Losartan (5-25 mg kg-1  s.c.) for 3 days inhibited these changes in a dose-dependent manner. Moreover, repeated WAS (1 hour daily for 3 days) or intraperitoneal injection of CRF (50 µg kg-1 ) induced the similar visceral changes as LPS, which were also eliminated by losartan. These effects by losartan in LPS model were reversed by GW9662 (a peroxisome proliferator-activated receptor-γ [PPAR-γ] antagonist), NG -nitro-L-arginine methyl ester (a nitric oxide [NO] synthesis inhibitor), or naloxone (an opioid receptor antagonist). Moreover, it also inhibited by sulpiride (a dopamine D2 receptor antagonist) or domperidone (a peripheral dopamine D2 antagonist). CONCLUSION & INFERENCES: Losartan prevented visceral allodynia and colonic hyperpermeability in rat IBS models. These actions may be PPAR-γ-dependent and also mediated by the NO, opioid, and dopamine D2 pathways. Losartan may be useful for IBS treatment.

DOI： 10.1111/nmo.13819

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/nmo.13819

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.gaitpost.2019.12.015.

Language：English   Publishing type：Research paper (scientific journal)  

© 2019 The Authors Background: Humans use different postural control strategies depending on perturbations. The shift from an ankle strategy to a hip strategy occurs at different perturbation magnitudes for different individuals. Although such differences relate to the differences in body parameters such as muscle strength, the parameter changes that affect the strategy shift are unclear. The relationship between tonus and strategy is especially unclear, but humans control tonus, which contributes to body stability. The objective of this study was to investigate the influence of tonus on postural control strategy. Research question: Is there a trend toward the use of a hip strategy with a decrease in the magnitude of tonus? Methods: Predictive simulations were performed for changing parameters of muscle weakness and increased sensory noise, which are considered the causes of different strategies and decreased tonus. A musculoskeletal model with 70 muscles and 15 degrees of freedom of joints was controlled using a neural controller model, and the support surface was translated backward to introduce perturbations. The parameters of the musculoskeletal and neural controller models were changed for 48 conditions of different muscle strengths, sensory noise, and tonus. The control parameters were optimized for each condition. Simulations were performed with the optimized control parameters to calculate an evaluation index to show the difference in postural control strategies (peak hip angle), and the relationship between the index and parameters was analyzed using analysis of variance and multiple regression. Results: The main effects of muscle weakness and decreased tonus and their interaction were confirmed. The results recognized a positive response to the research question. Significance: The study emphasizes the importance of considering tonus while investigating the postural control strategy. Furthermore, it was suggested that when the magnitude of tonus was larger than a threshold, only the ankle strategy was used, regardless of muscle strength.

DOI： 10.1016/j.gaitpost.2019.12.015

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41598-019-56132-4

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Language：English   Publishing type：Research paper (scientific journal)  

Lipopolysaccharide (LPS) or repeated water avoidance stress (WAS) induces visceral allodynia and gut hyperpermeability via corticotropin-releasing factor (CRF) and proinflammatory cytokines, which is a rat irritable bowel syndrome (IBS) model. As butyrate is known to suppress the release of proinflammatory cytokine, we hypothesized that butyrate alleviates these colonic changes in IBS models. The visceral pain was assessed by electrophysiologically measuring the threshold of abdominal muscle contractions in response to colonic distention. Colonic permeability was determined by measuring the absorbance of Evans blue in colonic tissue. Colonic instillation of sodium butyrate (SB; 0.37-2.9 mg/kg) for 3 days inhibited LPS (1 mg/kg)-induced visceral allodynia and colonic hyperpermeability dose-dependently. Additionally, the visceral changes induced by repeated WAS (1 h for 3 days) or CRF (50 µg/kg) were also blocked by SB. These effects of SB in the LPS model were eliminated by compound C, an AMPK inhibitor, or GW9662, a PPAR-γ antagonist, NG-nitro-L-arginine methyl ester, a NO synthesis inhibitor, naloxone or sulpiride. SB attenuated visceral allodynia and colonic hyperpermeability in animal IBS models. These actions may be AMPK and PPAR-γ dependent and also mediated by the NO, opioid and central dopamine D2 pathways. Butyrate may be effective for the treatment of IBS.

DOI： 10.1038/s41598-019-56132-4

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DOI： 10.1016/j.gaitpost.2019.12.015.

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Language：English   Publishing type：Research paper (scientific journal)  

Stress-induced altered visceral sensation and impaired gut barrier play an important role in the pathophysiology of irritable bowel syndrome (IBS). These responses were demonstrated to be peripheral corticotropin-releasing factor (CRF) dependent and also mediated via proinflammatory cytokine in animal IBS model. Dehydroepiandrosterone sulfate (DHEA-S) is known to have anti-inflammatory properties by suppressing proinflammatory cytokine release. We hypothesized that DHEA-S improves stress-induced visceral changes and is beneficial for IBS treatment. We explored the effects of DHEA-S on lipopolysaccharide (LPS)- or repeated water avoidance stress (WAS)-induced visceral allodynia and increased colonic permeability (rat IBS models). The threshold of visceromotor response, i.e. abdominal muscle contractions induced by colonic balloon distention was electrophysiologically measured. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue. DHEA-S abolished visceral allodynia and colonic hyperpermeability induced by LPS in a dose-dependent manner. It also blocked repeated WAS- or peripheral injection of CRF-induced visceral changes. These effects by DHEA-S in LPS model were reversed by bicuculline, a γ-aminobutyric acid (GABA)A receptor antagonist, NG-nitro-L-arginine methyl ester, a nitric oxide (NO) synthesis inhibitor, naloxone, an opioid receptor antagonist, or sulpiride, a dopamine D2 receptor antagonist. However, domperidone, a peripheral dopamine D2 receptor antagonist did not modify the effects. Peripheral injection of astressin2-B, a selective CRF receptor subtype 2 (CRF2) antagonist also reversed these effects. In conclusion, DHEA-S blocked stress-induced visceral changes via GABAA, NO, opioid, central dopamine D2 and peripheral CRF2 signaling. DHEA-S may be useful for IBS treating.

DOI： 10.1016/j.ejphar.2019.03.037

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DOI： 10.1016/j.ejphar.2019.03.037.

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DOI： 10.1371/journal.pone.0212613.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ejphar.2019.03.037

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DOI： 10.1371/journal.pone.0212613

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The human body is a complex system driven by hundreds of muscles, and its control mechanisms are not sufficiently understood. To understand the mechanisms of human postural control, neural controller models have been proposed by different research groups, including our feed-forward and feedback control model. However, these models have been evaluated under forward and backward perturbations, at most. Because a human body experiences perturbations from many different directions in daily life, neural controller models should be evaluated in response to multidirectional perturbations, including in the forward/backward, lateral, and diagonal directions. The objective of this study was to investigate the validity of an NC model with FF and FB control under multidirectional perturbations. We developed a musculoskeletal model with 70 muscles and 15 degrees of freedom of joints, positioned it in a standing posture by using the neural controller model, and translated its support surface in multiple directions as perturbations. We successfully determined the parameters of the neural controller model required to maintain the stance of the musculoskeletal model for each perturbation direction. The trends in muscle response magnitudes and the magnitude of passive ankle stiffness were consistent with the results of experimental studies. We conclude that the neural controller model can adapt to multidirectional perturbations by generating suitable muscle activations. We anticipate that the neural controller model could be applied to the study of the control mechanisms of patients with torso tilt and diagnosis of the change in control mechanisms from patients’ behaviors.

DOI： 10.1371/journal.pone.0212613

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DOI： 10.1007/s12311-019-01025-5

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DOI： 10.1016/j.jphs.2018.11.006

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DOI： 10.3389/fnins.2018.01042

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Visceral hypersensitivity and impaired gut barrier with minor inflammation are considered to play an important role in the pathophysiology of irritable bowel syndrome (IBS). Since pioglitazone is known to have anti-inflammatory property, we hypothesized that pioglitazone is beneficial for treating IBS. In this study, the effect was tested in rat IBS models such as lipopolysaccharide or repeated water avoidance stress-induced visceral allodynia and increased colonic permeability. Pioglitazone blocked these visceral changes, and GW9662, a peroxisome proliferator-activated receptor gamma (PPAR-γ) antagonist fully reversed the effect by pioglitazone. These results suggest that PPAR-γ activation by pioglitazone may be useful for IBS treatment.

DOI： 10.1016/j.jphs.2018.11.006

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BACKGROUND AND AIM: Metformin has been shown to have anti-cytokine property. Lipopolysaccharide (LPS)-induced or repeated water avoidance stress (WAS)-induced visceral allodynia and increased gut permeability were pro-inflammatory cytokine-dependent responses, which were considered to be animal models of irritable bowel syndrome (IBS). We hypothesized that metformin improves symptoms in the patients with IBS by attenuating these visceral changes and tested the hypothesis in rats. METHODS: The threshold of the visceromotor response induced by colonic balloon distention was measured. Colonic permeability was determined in vivo by quantifying the absorbed Evans blue for 15 min spectrophotometrically. RESULTS: Subcutaneously injected LPS (1 mg/kg) reduced the threshold of visceromotor response, and metformin (5-50 mg/kg for 3 days) intraperitoneally attenuated this response in a dose-dependent manner. Repeated WAS (1 h daily for 3 days) induced visceral allodynia, which was also blocked by metformin. The antinociceptive effect of metformin on the LPS-induced allodynia was reversed by compound C, an adenosine monophosphate-activated protein kinase inhibitor or NG -nitro-L-arginine methyl ester, a nitric oxide synthesis inhibitor but not modified by naloxone. Additionally, it was blocked by sulpiride, a dopamine D2 receptor antagonist, but domperidone, a peripheral dopamine D2 receptor antagonist, did not alter it. Metformin also blocked the LPS-induced or repeated WAS-induced increased colonic permeability. CONCLUSIONS: Metformin attenuated the visceral allodynia and increased gut permeability in animal IBS models. These actions may be evoked via activation of adenosine monophosphate-activated protein kinase, nitric oxide, and central dopamine D2 pathways. These results indicate the possibility that metformin can be useful for treating IBS.

DOI： 10.1111/jgh.14367

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DOI： 10.3389/fnins.2018.01042.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jphs.2018.11.006.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/jgh.14367.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jphs.2018.11.006.

Language：English   Publishing type：Research paper (scientific journal)  

The sit-to-stand motion is a common movement in daily life and understanding the mechanism of the sit-to-stand motion is important. Our previous study shows that four muscle synergies can characterize the sit-to-stand motion, and they have specific roles, such as upper body flexion, rising from a chair, body extension, and posture stabilization. The time-varying weight of these synergies are changed to achieve adaptive movement. However, the relationship between sensory input and the activation of the muscle synergies is not completely understood. In this paper, we aim to clarify how vestibular and visual inputs affect the muscle synergy in sit-to-stand motion. To address this, we conducted experiments as follows. Muscle activity, body kinematics, and ground reaction force were measured for the sit-to-stand motion under three different conditions: control, visual-disturbance, and vestibular-disturbance conditions. Under the control condition, the participants stood without any intervention. Under the visual-disturbance condition, the participants wore convex lens glasses and performed the sit-to-stand motion in a dark room. Under the vestibular-disturbance condition, a caloric test was performed. Muscle synergies were calculated for these three conditions using non-negative matrix factorization. We examined whether the same four muscle synergies were employed under each condition, and the changes in the time-varying coefficients were determined. These experiments were conducted on seven healthy, young participants. It was found that four muscle synergies could explain the muscle activity in the sit-to-stand motion under the three conditions. However, there were significant differences in the time-varying weight coefficients. When the visual input was disturbed, a larger amplitude was found for the muscle synergy that activated mostly in the final posture stabilization phase of the sit-to-stand motion. Under vestibular-disturbance condition, a longer activation was observed for the synergies that extended the entire body and led to posture stabilization. The results implied that during human sit-to-stand motion, visual input has less contribution to alter or correct activation of muscle synergies until the last phase. On the other hand, duration of muscle synergies after the buttocks leave are prolonged in order to adapt to the unstable condition in which sense of verticality is decreased under vestibular-disturbance.

DOI： 10.3389/fnins.2018.01042

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When elderly and young people are compared, strategy shift from ankle strategy to hip strategy occurs at smaller perturbations in the elderly. Although understanding of how the changes of humans' body accompanying with aging cause the difference is important, experiments only are insufficient to understand it. A simulation study reported that sensory noise increase could explain the difference, but a torque-driven model was used and internal forces which contribute to postural control were not considered. The purpose of this study was to elucidate what is the main cause of the difference in strategy shift between young and elderly considering internal forces. We executed musculoskeletal simulations of postural control against a perturbation changing the conditions of muscle and sensory functions. We utilized a neural controller model with feedback control based on proprioceptive information and translated the support surface backward as a perturbation. The magnitude of internal forces was fixed to focus on postural control with high stiffness. 9 conditions (33)()

DOI： 10.1109/MHS.2018.8886944

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Visceral allodynia and increased colonic permeability are considered to be crucial pathophysiology of irritable bowel syndrome (IBS). Corticotropin-releasing factor (CRF) and immune-mediated mechanisms have been proposed to contribute to these changes in IBS, but the precise roles have not been determined. We explored these issues in rats in vivo. The threshold of visceromotor response, i.e., abdominal muscle contractions induced by colonic balloon distention was electrophysiologically measured. Colonic permeability was estimated by quantifying the absorbed Evans blue in colonic tissue. Intraperitoneal injection of CRF increased the permeability, which was blocked by astressin, a non-selective CRF receptor antagonist, but astressin2-B, a selective CRF receptor subtype 2 (CRF2) antagonist did not modify it. Urocortin 2, a selective CRF2 agonist inhibited the increased permeability by CRF. Eritoran, a toll-like receptor 4 (TLR4) antagonist or anakinra, an interleukin-1 receptor antagonist blocked the visceral allodynia and the increased gut permeability induced by CRF. Subcutaneous injection of lipopolysaccharide (immune stress) or repeated water avoidance stress (WAS, psychological stress), 1 h daily for 3 days induced visceral allodynia and increased gut permeability (animal IBS models), which were also blocked by astressin, eritoran or anakinra. In conclusion, stress-induced visceral allodynia and increased colonic permeability were mediated via peripheral CRF receptors. CRF induced these visceral changes via TLR4 and cytokine system, which were CRF1 dependent, and activation of CRF2 inhibited these CRF1-triggered responses. CRF may modulate immune system to alter visceral changes, which are considered to be pivotal pathophysiology of IBS.

DOI： 10.1530/JOE-18-0441

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DOI： 10.1016/j.brainres.2018.02.024

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier B.V.  

Increasing evidence implicates brain ghrelin in a wide variety of physiological functions. Among its gastrointestinal functions, ghrelin is known to act centrally to regulate gastrointestinal motility. Visceral sensation is one of the key gastrointestinal functions controlled by the central nervous system. Little is, however, known about the role of central ghrelin in visceral sensation. The present study thus aimed to clarify whether brain ghrelin is involved in visceral sensation. Visceral sensation was evaluated by the colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Intracisternally administered ghrelin increased the threshold volume of colonic distension-induced AWR in a dose-dependent manner. By contrast, neither intraperitoneal injection of ghrelin nor intracisternal des-acyl-ghrelin altered the threshold volume. Pretreatment with subcutaneous injection of either naloxone hydrochloride or sulpiride, a dopamine D2 receptor antagonist, significantly blocked ghrelin-induced visceral antinociception
furthermore, neither subcutaneous injection of naloxone methiodide, a peripheral selective opioid antagonist, SCH23390, a dopamine D1 receptor antagonist, nor DPCPX, an adenosine A1 receptor antagonist, blocked antinociception. Although intracisternal SB334867, an orexin 1 receptor antagonist, alone failed to change the threshold volume, centrally injected SB334867 potently blocked ghrelin-induced antinociceptive action during colonic distension. These results provide the first evidence that ghrelin acts centrally in the brain to enhance antinociceptive response to colonic distension through the central opioid system, dopamine D2 signaling, and the orexinergic pathway.

DOI： 10.1016/j.brainres.2018.02.024

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In sensory inputs of postural control, visual and vestibular inputs, as well as both proprioceptive and tactile somatosensory inputs, are required to control posture-regulating muscles in the whole body, especially in the lower limbs and trunk. Changes in multisensory inputs elicit appropriate changes immediately in posture corresponding to the sensory information. Because the central nerve system is complex, the mechanism by which this regulation occurs is still unknown. In this study, we set up experiments with measurements of muscular activities by multisensory alterations to investigate the tonus control in postural control. We focus on visual, vestibular and proprioceptive sensations in this paper. From the results of the positions and the standard deviations of CoPs, we confirm that the experiments were well-done to our aim. In the standard deviations of CoPs, the effects of instability rise up in the order of GVS, closed eyes and vibration. However, it is interesting that these are not simple summation but with something to be integrated. From the result of EMGs, comparing with control conditions, almost muscular activities rise up in several conditions. However, it is difficult to find regularity between sensations and muscular activities. We should continue to analyze the results for our hypothesis.

DOI： 10.1109/MHS.2017.8305207

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.15406/smdij.2018.02.00031

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ejphar.2017.10.056

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier B.V.  

Statins have been reported to block inflammatory somatic pain and have an anti-cytokine property. Lipopolysaccharide (LPS) or repeated water avoidance stress (WAS) induces visceral hypersensitivity and increases gut permeability in rats, which are mediated through proinflammatory cytokine-dependent pathways. Since visceral hypersensitivity with increased gut permeability plays a crucial role in the pathophysiology of irritable bowel syndrome (IBS), these above animal models are considered to simulate IBS. We hypothesized that lovastatin improves symptoms in the patients with IBS by attenuating these visceral changes. The threshold of visceromotor response (VMR) induced by colonic balloon distention was measured for the assessment of visceral sensation in rats. Colonic permeability was determined in vivo by quantifying the absorbed Evans blue in colonic tissue for 15 min using a spectrophotometer. Subcutaneously (s.c.) injected LPS (1 mg/kg) reduced the threshold of VMR after 3 h. Pretreatment with lovastatin (20 mg/kg s.c. daily for 3 days) abolished this response by LPS. Repeated WAS (1 h daily for 3 days) induced visceral allodynia, which was also blocked by repeated injection of lovastatin before each stress session. The antinociceptive effect of lovastatin on the LPS-induced allodynia was reversed by mevalonolactone, NG-nitro-L-arginine methyl ester or naloxone. Lovastatin also blocked the LPS- or repeated WAS-induced increased gut permeability. These results indicate the possibility that lovastatin can be useful for treating IBS.

DOI： 10.1016/j.ejphar.2017.10.056

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing  

Background and Aim: A glucagon-like peptide-1 analog, liraglutide, has been reported to block inflammatory somatic pain. We hypothesized that liraglutide attenuates lipopolysaccharide (LPS)-induced and repeated water avoidance stress (WAS)-induced visceral hypersensitivity and tested the hypothesis in rats. Methods: The threshold of the visceromotor response induced by colonic balloon distention was measured to assess visceral sensation. Colonic permeability was determined in vivo by quantifying the absorbed Evans blue spectrophotometrically, which was instilled in the proximal colon for 15 min. The interleukin-6 level in colonic mucosa was also quantified using ELISA. Results: Subcutaneously injected LPS (1 mg/kg) reduced the visceromotor response threshold after 3 h. Liraglutide (300 μg/kg subcutaneously) at 15 h and 30 min before injecting LPS eliminated LPS-induced allodynia. It also blocked the allodynia induced by repeated water avoidance stress for 1 h for three consecutive days. Neither vagotomy nor naloxone altered the antinociceptive effect of liraglutide, but NG-nitro-L-arginine methyl ester, a nitric oxide synthesis inhibitor, blocked it. LPS increased colonic permeability and the interleukin-6 level, and the analog significantly inhibited these responses. Conclusions: This study suggests that liraglutide blocked LPS-induced visceral allodynia, which may be a nitric oxide-dependent response, and was probably mediated by inhibiting pro-inflammatory cytokine production and attenuating the increased gut permeability. Because the LPS-cytokine system is considered to contribute to altered visceral sensation in irritable bowel syndrome, these results indicate the possibility that liraglutide can be useful for treating this disease.

DOI： 10.1111/jgh.13808

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DOI： 10.1111/jgh.13808

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1109/EMBC.2018.8512641.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1530/JOE-18-0441.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.brainres.2018.02.024.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ejphar.2017.10.056.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/jgh.13808.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.15406/smdij.2018.02.00031

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing  

Background and Aim: Repeated water avoidance stress (WAS) induces visceral hypersensitivity. Additionally, it is also known to activate corticotropin-releasing factor (CRF), mast cells, and pro-inflammatory cytokines systems, but their precise roles on visceral sensation have not been determined definitely. The aim of the study was to explore this issue. Methods: Abdominal muscle contractions induced by colonic balloon distention, that is, visceromotor response (VMR) was detected electrophysiologically in conscious rats. WAS or sham stress as control for 1 h daily was loaded, and the threshold of VMR was determined before and at 24 h after the stress. Results: Repeated WAS for three consecutive days reduced the threshold of VMR, but sham stress did not induce any change. Astressin, a CRF receptor antagonist (50 μg/kg) intraperitoneally (ip) at 10 min before each WAS session, prevented the visceral allodynia, but the antagonist (200 μg/kg) ip at 30 min and 15 h before measurement of the threshold after completing 3-day stress session did not modify the response. Ketotifen, a mast cell stabilizer (3 mg/kg), anakinra, an interleukin (IL)-1 receptor antagonist (20 mg/kg) or IL-6 antibody (16.6 μg/kg) ip for two times before the measurement abolished the response. Conclusions: Repeated WAS for three consecutive days induced visceral allodynia, which was mediated through mast cells, IL-1, and IL-6 pathways. Inhibition of peripheral CRF signaling prevented but did not reverse this response, suggesting that peripheral CRF may be an essential trigger but may not contribute to the maintenance of repeated WAS-induced visceral allodynia.

DOI： 10.1111/jgh.13787

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© 2017 IEEE. Proprioception plays an important role in postural stability. Here, we developed a hypothesis that when we cannot use all sensory information, we maintain upright posture with high muscle stiffness. To validate the hypothesis, we needed to confirm another hypothesis that humans can keep standing with some stiffness levels compensating for the loss of visual and vestibular information. We expanded a neural controller for an unperturbed stance with feedforward and proprioceptive feedback mechanisms to simulate a perturbed stance. A musculoskeletal model with 70 muscles and 13 degrees of freedom was prepared as a human body. We succeeded in ensuring that the musculoskeletal model maintains an upright standing posture against support surface translations in 12 directions with one stiffness level. The responses of leg muscles in our simulations were consistent with those in the previous work. Moreover, the limitation, i.e., the inability of high level control of the neural controller could be explained using the responses of the trunk muscles.

DOI： 10.1109/robio.2017.8324592

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Language：Japanese   Publisher：(一社)日本救急医学会  

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DOI： 10.4236/psych.2017.87064

Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.11477/mf.1551200861

Language：Japanese   Publisher：(一社)日本生理学会  

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DOI： 10.1111/jgh.13787

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Early diagnosis of potential cerebellar disease is incredibly important, as it allows rapid intervention and treatment of the identified disorder. More effective diagnosis and treatment would be aided by identification of which specific cerebellar regions are impaired. In this paper, we propose a method for initial diagnosis of regional cerebellar impairments. Our model uses motor functions as regional intermediaries for the outputs and various indexes (motor assessments) as the inputs. We also discuss which indexes indicate possible disordered functions. We tested our proposed method by applying it experimentally to the diagnosis of cerebellar disorder in rats. The percentage of correct estimations was 74.5%. We consider this a sufficiently high rate for initial diagnosis and suggest that it may be more effective when applied to humans.

DOI： 10.1080/01691864.2016.1272490

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Maintenance of the upright stance is one of the basic requirements in human daily life. Stance postural control is achieved through muscle coordination based on the integration of multisensory inputs such as visual, vestibular, and proprioceptive somatosensory inputs. In this study, our aim was to develop a stance postural control model including a neural controller with feed-forward control and sensory feedback control based on visual, vestibular, and proprioceptive somatosensory feedback inputs. The feed-forward control consists of conventional feed-forward control, which sends constant inputs (necessary to maintain the posture) to the muscles, as well as stiffness regulationwhich controls the body stiffness (overall joint stiffness) based on sensory input conditions. In contrast to previous studies, a musculoskeletal model with 70 muscles rather than an inverted pendulum was selected to represent the human body. A bipedal stance under the influence of a maximal 120-ms neurological time delay was achieved by muscle control rather than joint torque control. Furthermore, we considered four sensory input conditions: normal, vision exclusion, vestibular loss, and vision exclusion together with vestibular loss. In each condition, variables of the neural controller were searched to keep the musculoskeletal model standing during a five-second forward dynamics simulation by the optimization method. As a result, we found that when all three types (visual, vestibular, and proprioceptive) of the sensory inputs are available, low muscle stiffness is sufficient to maintain the balance of a musculoskeletal model. When one (visual or vestibular) or several (both visual and vestibular) sensory inputs get excluded, high stiffness may be desirable for maintenance of the balance. This simulation result indicates that our newly developed computational model resembles the physiological features reported in experimental study, namely that individuals might stiffen their body during upright standing to cope with deterioration in sensory input.

DOI： 10.1080/01691864.2016.1266095

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This review argues neuronal mechanisms of postural control. Multi-sensory information such as somatosensory, visual, and vestibular sensation act on various areas of the brain so that adaptable postural control can be achieved. Automatic process of postural control, which is termed as postural reflexes including head–eye coordination accompanied by appropriate alignment of body segments, is mediated by the descending pathways from the brainstem. Cooperation of the vestibulospinal, reticulospinal, and tectospinal tracts contributes to this process. On the other hand, walking in unfamiliar circumstance requires cognitive process of postural control, which depends on knowledge of self-body, such as body schema, sense of postural verticality, and body motion in space. Such a bodily cognitive information is produced at the temporoparietal cortex. They are fundamental to sustention of vertical posture and construction of motor programs. The programs then run to execute anticipatory postural adjustment which is appropriate for achievement of goal-directed movements. The basal ganglia and cerebellum may affect both the automatic and cognitive processes of postural control through reciprocal connections with the brainstem and cerebral cortex, respectively. Consequently, impairments in cognitive function in addition to damages in the motor cortex, basal ganglia, and cerebellum may disturb appropriate postural control, resulting in falling.

DOI： 10.1080/01691864.2016.1252690

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1080/01691864.2016.1272490

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s00535-016-1208-y

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.14802/jmd.16062

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Lipopolysaccharide (LPS) induces visceral hypersensitivity, and corticotropin-releasing factor (CRF) also modulates visceral sensation. Besides, LPS increases CRF immunoreactivity in rat colon, which raises the possibility of the existence of a link between LPS and the CRF system in modulating visceral sensation. The present study tried to clarify this possibility. METHODS: Visceral sensation was assessed by abdominal muscle contractions induced by colonic balloon distention, i.e., visceromotor response, electrophysiologically in conscious rats. The threshold of visceromotor response was measured before and after administration of drugs. RESULTS: LPS at a dose of 1 mg/kg subcutaneously (sc) decreased the threshold at 3 h after the administration. Intraperitoneal (ip) administration of anakinra (20 mg/kg), an interleukin-1 (IL-1) receptor antagonist, or interleukin-6 (IL-6) antibody (16.6 µg/kg) blocked this effect. Additionally, IL-1β (10 µg/kg, sc) or IL-6 (10 µg/kg, sc) induced visceral allodynia. Astressin (200 µg/kg, ip), a non-selective CRF receptor antagonist, abolished the effect of LPS, but astressin2-B (200 µg/kg, ip), a CRF receptor type 2 (CRF2) antagonist, did not alter it. Peripheral CRF receptor type 1 (CRF1) stimulation by cortagine (60 µg/kg, ip) exaggerated the effect of LPS, but activation of CRF2 by urocortin 2 (60 µg/kg, ip) abolished it. CONCLUSIONS: LPS induced visceral allodynia possibly through stimulating IL-1 and IL-6 release. In addition, this effect was mediated through peripheral CRF signaling. Since the LPS-cytokine system is thought to contribute to altered visceral sensation in the patients with irritable bowel syndrome, these results may further suggest that CRF plays a crucial role in the pathophysiology of this disease.

DOI： 10.1007/s00535-016-1208-y

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Here we argue functional neuroanatomy for posture-gait control. Multi-sensory information such as somatosensory, visual and vestibular sensation act on various areas of the brain so that adaptable posture-gait control can be achieved. Automatic process of gait, which is steady-state stepping movements associating with postural reflexes including headeye coordination accompanied by appropriate alignment of body segments and optimal level of postural muscle tone, is mediated by the descending pathways from the brainstem to the spinal cord. Particularly, reticulospinal pathways arising from the lateral part of the mesopontine tegmentum and spinal locomotor network contribute to this process. On the other hand, walking in unfamiliar circumstance requires cognitive process of postural control, which depends on knowledges of self-body, such as body schema and body motion in space. The cognitive information is produced at the temporoparietal association cortex, and is fundamental to sustention of vertical posture and construction of motor programs. The programs in the motor cortical areas run to execute anticipatory postural adjustment that is optimal for achievement of goal-directed movements. The basal ganglia and cerebellum may affect both the automatic and cognitive processes of posturegait control through reciprocal connections with the brainstem and cerebral cortex, respectively. Consequently, impairments in cognitive function by damages in the cerebral cortex, basal ganglia and cerebellum may disturb posture-gait control, resulting in falling.

DOI： 10.14802/jmd.16062

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/jgh.13787.

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1080/01691864.2016.1252690

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1080/01691864.2016.1266095

Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：Springer Verlag  

Maintenance of upright stance is one of the basic requirements in human daily life. Stance postural control is achieved based on multisensory inputs such as visual, vestibular and proprioceptive somatosensory inputs. In this paper, we proposed a stance postural control model including a neural controller with feed-forward inputs (muscle stiffness regulation) and sensory feedback of vestibular and proprioceptive somatosensory sensation. Through the optimization, variables of neural controller were designed to keep a musculoskeletal model standing during a 5 s forward dynamics simulation. From the results, we found that when both vestibular and proprioceptive somatosensory sensory input are available, low muscle stiffness is enough to maintain the balance of a musculoskeletal model in a stance posture. However, when vestibular sensory input get lost, higher muscle stiffness will be desired to keep the musculoskeletal model standing.

DOI： 10.1007/978-3-319-48036-7_4

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Language：English   Publishing type：Research paper (scientific journal)  

コンピュータシミュレーションにより順動力学を基盤とした人型立位維持２足筋骨格モデルの作成に成功した（世界初）

DOI： 10.1371/journal.pone.0163212

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Language：English   Publishing type：Research paper (scientific journal)  

The development of a physiologically plausible computational model of a neural controller that can realize a human-like biped stance is important for a large number of potential applications, such as assisting device development and designing robotic control systems. In this paper, we develop a computational model of a neural controller that can maintain a musculoskeletal model in a standing position, while incorporating a 120-ms neurological time delay. Unlike previous studies that have used an inverted pendulum model, a musculoskeletal model with seven joints and 70 muscular-tendon actuators is adopted to represent the human anatomy. Our proposed neural controller is composed of both feed-forward and feedback controls. The feed-forward control corresponds to the constant activation input necessary for the musculoskeletal model to maintain a standing posture. This compensates for gravity and regulates stiffness. The developed neural controller model can replicate two salient features of the human biped stance: (1) physiologically plausible muscle activations for quiet standing; and (2) selection of a low active stiffness for low energy consumption.

DOI： 10.1371/journal.pone.0163212

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ストレス性消化管機能障害には神経免疫学的機序とドーパミン受容体が関与することを示した。

DOI： 10.1111/nmo.12747

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Language：English  

DOI： 10.1111/nmo.12747

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：Institute of Electrical and Electronics Engineers Inc.  

Car race drivers are always in dangerous and harsh environments. In order to reduce risks due to mental stress, it is important to evaluate stress during a car race in real-time. The present study measured three physiological indices, heart rate variability, sweat rate, and electromyogram of massester from a professional racer during a car race. However, the relation between these indices, and the types of stress still remains unclear. In the present study, we examined the relations between the three indices and factors linked with these indices during car race with factor analysis. The results suggested that the three physiological indices related to two different factors. One factor scored high when driver saw other nearby car, and was influenced mainly by heart rate variability and sweat rate. We suggest that mental stress is probably high in such scenes, and named this factor as mental stress. Furthermore, the other factor showed high values during urgent accelerations and decelerations, and was influenced mainly by electromyogram of massester. During urgent accelerations and decelerations, the driver probably suffered from large physical discomfort. Therefore, we named the second factor as physical stress. In summary, we found the three physiological indices reflected two different types of stress during car race. Moreover, according to the results of factor analysis, we proposed a method of real-time estimation of both mental and physical stress with the three physiological indices during car race.

DOI： 10.1109/MHS.2015.7438258

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We have recently demonstrated that orexin acts centrally through the brain orexin 1 receptors to induce an antinociceptive action against colonic distension in conscious rats. Adenosine signaling is capable of inducing an antinociceptive action against somatic pain; however, the association between changes in the adenosinergic system and visceral pain perception has not been investigated. In the present study, we hypothesized that the adenosinergic system may be involved in visceral nociception, and thus, adenosine signaling may mediate orexin-induced visceral antinociception. Visceral sensation was evaluated based on the colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Subcutaneous (0.04-0.2mg/rat) or intracisternal (0.8-4μg/rat) injection of N(6)-cyclopentyladenosine (CPA), an adenosine A1 receptor (A1R) agonist, increased the threshold volume of colonic distension-induced AWR in a dose-dependent manner, thereby suggesting that CPA acts centrally in the brain to induce an antinociceptive action against colonic distension. Pretreatment with theophylline, an adenosine antagonist, or 1,3-dipropyl-8-cyclopentylxanthine, an A1R antagonist, subcutaneously injected potently blocked the centrally injected CPA- or orexin-A-induced antinociceptive action against colonic distension. These results suggest that adenosinergic signaling via A1Rs in the brain induces visceral antinociception and that adenosinergic signaling is involved in the central orexin-induced antinociceptive action against colonic distension.

DOI： 10.1016/j.jns.2016.01.031

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Levodopa possesses antinociceptive actions against several somatic pain conditions. However, we do not know at this moment whether levodopa is also effective to visceral pain. The present study was therefore performed to clarify whether levodopa is effective to visceral pain and its mechanisms. Visceral sensation was evaluated by colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Subcutaneously (80 mg/rat) or intracisternally (2.5 μg/rat) administered levodopa significantly increased the threshold of colonic distension-induced AWR in conscious rats. The dose difference to induce the antinociceptive action suggests levodopa acts centrally to exert its antinociceptive action against colonic distension. While neither sulpiride, a D2 dopamine receptor antagonist, nor SCH23390, a D1 dopamine receptor antagonist by itself changed the threshold of colonic distension-induced AWR, the intracisternally injected levodopa-induced antinociceptive action was significantly blocked by pretreatment with subcutaneously administered sulpiride but not SCH23390. Treatment with intracisternal SB334867, an orexin 1 receptor antagonist, significantly blocked the subcutaneously administered levodopa-induced antinociceptive action. These results suggest that levodopa acts centrally to induce an antinociceptive action against colonic distension through activation of D2 dopamine receptors and the orexinergic system in the brain.

DOI： 10.1016/j.jphs.2016.01.007

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大腸の運動に脳内のドーパミン受容体が関与することを示した。

DOI： 10.1016/j.jphs.2016.01.007

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

姿勢と歩行の制御における脳幹網様体の機能を概説した

DOI： 10.1007/s00702-015-1475-4

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Language：English   Publishing type：Research paper (scientific journal)  

消化管の感受性亢進には炎症性内分泌神経機構が動員されることを示した

PubMed

Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

消化管の拡張によって末梢の免疫炎症機構が作動することを示した。

DOI： 10.1007/s00535-015-1070-3

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Most studies evaluating visceral sensation measure visceromotor response (VMR) to colorectal distention (CRD). However, CRD itself induces visceral sensitization, and little is known about the detailed characteristics of this response. The present study tried to clarify this question. METHODS: VMR was determined by measuring abdominal muscle contractions as a response to CRD in rats. The CRD set consisted of two isobaric distentions (60 mmHg for 10 min twice, with a 30-min rest), and the CRD set was performed on two separate days, i.e., days 1 and 3, 8. RESULTS: On day 1, VMR to the second CRD was increased as compared with that to the first CRD, which is the acute sensitization. VMR to the first CRD on day 3 returned to the same level as that to the first CRD on day 1, and total VMR, i.e., the whole response to the CRD set, was not different between day 1 and day 3. However, total VMR was significantly increased on day 8 as compared with that on day 1, suggesting CRD induced the delayed sensitization. Intraperitoneally administered astressin (200 µg/kg), a corticotropin-releasing factor receptor antagonist, at the end of the first CRD blocked the acute sensitization, but anakinra (20 mg/kg, intraperitoneally), an interleukin-1 receptor antagonist, did not modify it. Astressin (200 µg/kg, twice before CRD on day 8) did not alter the delayed sensitization, but anakinra (20 mg/kg, twice) abolished it. CONCLUSIONS: CRD induced both acute sensitization and delayed sensitization, which were mediated through peripheral corticotropin-releasing factor and interleukin-1 pathways, respectively.

DOI： 10.1007/s00535-015-1070-3

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脳内のオレキシン作動系がドーパミン作動系に作用して消化管運動に寄与することを示した。

DOI： 10.1016/j.neulet.2015.08.013

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

We have recently demonstrated that orexin acts centrally in the brain to induce antinociceptive action against colonic distension through orexin 1 receptors in conscious rats. Although the dopaminergic system can induce antinociceptive action for somatic pain, the association between changes in the dopaminergic system and visceral pain perception has not been investigated. In the present study, we hypothesized that the dopaminergic system may be involved in visceral nociception, and if so, the dopaminergic system may mediate the orexin-induced visceral antinociception. Visceral sensation was evaluated using the colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Intracisternal injection of D1 (SKF38398) or D2 (quinpirole) dopamine receptor agonist increased the threshold volume of colonic distension-induced AWR in a dose-dependent manner. Pretreatment with either the D1 or D2 dopamine receptor antagonist (SCH23390 or sulpiride, respectively) potently blocked the centrally injected orexin-A-induced antinociceptive action against colonic distension. These results suggest for the first time that dopaminergic signaling via D1 and D2 dopamine receptors in the brain may induce visceral antinociception and that the dopaminergic signaling may be involved in the central orexin-induced antinociceptive action against colonic distension. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.neulet.2015.08.013

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起立姿勢維持における感覚情報の機能的役割について概説した

DOI： 10.1016/j.neures.2015.12.002.

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Language：English   Publishing type：Research paper (scientific journal)  

Increasing evidence has suggested that brain orexins are implicated in a wide variety of physiological functions. With regard to gastrointestinal functions, orexin-A acts centrally to regulate gastrointestinal functions such as gastric and pancreatic secretion, and gastrointestinal motility. Visceral sensation is also known as one of key gastrointestinal functions which are controlled by the central nervous system. Little is, however, known about a role of central orexin in visceral sensation. This study was therefore performed to clarify whether brain orexin may be involved in the process of visceral sensation. Visceral sensation was evaluated by colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Intracisternally administered orexin-A dose-dependently increased the threshold volume of colonic distension-induced AWR. In contrast, neither intraperitoneal injection of orexin-A nor intracisternal orexin-B altered the threshold volume. While intracisternal SB334867, an orexin 1 receptor antagonist, by itself failed to change the threshold volume, SB334867 injected centrally completely blocked the morphine-induced antinociceptive action against colonic distension. These results suggest for the first time that orexin-A specifically acts centrally in the brain to enhance antinociceptive response to colonic distension. We would furthermore suggest that endogenous orexin-A indeed mediates the antinociceptive effect of morphine on visceral sensation through the orexin 1 receptors. All these evidence might indicate that brain orexin plays a role in the pathophysiology of functional gastrointestinal disorders such as irritable bowel syndrome because visceral hypersensitivity of the gut is considered to play a vital role in the diseases.

DOI： 10.1016/j.brainres.2014.12.021

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脳内のオレキシン作動系が消化管運動に関与することを示した。

DOI： 10.1016/j.brainres.2014.12.021

PubMed

Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (international conference proceedings)  

Language：English   Publishing type：Research paper (international conference proceedings)  

Language：English   Publishing type：Research paper (international conference proceedings)  

DOI： 10.1109/SICE.2015.7285391

Language：English   Publishing type：Research paper (scientific journal)  

末梢のCorticotropine 放出因子１と２のバランスによって消化管収縮と臓器感覚が調節されていることを見出した

DOI： 10.1210/en.2014-1421

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：PHARMACEUTICAL SOC JAPAN  

TRPV2, a member of the transient receptor potential family, has been isolated as a capsaicin-receptor homolog and is thought to respond to noxious heat. Here we show that TRPV2 mRNA is predominantly expressed in the subpopulation of olfactory sensory neurons (OSNs). We carried out histochemical analyses of TRPV2 and insulin-like growth factor-I receptor (IGF-IR) using in situ hybridization and immunofluorescence in the adult olfactory system. In olfactory mucosa, intensive TRPV2 immunostaining was observed at the olfactory axon bundles but not at the soma. TRPV2-positive labeling was preferentially found in the olfactory nerve layer in the olfactory bulb (OB). Furthermore, we demonstrated that a positive signal for IGF-IR mRNA was detected in OSNs expressing TRPV2 mRNA. In embryonic stages, TRPV2 immunoreactivity was observed on axon bundles of developing OSNs in the nasal region starting from 12.5d of gestation and through fetal development. Observations in this study suggest that TRPV2 coupled with IGF-IR localizes to growing olfactory axons in the OSNs.

DOI： 10.1248/bpb.b14-00413

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Several recent studies suggest that peripheral corticotropin-releasing factor (CRF) receptor type 1 (CRF1) and CRF2 have a counter regulatory action on gastrointestinal functions. We hypothesized that the activity balance of each CRF subtype signaling may determine the changes in colonic motility and visceral sensation. Colonic contractions were assessed by the perfused manometry, and contractions of colonic muscle strips were measured in vitro in rats. Visceromotor response was determined by measuring contractions of abdominal muscle in response to colorectal distensions (CRDs) (60 mm Hg for 10 min twice with a 30-min rest). All drugs were administered through ip route in in vivo studies. CRF increased colonic contractions. Pretreatment with astressin, a nonselective CRF antagonist, blocked the CRF-induced response, but astressin2-B, a selective CRF2 antagonist, enhanced the response by CRF. Cortagine, a selective CRF1 agonist, increased colonic contractions. In in vitro study, CRF increased contractions of muscle strips. Urocortin 2, a selective CRF2 agonist, itself did not alter the contractions but blocked this increased response by CRF. Visceromotor response to the second CRD was significantly higher than that of the first. Astressin blocked this CRD-induced sensitization, but astressin2-B or CRF did not affect it. Meanwhile, astressin2-B together with CRF significantly enhanced the sensitization. Urocortin 2 blocked, but cortagine significantly enhanced, the sensitization. These results indicated that peripheral CRF1 signaling enhanced colonic contractility and induced visceral sensitization, and these responses were modulated by peripheral CRF2 signaling. The activity balance of each subtype signaling may determine the colonic functions in response to stress.

DOI： 10.1210/en.2014-1421

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DOI： 10.1007/s00535-013-0828-8

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DOI： 10.1016/j.regpep.2014.04.004.

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Language：English   Publishing type：Research paper (scientific journal)  

Lipopolysaccharide (LPS) inhibits gastric antral contractions in conscious rats. Since LPS regulates corticotropin-releasing factor type 2 receptor (CRF2) expression in the rat stomach, and activation of peripheral CRF2 alters gastric motility, we tried to determine the role of peripheral CRF2 in the LPS-induced suppression of gastric antral contractions. Intraluminal gastric pressure waves were measured in freely moving conscious non-fasted rats using the perfused manometric method. We assessed the area under the manometric trace as the motor index (MI), and compared this result with those obtained 1h before and after intraperitoneal injection of drugs. LPS (0.2 mg/kg) significantly decreased MI. Indomethacin (10 mg/kg) itself did not alter MI but blocked this inhibitory action by LPS. Astressin 2-B (200 μg/kg), a selective CRF2 antagonist, modified neither the basal MI nor the action by LPS. Meanwhile, urocortin 2 (30 μg/kg), a selective CRF2 agonist, reversed the suppression by LPS without affecting the basal MI. This action by urocortin 2 was blocked by pretreatment with astressin 2-B. In conclusion, LPS inhibited gastric antral contractions possibly through a prostaglandin-dependent pathway. Peripheral CRF2 stimulation reversed this response by LPS.

DOI： 10.1016/j.regpep.2014.04.004

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BACKGROUND: Stress alters gastrointestinal motility through central and peripheral corticotropin-releasing factor (CRF) pathways. Accumulating evidence has demonstrated that peripheral CRF is deeply involved in the regulation of gastric motility, and enhances gastric contractions through CRF receptor type 1 (CRF1) and delays gastric emptying (GE) through CRF receptor type 2 (CRF2). Since little is known whether water-avoidance stress (WAS) alters gastric motility, the present study tried to clarify this question and the involvement of peripheral CRF receptor subtypes in the mechanisms. METHODS: We recorded intraluminal gastric pressure waves using a perfused manometric method. The rats were anesthetized and the manometric catheter was inserted into the stomach 4-6 days before the experiments. We assessed the area under the manometric trace as the motor index (MI), and compared this result with those obtained 1 h before and after initiation of WAS in nonfasted conscious rats. Solid GE for 1 h was also measured. RESULTS: WAS significantly increased gastric contractions. Intraperitoneal (ip) administration of astressin (100 μg/kg, 5 min prior to stress), a nonselective CRF antagonist, blocked the response to WAS. On the other hand, pretreatment (5 min prior to stress) with neither astressin2-B (200 μg/kg, ip), a selective CRF2 antagonist, nor urocortin 2 (30 μg/kg, ip), a selective CRF2 agonist, modified the response to WAS. These drugs did not alter the basal MI. WAS did not change GE. CONCLUSIONS: WAS may activate peripheral CRF1 but not CRF2 signaling and stimulates gastric contractions without altering GE.

DOI： 10.1007/s00535-013-0828-8

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TRP受容体とインスリン様受容体がマウスの嗅神経細胞に共存することを示した。

DOI： 10.1248/bpb.b14-00413

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Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.neuroscience.2013.09.036

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Lateral lemniscus, a relay nucleus of auditory sensation, is involved in the control of phonatory movements such as human speech and vocalization of animals. The present study was designed to test whether neurons in the lateral lemniscus contributed to the control of swallowing, one of non-phonic oro-pharyngolaryngeal movements. In acutely decerebrated cats (n = 15), swallowing was induced by electrical stimulation (20-80 pA at 10 Hz for 20 s with rectangular pulses of 0.2 ms duration) delivered to the superior laryngeal nerve (SLN). Repetitive electrical stimulation (30-50 pA at 50 Hz for 10-20 s) applied to the dorsal nucleus of the lateral lemniscus (LLD) increased the number and reduced the latency to the onset of the SLNinduced swallowing. On the other hand, stimulation of the ventral nucleus of the lateral lemniscus and the paralemniscal area, corresponding to the ventrolateral part of the parabrachial nucleus and the Kolliker-Fuse nucleus, often suppressed the SLN-induced swallowing. Microinjection of NMDA (0.1-0.15 pl, 5.0-10 mM) into the LLD through a stereotaxically placed glass micropipette facilitated the SLNinduced swallowing, i.e., the number was increased and muscimol (a gamma amino-butyric acid (GABA)A receptor agonist), bicuculline (a GABAA receptor antagonist) and baclofen (a GABAB receptor agonist) into the LLD (0.10.15 pl and 5.0 mM for each substance). It was observed that an injection of muscimol suppressed the SLN-induced swallowing. However, an injection of bicuculline facilitated the swallowing. An injection of baclofen did not alter the swallowing. These results suggest the presence of functional topography in the lateral lemniscus and the paralemniscal area in relation to the control of swallowing. The facilitatory LLD-effects on swallowing are modulated by glutamatergic and GABAergic receptors on neurons in the LLD. (C) 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.neuroscience.2013.09.036

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Language：English   Publishing type：Research paper (bulletin of university, research institution)  

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/nmo.12050

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1109/ROBIO.2013.6739483

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DOI： 10.1109/SMC.2013.212

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1109/ARSO.2013.6705511

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/mds.25669.

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/978-3-642-33932-5_44

Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (international conference proceedings)  

For understanding of human posture control, changes in muscular activity caused by changes in sensory inputs are very important because the control mechanism is complicated with integrating multi-inputs and outputting various and simultaneous muscular activity. In this research, we aim to obtain quantitative changes in muscular activity caused by changes in sensory inputs. For this purpose, we propose a method to be founded on the idea that muscle activity is divided into external force elements and internal elements. With this method, we can show the existence of internal muscular activity as well as external muscular activity. And it is considered that new model of human posture control with the difference of sensory inputs might be obtained. © 2013 Springer-Verlag.

DOI： 10.1007/978-3-642-33932-5_44

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

オーファン受容体に作用する新規ニューロペプチドであるオレキシン（A)が中枢神経系に作用することにより消化管（大腸）の運動機能の調節に関与することを見出した．

Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

オレキシン（A)によって誘発される胃運動には2-deoxy-glucoseが関与することを証明した．

DOI： 10.1007/s00535-011-0506-7

Language：English   Publishing type：Research paper (scientific journal)  

Background: Increasing evidence has indicated that brain orexin plays a vital role in the regulation of gastrointestinal (GI) physiology such as gastric acid secretion and GI motility. The aim of this study was to elucidate the effects and mechanisms of orexin on gastric motility in non-fasted rats. Methods: In this study, we recorded intraluminal gastric pressure waves in freely moving conscious rats with a manometric catheter located in the antrum. We assessed the area under the manometric trace as the motor index (MI), and compared its values for 1 h before and after drug administration. Results: Intracisternal (ic) injection of orexin-A (10 μg) significantly increased the MI, but intraperitoneal (ip) injection did not have any effect. Pretreatment of ip injection of atropine significantly blocked the orexin-A-induced stimulation of gastric motility. Intravenous injection of 2-deoxy-D-glucose (2-DG, 200 mg/kg), a central vagal stimulant, significantly increased the MI. The ic injection of SB-334687 (40 μg), a selective orexin-A antagonist, did not modify the basal MI, but this antagonist significantly suppressed the stimulant action of 2-DG. Conclusions: These results suggest that endogenous orexin-A in the brain is involved in the vagal-dependent stimulation of gastric contractions. © Springer 2012.

DOI： 10.1007/s00535-011-0506-7

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Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (international conference proceedings)  

I review substrates for the execution of normal gait and to understand pathophysiological mechanisms of gait failure in basal ganglia dysfunctions. In Parkinson's disease, volitional and emotional expressions of movement processes are seriously affected in addition to the disturbance of automatic movement processes, such as adjustment of postural muscle tone and rhythmic limb movements during walking. These patients also suffer from muscle tone rigidity and postural instability, which may also cause reduced walking capabilities. Clinical and neurophysiological studies have suggested the importance of basal ganglia connections with the cerebral cortex and limbic system in the expression of volitional and emotional behaviors, respectively. On the other hand, basal ganglia output toward the brainstem (basal ganglia-brainstem system) can be critically involved in the integrative control of muscle tone and locomotion. Recently emphasis has been placed on the importance of body schema, or internal postural model, which is generated at parietal cortex by integrating multimodal (proprioceptive, visual, auditory and vestibular) sensory inputs. The body schema can be required for motor programing of intentionally controlled precise movements and anticipatory postural control. Based on these considerations I provide a hypothetical model for understanding the role of the basal ganglia in the control of volitional and automatic aspects of movements and pathophysiological mechanisms of basal ganglia motor disorders. © 2012 IEEE.

DOI： 10.1109/ICCME.2012.6275707

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This paper is an introduction to the Mobiligence Program by MEXT (the Japanese Ministry of Education, Culture, Sports, Science, and Technology) from 2005 through 2009. The concept, subject, methodology, and results regarding the Mobiligence Program are discussed. Next, the future of mobiligence research is proposed with respect to a research target (the methodology focusing on embodiment) and research methodology (integrated dynamic model combining physiological and behavioral data and knowledge). © 2012 IEEE.

DOI： 10.1109/ICCME.2012.6275711

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Authorship：Lead author   Language：English   Publishing type：Research paper (international conference proceedings)  

Authorship：Lead author   Language：English   Publishing type：Research paper (international conference proceedings)  

Language：English   Publishing type：Research paper (scientific journal)  

Increasing evidence has indicated that brain orexin plays a vital role in the regulation of gastrointestinal physiology such as gastric secretion, gastric motility and pancreatic secretion. However, little is known whether orexin in the brain is involved in the physiology of the lower gastrointestinal tract. The aim of this study was therefore to elucidate whether orexin-A in the brain is involved in the regulation of colonic motility. In this study, we measured fecal pellet output and recorded intraluminal colonic pressure waves in freely moving conscious rats to evaluate the effects of central orexin-A on colonic motor functions. Intracisternal but not intraperitoneal injection of orexin-A dose-dependently (1-10μg) increased fecal pellet output. Findings obtained from manometric recordings revealed that intracisternal administration of orexin-A at a dose of 10μg significantly enhanced colonic motor contractions. These results suggest for the first time that orexin-A acts centrally in the brain to enhance fecal pellet output and stimulate colonic motility in conscious rats. The present study would furthermore support our hypothesis that orexin-A in the brain may be an important candidate as a mediator of the cephalic phase gut stimulation including stimulated colonic motility in addition to well known physiological response such as stimulation of gastric acid and pancreatic acid secretion, and gastric motility. © 2011 Elsevier Ireland Ltd.

DOI： 10.1016/j.neulet.2011.04.078

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Pedunculopontine tegmental nucleus (PPN) contributes to the control of muscle tone by modulating the activities of pontomedullary reticulospinal systems during wakefulness and rapid eye movement (REM) sleep. The PPN receives GABAergic projection from the substantia nigra pars reticulata (SNr), an output nucleus of the basal ganglia. Here we examined how GABAergic SNr-PPN projection controls the activity of the pontomedullary reticulospinal tract that constitutes muscle tone inhibitory system. Intracellular recording was made from 121 motoneurons in the lumbosacral segments in decerebrate cats (n = 14). Short train pulses of stimuli (3 pulses with 5 ms intervals, 10-40 mA) applied to the PPN, where cholinergic neurons were densely distributed, evoked eye movements toward the opposite side and bilaterally suppressed extensor muscle activity. The identical PPN stimulation induced IPSPs, which had a peak latency of 40-50 ms with a duration of 40-50 ms, in extensor and flexor motoneurons. The latelatency IPSPs were mediated by chloride ions. Microinjection of atropine sulfate (20 mM, 0.25 μl) into the pontine reticular formation (PRF) reduced the amplitude of the IPSPs. Although conditioning stimuli applied to the SNr (40-60 μA and 100 Hz) alone did not induce any postsynaptic effects in motoneurons, they reduced the amplitude of the PPN-induced IPSPs. Subsequent injection of bicuculline (5 mM, 0.25 μl) into the PPN blocked the SNr effects. Microinjections of NMDA (5 mM, 0.25 μl) and muscimol (5 mM, 0.25 μl) into the SNr reduced and increased the amplitude of the PPN-induced IPSPs, respectively. These results suggest that GABAergic basal ganglia output controls postural muscle tone by modulating the activity of cholinergic PPN neurons which activate the muscle tone inhibitory system. The SNr-PPN projection may contribute to not only control of muscle tone during movements in wakefulness but also modulation of muscular atonia of REM sleep. Dysfunction of the SNr-PPN projection may therefore be involved in sleep disturbances in basal ganglia disorders.

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Language：Japanese   Publishing type：Research paper (scientific journal)  

One of the fundamental characteristics of animal is locomotion. Although not visually apparent, goal-directed locomotor movements are always accompanied by automatic adjustment of muscle tone and postural reactions. Because the basic and essential mechanisms that control postural muscle tone and locomotion are located in the brainstem and spinal cord, a variety of locomotor behaviors are achieved by the projections from the forebrain structures (cerebral cortex, basal ganglia, and limbic-hypothalamic systems) and cerebellum to the brainstem-spinal cord. In this short review, we particularly focus on the role of the brainstem and spinal cord in the control of postural muscle tone and generation of locomotor rhythm. Abnormalities in the convergence inputs from the forebrain structures to the brainstem-spinal cord are further discussed in relation to the pathogenesis of disturbances in locomotor control.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

To understand the role of cholinoceptive, medial pontine reticular formation (mPRF) neurons in the control of upper airway, pharyngolaryngeal reflexes, we measured activities of intrinsic laryngeal muscles (posterior cricoarytenoid, PCA; thyroarytenoid, TA), diaphragm (DIA), genioglossus (GG) and a neck muscle (trapezius) in unanesthetized, decerebrated, spontaneously breathing cats with and without mPRF carbachol injections. The ethimoidal nerve was electrically stimulated to evoke sneezing, and the superior laryngeal nerve to evoke the laryngeal reflex, swallowing, and coughing. Carbachol reduced the amplitudes of the spontaneous electromyographic activities in the neck, TA, PCA, GG, and DIA to 7%, 30%, 54%, 45% and 71% of control, respectively, reduced the respiratory rate to 53% without changes in expiratory CO(2) concentration; the magnitude of the laryngeal reflex in the TA muscle to 56%; increased its latency by 13%; and reduced the probability of stimulus-induced sneezing, swallowing, and coughing to less than 40%. These changes lasted more than 1 h. These data demonstrate that important upper airway reflexes are suppressed by increasing cholinergic neurotransmission in the mPRF. Because acetylcholine release in the mPRF changes in accordance with sleep-wake cycles, the present findings are relevant to the control of upper airway reflexes during various vigilance states. (C) 2010 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

DOI： 10.1016/j.neures.2010.01.009

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DOI： 10.1016/j.neures.2010.01.009

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Lipin-1 is a multifunctional metabolic regulator, involving in triacylglycerol and bioactive glycerolipids synthesis as an enzyme, transcriptional regulation as a coactivator, and adipogenesis. In obesity, adipose lipin-1 expression is decreased. Although lipin-1 is implicated in the pathogenesis of obesity, the mechanism is still not clear. Since TNF-α is deeply involved in the pathogenesis of obesity, insulin resistance, and diabetes, here we investigated the role of TNF-α on lipin-1 expression in adipocytes. Quantitative PCR studies showed that TNF-α suppressed both lipin-1A and -1B isoform expression in time- and dose-dependent manners in mature 3T3-L1 adpocytes. A Jak2 inhibitor, AG490, reversed the suppressive effect of TNF-α on both lipin-1A and -1B. In contrast, NF-κB, MAPKs, ceramide, and β-catenin pathway tested were not involved in the mechanism. These results suggest that TNF-α could be involved in obesity-induced lipin-1 suppression in adipocytes and Jak2 may play an important role in the mechanism. © 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2009.03.021

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DOI： 10.1016/j.bbrc.2009.01.134

Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

We examined the effects of troglitazone on expression of E-cadherin and claudin 4 in human pancreatic cancer cells. Troglitazone dose-dependently increased expression of E-cadherin and claudin 4 mRNA and protein in PK-1 cells. Snail, Slug and ZEB1, mRNAs were not changed by troglitazone, indicating that these three transcriptional repressors would not play a role in the induction of E-cadherin by troglitazone. GW9662, a PPARγ antagonist, failed to block the increased expression of E-cadherin or claudin 4 mRNA, suggesting a PPARγ-independent pathway. A MEK inhibitor, U0126, increased E-cadherin or claudin 4 mRNA and protein expression, and potently inhibited cell invasion. Because troglitazone down-regulates MEK-ERK signaling and inhibit cell invasion in PK-1 as shown in our previous study, these results suggest that troglitazone increases expression of E-cadherin and claudin 4 possibly through inhibition of MEK-ERK signaling in pancreatic cancer cells, which might be involved in the troglitazone-induced inhibition of cell invasive activity. © 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2009.01.134

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Language：English   Publishing type：Part of collection (book)   Publisher：Nova Science Publishers, Inc.  

The neural control of locomotion in vertebrates involves continuous interactions between various kinds of neural subsystems which are widely distributed throughout the central nervous system. Among these subsystems, the long descending reticulospinal pathways and their targets' spinal lamina VIII commissural neurons with axons projecting across the midline to the contralateral side form a continuous, anatomical system that is involved in the generation and coordination of left-right reciprocal and bilateral locomotor activities. To advance understanding of locomotor roles of this brainstem-spinal cord system, we performed a series of neural tracing studies using anterograde neural tracers to characterize the axonal morphology of reticulospinal neurons and lamina VIII commissural neurons in the cat, with the goal of revealing some of the organizing principles of their projections along their rostrocaudal extent in the spinal cord, including: the number and frequency of their axon collaterals in the white matter, the patterns of their collateral arborizations in the gray matter, and the relationships between locations of the parent axons and their collateral termination areas. The reticulospinal pathways are morphologically heterogeneous, being composed of various types of in-parallel-descending axons, each of which has a commonality of the pattern of collateral termination along its rostrocaudal extent in the spinal cord. Commissural neurons can be classified into two major groups on the basis of their projections, viz. those that project primarily to laminae VIII-VII and those that project to the motor nuclei in lamina IX. These suggest that the reticulospinal pathways and their targets' commissural neurons as a whole comprise varying types of functional subunits, which may serve as the flexible optimal neural substrate essential for the generation and coordination of the bilateral locomotor rhythm in self-induced, goal-directed locomotion.

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DOI： 10.1016/j.neures.2009.09.238

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Language：English   Publishing type：Research paper (scientific journal)  

Posture and movements are our only physical means of interacting with the environment. As we express our thoughts and emotions through posture and movements, they indicate our will or intentions. Locomotion is representative of purposeful goal-directed behaviors that are initiated by signals arising from either volitional processing in the cerebral cortex or emotional processing in the limbic system. Regardless of whether the locomotion is volitional or emotional, it is accompanied by automatically controlled movement processes such as the adjustment of postural muscle tone and rhythmic limb movements that are unconsciously executed. Sensori-motor integration at the level of the brainstem and spinal cord plays major roles in this automatic control. Signals processed in the basal ganglia and the cerebellum act on the cerebral cortex, the limbic system and the brainstem so that locomotor behaviors are appropriately and precisely regulated depending on the behavioral context. The purpose of this review is to describe how purposeful locomotor behaviors are initiated, executed and regulated so as to enable locomotive subjects to interact with and adapt to the environment. © 2008 VSP.

DOI： 10.1163/156855308X368958

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Language：English   Publishing type：Research paper (international conference proceedings)  

In this review, we have tried to elucidate substrates for the execution of normal gait and to understand pathophysiological mechanisms of gait failure in basal ganglia dysfunctions. In Parkinson's disease, volitional and emotional expressions of movement processes are seriously affected in addition to the disturbance of automatic movement processes, such as adjustment of postural muscle tone before gait initiation and rhythmic limb movements during walking. These patients also suffer from muscle tone rigidity and postural instability, which may also cause reduced walking capabilities in adapting to various environments. Neurophysiological and clinical studies have suggested the importance of basal ganglia connections with the cerebral cortex and limbic system in the expression of volitional and emotional behaviors. Here we hypothesize a crucial role played by the basal ganglia-brainstem system in the integrative control of muscle tone and locomotion. The hypothetical model may provide a rational explanation for the role of the basal ganglia in the control of volitional and automatic aspects of movements. Moreover, it might also be beneficial for understanding pathophysiological mechanisms of basal ganglia movement disorders. A part of this hypothesis has been supported by studies utilizing a constructive simulation engineering technique that clearly shows that an appropriate level of postural muscle tone and proper acquisition and utilization of sensory information are essential to maintain adaptable bodily functions for the full execution of bipedal gait. In conclusion, we suggest that the major substrates for supporting bipedal posture and executing bipedal gait are 1) fine neural networks such as the cortico-basal ganglia loop and basal ganglia-brainstem system, 2) fine musculoskeletal structures with adequately developed (postural) muscle tone, and 3) proper sensory processing. It follows that any dysfunction of the above sensorimotor integration processes would result in gait disturbance. © 2008 Springer.

DOI： 10.1007/s00415-008-4004-7

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s00415-008-4004-7

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Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

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Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/j.1460-9568.2008.06474.x

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Language：English   Publishing type：Research paper (international conference proceedings)  

Recently, many older people have difficulty standing up despite that motion's importance in daily life. Therefore, a machine to support their standing-up motion is needed
yet we still do not know how people control their motor system when they stand up. For that reason, we can not produce such a machine. In this study, we analyze the system of people's standing-up motion using information related to muscle activity. Muscle synergy-coherent activations of groups of muscles are an efficient means to achieve this goal. The results of experiments demonstrate the importance of muscle synergies that exist when people stand up. © 2008 IEEE.

DOI： 10.1109/ROBIO.2009.4913307

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s00535-007-2007-2

Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：Japanese   Publishing type：Research paper (other academic)  

The importance of an appropriate combination of excitability for the higher (neocortex, basal ganglia, and limbic system) and lower (brainstem - spinal cord) motor systems could be necessary for normal behavior during wakefulness and REM sleep. Neurotransmitters such as acetylcholine, the monoamines, GABA, and the orexins regulate the background excitability of the higher and lower motor systems so that an interaction of these systems can be appropriately maintained. Pathophysiological mechanisms of sleep deficiency may be induced, not only by an organic disturbance of brain structures (hardware), but also by dysfunctioning of the neurotransmitter systems (software). From these considerations, this review provides a hypothetical model for &quot;state-dependent interaction of the higher and lower motor systems&quot; for understanding normal behavior and pathophysiological mechanisms of sleep-related disorders such as narcolepsy and the REM-sleep behavioral syndrome. © 2006 The Authors; Journal compilation © 2006 Japanese Society of Sleep Research.

DOI： 10.1111/j.1479-8425.2006.00210.x

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Language：English   Publishing type：Research paper (scientific journal)  

Orexinergic neurones in the perifornical lateral hypothalamus project to structures of the midbrain, including the substantia nigra and the mesopontine tegmentum. These areas contain the mesencephalic locomotor region (MLR), and the pedunculopontine and laterodorsal tegmental nuclei (PPN/LDT), which regulate atonia during rapid eye movement (REM) sleep. Deficiencies of the orexinergic system result in narcolepsy, suggesting that these projections are concerned with switching between locomotor movements and muscular atonia. The present study characterizes the role of these orexinergic projections to the midbrain. In decerebrate cats, injecting orexin-A (60 microm to 1.0 mm, 0.20-0.25 microl) into the MLR reduced the intensity of the electrical stimulation required to induce locomotion on a treadmill (4 cats) or even elicit locomotor movements without electrical stimulation (2 cats). On the other hand, when orexin was injected into either the PPN (8 cats) or the substantia nigra pars reticulata (SNr, 4 cats), an increased stimulus intensity at the PPN was required to induce muscle atonia. The effects of orexin on the PPN and the SNr were reversed by subsequently injecting bicuculline (5 mm, 0.20-0.25 microl), a GABA(A) receptor antagonist, into the PPN. These findings indicate that excitatory orexinergic drive could maintain a higher level of locomotor activity by increasing the excitability of neurones in the MLR, while enhancing GABAergic effects on presumably cholinergic PPN neurones, to suppress muscle atonia. We conclude that orexinergic projections from the hypothalamus to the midbrain play an important role in regulating motor behaviour and controlling postural muscle tone and locomotor movements when awake and during sleep. Furthermore, as the excitability is attenuated in the absence of orexin, signals to the midbrain may induce locomotor behaviour when the orexinergic system functions normally but elicit atonia or narcolepsy when the orexinergic function is disturbed.

DOI： 10.1113/jphysiol.2005.085829

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DOI： 10.1016/j.neures.2004.12.007

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：Japanese   Publishing type：Research paper (other academic)  

Authorship：Lead author   Language：Japanese   Publishing type：Research paper (other academic)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

The purpose of this study was to elucidate the role of the GABAergic system in the medullary reticular formation (MRF) in the control of swallowing. In acutely decerebrated cats (n = 12), swallowing was induced by electrical stimulation (0.3-6 Vat 10-20 Hz for 10-20 s every minute) applied to the superior laryngeal nerve (SLN). The stimulus intensity was adjusted so that swallowing was induced two or four times during the period of the stimulation. Bicuculline, a GABA(A) receptor antagonist, was then injected (0.10-0.15 mu l, 5 mM) into the MRF through a stereotaxically placed glass micropipette. In a total of 62 injections, 19 injections (30.6%) increased the frequency of SLN-induced swallowing when it was injected into the lateral part of the MRF corresponding to the nucleus reticularis parvocellularis (NRPv). In eight of the effective injections (42.1 %) which increased the frequency of SLN-induced swallowing, SLN stimulation also induced coughing. With two injections, stimulation of the SLN-induced coughing but not facilitation of swallowing. On the other hand, an injection of 0.10-0.15 mu l of 5 mM muscimol, a GABAA receptor agonist, into the NRPv decreased the frequency of SLN-induced swallowing.
These results suggest that the NRPv neurons which are responsible for evoking swallowing are under the tonic inhibitory control of the GABAergic system. (c) 2004 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

DOI： 10.1016/j.neures.2004.12.007

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Ireland Ltd  

We have previously demonstrated that intracisternal orexin-A potently stimulated gastric acid secretion through the vagus nerve. Considering its stimulatory action on feeding, we hypothesized that orexin-A is a candidate mediator of cephalic phase gastric secretion. It has also been suggested that the stimulation of acid by central orexin-A may be mediated by orexin 1 receptor (OX1R) in the brain. In the present study, we tried to clarify whether endogenously released orexin-A in the brain indeed plays a physiological role in gastric secretion. To address the question, the effects of OX1R antagonist on gastric acid secretion was examined in rats. Intraperitoneal administration of SB334867, a specific OX1R antagonist, by itself did not change gastric acid secretion in pylorus-ligated conscious rats. Pretreatment with SB334867 in a dose of 10 mg/kg completely blocked the stimulated acid output by intracisternal orexin-A but not thyrotropin-releasing hormone, suggesting that SB334867 specifically blocked the action of orexin-A in the brain. 2-Deoxy-D-glucose (2-DG)-induced stimulation of gastric acid output was significantly blocked by pretreatment with intraperitoneal administration of SB334867. These results suggest that endogenously released orexin-A in the brain plays a vital role in central regulation of gastric secretion. Since 2-DG induces central glucoprivation as a hunger state, the present study furthermore supports the speculation that orexin-A may be an important molecule that triggers the cephalic phase gastric acid secretion. © 2004 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.neulet.2004.11.043

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Language：English   Publisher：ELSEVIER SCI IRELAND LTD  

Here we review a role of a basal ganglia-brainstem (BG-BS) system throughout the mesopontine tegmentum in the control of various types of behavioral expression. First the basal ganglia-brainstem system may contribute to an automatic control of movements, such as rhythmic limb movements and adjustment of postural muscle tone during locomotion, which occurs in conjunction with voluntary control processes. Second, the basal ganglia-brainstem system can be involved in the regulation of awake-sleep states. We further propose the possibility that the basal ganglia-brainstem system is responsible for the integration of volitionally-guided and emotionally-triggered expression of motor behaviors. It can be proposed that dysfunction of the basal ganglia-brainstem system together with that of cortico-basal ganglia loop underlies the pathogenesis of behavioral disturbances expressed in basal ganglia dysfunction. (C) 2004 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

DOI： 10.1016/j.neures.2004.06.015

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Publisher：9  

DOI： 10.1111/j.0953-816X.2004.03337.x

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.neuroscience.2003.10.028

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DOI： 10.1016/j.neuroscience.2003.12.016

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/j.0953-816X.2004.03337.x

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/S0079-6123(03)43023-9

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

We have previously reported that electrical stimulation delivered to the ventral part of the pedunculopontine tegmental nucleus (PPN) produced postural atonia in acutely decerebrated cats [Neuroscience 119 (2003) 293]. The present study was designed to elucidate synaptic mechanisms acting on motoneurons during postural atonia induced by PPN stimulation. Intracellular recording was performed from 72 hindlimb motoneurons innervating extensor and flexor muscles, and the changes in excitability of the motoneurons following the PPN stimulation were examined. Repetitive electrical stimulation (20-50 muA, 50 Hz, 5-10 s) of the PPN hyperpolarized the membrane potentials of both the extensor and flexor motoneurons by 2.0-12 mV (6.0 +/- 2.3 mV, n=72). The membrane hyperpolarization persisted for 10-20 s even after termination of the stimulation. During the PPN stimulation, the membrane hyperpolarization was associated with decreases in the firing capability (n=28) and input resistance (28.5 +/- 6.7%, n=14) of the motoneurons. Moreover the amplitude of la excitatory postsynaptic potentials was also reduced (44.1 +/- 13.4%, n=14). After the PPN stimulation, these parameters immediately returned despite that the membrane hyperpolarization persisted. lontophoretic injections of chloride ions into the motoneurons reversed the polarity of the membrane hyperpolarization during the PPN stimulation. The polarity of the outlasting hyperpolarization however was not reversed.
These findings suggest that a postsynaptic inhibitory mechanism, which was mediated by chloride ions, was acting on hindlimb motoneurons during PPN-induced postural atonia. However the outlasting motoneuron hyperpolarization was not due to the postsynaptic inhibition but it could be due to a decrease in the activity of descending excitatory systems. The functional role of the PPN in the regulation of postural muscle tone is discussed with respect to the control of behavioral states of animals. (C) 2004 IBRO. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.neuroscience.2003.12.016

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

The present study was to determine how afferents from the substantia nigra pars reticulata (SNr) of the basal ganglia to the pedunculopontine tegmental nucleus (PPN) in the brainstem could contribute to the control of behavioral states. We used anesthetized and acutely decerebrated cats (n=22). Repetitive electrical stimulation (10-100 Hz, 2050 muA, for 4-20 s) to the ventrolateral part of the PPN produced rapid eye movement (REM) associated with a suppression of postural muscle tone (REM with atonia). Although repetitive electrical stimuli (10-200 Hz, 10-60 muA, for 5-20 s) delivered to the dorsolateral part of the SNr did not evoke eye movements or muscular tonus in baseline conditions, it altered the PPN-induced REM with atonia. The following three types of effects were induced: (1) attenuation of the REM with atonia; (2) attenuation of muscular atonia without changes in REM (REM without atonia); and (3) attenuation of only REM. The optimal stimulus sites for these effects were intermingled within the lateral part of the SNr. The PPN-induced REM with atonia was abolished by an injection into the PPN of muscimol (1-15 mM, 0.1-0.25 mul), a GABA(A) receptor agonist, but not altered by an injection of baclofen (1-10 mM, 0.1-0.25 mul), a GABA(B) receptor agonist. Moreover, an injection of bicuculline (1-15 mM, 0.1-0.25 mul), a GABAA receptor antagonist, into the PPN, resulted in REM with atonia. On the other hand, an injection of muscimol into the dorsolateral part of the SNr (1-15 mM, 0.1-0.25 RI) induced REM with atonia, which was in turn eliminated by a further injection of muscimol into the PPN (5-10 mM, 0.2-0.25 mul).
These results suggest that a GABAergic projection from the SNr to the PPN could be involved in the control of REM with atonia, signs which indicate REM sleep. An excessive GABAergic output from the basal ganglia to the PPN in par-kinsonian patients may induce sleep disturbances, including a reduction of REM sleep periods and REM sleep behavioral disorders (REM without atonia). (C) 2004 IBRO. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.neuroscience.2003.10.028

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：UNIV OREGONBOOKS  

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：ELSEVIER SCIENCE PUBL B V  

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Language：Japanese   Book type：Textbook, survey, introduction

Language：Japanese   Book type：Textbook, survey, introduction

Language：Japanese   Book type：Scholarly book

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Language：Japanese   Book type：Scholarly book

Language：Japanese   Book type：Scholarly book

Language：Japanese   Book type：Textbook, survey, introduction

Language：Japanese   Book type：Textbook, survey, introduction

Language：Japanese   Book type：Textbook, survey, introduction

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Language：Japanese   Publisher：(一社)日本生理学会  

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (bulletin of university, research institution)   Publisher：医学書院  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (bulletin of university, research institution)   Publisher：医学書院　  

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© 2018 IEEE. While standing, the elderly exhibit different move- ment behaviors compared to young people. However, the causes of these differences remain clear. The purpose of this study was to verify a hypothesis that only the magnitude of sensory noise and stiffness can reproducibly determine trends in the hip or ankle movement strategies. Simulations of postural control of a musculoskeletal model for three noise conditions and three stiffness conditions were performed. Variations in the angles of the hip and ankle suggested that the sensory noise amplitude had no influence on the selection. However, the ankle strategy tended to be selected with the increase of stiffness. Strategy shifts of elderly may be derived from other components; muscle weakness, increase of neurological time delay, or learning based on other evaluation index.

DOI： 10.1109/EMBC.2018.8512641

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Authorship：Lead author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：ニューロサイエン社  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：北隆館  

Authorship：Lead author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：医学評論社  

Language：Japanese   Publisher：臨床歩行分析研究会  

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (bulletin of university, research institution)   Publisher：東京大学出版会  

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Authorship：Lead author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：中外医学社  

Language：Japanese   Publisher：(株)中外医学社  

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Language：Japanese   Publisher：臨床歩行分析研究会  

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© 2015, The Author(s). The lateral part of the mesopontine tegmentum contains functionally important structures involved in the control of posture and gait. Specifically, the mesencephalic locomotor region, which may consist of the cuneiform nucleus and pedunculopontine tegmental nucleus (PPN), occupies the interest with respect to the pathophysiology of posture-gait disorders. The purpose of this article is to review the mechanisms involved in the control of postural muscle tone and locomotion by the mesopontine tegmentum and the pontomedullary reticulospinal system. To make interpretation and discussion more robust, the above issue is considered largely based on our findings in the experiments using decerebrate cat preparations in addition to the results in animal experimentations and clinical investigations in other laboratories. Our investigations revealed the presence of functional topographical organizations with respect to the regulation of postural muscle tone and locomotion in both the mesopontine tegmentum and the pontomedullary reticulospinal system. These organizations were modified by neurotransmitter systems, particularly the cholinergic PPN projection to the pontine reticular formation. Because efferents from the forebrain structures as well as the cerebellum converge to the mesencephalic and pontomedullary reticular formation, changes in these organizations may be involved in the appropriate regulation of posture-gait synergy depending on the behavioral context. On the other hand, abnormal signals from the higher motor centers may produce dysfunction of the mesencephalic-reticulospinal system. Here we highlight the significance of elucidating the mechanisms of the mesencephalic-reticulospinal control of posture and locomotion so that thorough understanding of the pathophysiological mechanisms of posture-gait disorders can be made.

DOI： 10.1007/s00702-015-1475-4

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© 2015 IEEE. In order to understand insights into human stance postural control mechanism, generation of biped stance motion in consideration of both muscles and neurological time delay is important. In this paper, we proposed a neural controller composed by feed-forward and feedback control to keep a musculoskeletal model with 70 muscles standing when neurological time delay is 100 ms. Through the optimization, we obtained the parameters of proposed controller able to keep musculoskeletal model standing.

DOI： 10.1109/MHS.2015.7438243

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Posture control to maintain an upright stance is one of the most important and basic requirements in the daily life of humans. The sensory inputs involved in posture control include visual and vestibular inputs, as well as proprioceptive and tactile somatosensory inputs. These multisensory inputs are integrated to represent the body state (body schema); this is then utilized in the brain to generate the motion. Changes in the multisensory inputs result in postural alterations (fast dynamics), as well as long-term alterations in multisensory integration and posture control itself (slow dynamics). In this review, we discuss the fast and slow dynamics, with a focus on multisensory integration including an introduction of our study to investigate "internal force control" with multisensory integration-evoked posture alteration. We found that the study of the slow dynamics is lagging compared to that of fast dynamics, such that our understanding of long-term alterations is insufficient to reveal the underlying mechanisms and to propose suitable models. Additional studies investigating slow dynamics are required to expand our knowledge of this area, which would support the physical training and rehabilitation of elderly and impaired persons.

DOI： 10.1016/j.neures.2015.12.002

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© 2015 The Society of Instrument and Control Engineers-SICE. In order to understand insights into the postural control mechanism, realization of biped stance motion in consideration of both muscles and neurological time delay (NTD) is important. In this paper, we proposed a neural controller composed of feed-forward (FF) and feedback (FB) control to keep a musculoskeletal model with 70 muscles standing stably when NTD was 100ms. FF control is modelled as a set of constant activations necessary to keep musculoskele-tal model standing in objective posture. FB control is modelled as a PD control based on muscular-tendon length and lengtening velocity. Parameter tuning was conducted to search feed-forward controls and feedback gains of PD control to keep musculoskeletal model standing. As a result, we successfully found the suitable parameters to keep musculoskeletal model standing when NTD was 100ms. We found FF control contribute more to compensate disturbances caused by NTD.

DOI： 10.1109/SICE.2015.7285391

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Language：Japanese   Publisher：(株)中外医学社  

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© 2014 IEEE. Neurological time delay is one of the important elements threatening human postural stability. Previous studies mainly focused on the neural controller to stabilize a human size inverted pendulum model. What kind of postural control mechanism is necessary for compensating neurological time delay by controlling muscles still remains a question. This research proposed to investigate whether a stance control model with constant feed-forward control input to muscles will enable the musculoskeletal model to stand when neurological time delay exists. A musculoskeletal model with 70 muscular-tendon actuators was used to represent the human body. We hypothesized that stance postural control model consists of both feedback and feed-forward control. And the latter one is a pre-added constant control input, necessary to keep musculoskeletal model standing when there is no neurological time delay, to the muscles for compensating neurological time delay. We calculated feed-forward controls and found the longest neurological time delay it could compensate. As a result, we succeeded in keeping a musculoskeletal model standing when neurological time delay was 65ms at most, where transmission time delay was 45ms and activation dynamics time delay was 20ms.

DOI： 10.1109/ROBIO.2014.7090484

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Language：Japanese   Publisher：公益社団法人 精密工学会  

小脳疾患は運動失調の一因であり，特にその機能の部位特異性から，障害部位ごとに異なる症状が発生する．しかし，現在，部位特異性の評価は不十分である．そこで，本研究では，部位特異性の解明を目的とし，部位特異性は前・後肢の運動に相違をもたらすという仮説のもと，小脳を部分的に除去したラットの傾斜面での歩行実験を行う．本稿では，歩行中の四肢の軌道や伸筋の筋電を計測することにより，小脳の部位特異性の考察を行う．

DOI： 10.11522/pscjspe.2014S.0_893

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Language：English   Publisher：WILEY  

Locomotion is a purposeful, goal-directed behavior initiated by signals arising from either volitional processing in the cerebral cortex or emotional processing in the limbic system. Regardless of whether the locomotion initiation is volitional or emotional, locomotion is accompanied by automatic controlled movement processes, such as the adjustment of postural muscle tone and rhythmic limb movements. Sensori-motor integration in the brainstem and the spinal cord plays crucial roles in this process. The basic locomotor motor pattern is generated by spinal interneuronal networks, termed central pattern generators (CPGs). Responding to signals in proprioceptive and skin afferents, the spinal interneuronal networks modify the locomotor pattern in cooperation with descending signals from the brainstem structures and the cerebral cortex. Information processing between the basal ganglia, the cerebellum, and the brainstem may enable automatic regulation of muscle tone and rhythmic limb movements in the absence of conscious awareness. However, when a locomoting subject encounters obstacles, the subject has to intentionally adjust bodily alignment to guide limb movements. Such an intentional gait modification requires motor programming in the premotor cortices. The motor programs utilize one's bodily information, such as the body schema, which is preserved and updated in the temporoparietal cortex. The motor programs are transmitted to the brainstem by the corticoreticulospinal system, so that one's posture is anticipatorily controlled. These processes enable the corticospinal system to generate limb trajectory and achieve accurate foot placement. Loops from the motor cortical areas to the basal ganglia and the cerebellum can serve this purpose. (c) 2013 International Parkinson and Movement Disorder Society

DOI： 10.1002/mds.25669

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This paper aims to investigate the function of constant feed-forward control from the reticulospinal tract (RST) on improving posture stability during standing from the viewpoint of ability to countering the disturbances. We presented a stance control model considering not only the balance control, a PD controller, from vestibular tract based on vestibular feedback but also the constant feed-forward control ur by reticulospinal tract. Parameters of PD controller, max muscle isometric force of back extensors and flexors and the constant strength of control from RST were optimized during a 3s forward dynamics simulation and the optimal ur was obtained. Then, we fixed the value of ur around the value of optimal one and only optimized other four parameters. After that, the abilities of countering the platform disturbance of the musculoskeletal (MSK) model under the control of different ur were investigated. As a result, we found that optimal u r would improve the posture stability and make MSK model more adaptive to the disturbance. © 2013 IEEE.

DOI： 10.1109/ROBIO.2013.6739483

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：札幌医科大学  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：日本てんかん学会北海道地方会機関誌  

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：SPRINGER TOKYO  

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Language：Japanese   Publisher：Societas Neurologica Japonica  

The cerebral cortex controls cognitive and voluntary process of movements. The brainstem and spinal cord are involved in the execution of innately acquired motor patterns such as postural reflexes, muscle tone regulation and locomotion. Cortico-reticular projections arising from the motor cortical areas contribute to the postural control that precedes the voluntary movement process. The basal ganglia cooperatively regulates the activities of the cerebral cortex and the brainstem-spinal cord by its strong inhibitory and dis-inhibitory effects upon these target structures so that goal-directed movements could be appropriately performed. We propose that basal ganglia disfunction, including the abnormality in the dopaminergic projection system, may disturb the cooperative regulation, resulting in motor deficiencies expressed in basal diseases.

DOI： 10.5692/clinicalneurol.49.325

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Language：English  

Activation of different areas in the forebrain evokes different types of goal directed adaptive behaviors. An important component of these different patterns of behavior is the locomotion that brings the animal to or away from a particular location. Here I review the role of projections from forebrain structures to the mesopontine tegmentum of the brainstem where neural mechanisms for initiation of locomotion and regulation of postural muscle tone are located that are activated during locomotor behavior. It is interesting is to understand how signals that converge from the forebrain structures to the mesopontine tegmentum control locomotor behavior, because the mesopontine tegmentum receives inhibitory efferents from the basal ganglia and excitatory efferents from the limbic-hypothalamic system and the neocortex. Here I hypothesize that the mesopontine tegmentum has functional gating mechanisms that determine whether the subject will initiate and select volitionally guided or emotionally triggered locomotor behaviors, depending on the behavioral context. © 2007 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.brainresrev.2007.06.024

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER IRELAND LTD  

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Language：English   Publishing type：Book review, literature introduction, etc.  

Orexins are neuropeptides that are localized in neurons within the lateral hypothalamus and regulate feeding behavior. The lateral hypothalamus plays an important role in not only feeding but also in the central regulation of gut function. Along this line, accumulating evidence has shown that orexins act in the central nervous system to regulate gastrointestinal functions. The purpose of this review is to summarize recent relevant findings on brain orexins and the digestive system, and discuss the pathophysiological roles of these peptides. Centrally administered orexin or endogenously released orexin in the brain potently stimulates gastric acid secretion in rats. The vagal cholinergic pathway is involved in the orexin-induced stimulation of acid secretion. Because of its stimulatory action on feeding, it can be hypothesized that orexin in the brain is a candidate mediator of cephalic phase gastric secretion. In addition, brain orexin may be involved in the development of depression and functional gastrointestinal disorders, which are frequently accompanied by inhibition of gut function, because lack of orexin activity might cause the inhibition of gastric physiological processes and evoke a depressive state. These lines of evidence suggest that orexin in the brain is a potential molecular target for treatment of functional gastrointestinal disorders. © Springer Japan 2008.

DOI： 10.1007/s00535-008-2218-1

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Language：Japanese   Publisher：(一社)日本生理学会  

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Language：English   Publisher：SPRINGER TOKYO  

Background. Accumulating evidence indicates that orexin-A in the brain stimulates vagal flow projecting to the stomach. Since the vagal system plays an important role in gastric mucosal integrity, we hypothesized that orexin-A in the brain might have a gastroprotective action. Methods. We examined the effect of centrally administered orexin-A on the development of gastric mucosal damage evoked by ethanol and its possible mechanism of action in rats. Results. Intracisternal but not intraperitoneal injection of orexin-A significantly inhibited the severity of gastric mucosal damage by 70% ethanol in a dose-dependent manner, suggesting that orexin-A acts in the brain to prevent ethanol-induced gastric mucosal damage. The antiulcer action was observed in rats administered with orexin-A centrally but not orexin-B, indicating that the action is mediated through orexin 1 receptors. The gastroprotective action of centrally administered orexin-A was blocked by pretreatment with atropine, Nw-nitro-L-arginine methylester, or indomethacin. Conclusions. These results suggest that orexin-A acts on orexin 1 receptors in the brain to exert a gastroprotective action against ethanol. The vagal muscarinic system, nitric oxide, and prostaglandins may mediate the cytoprotective action of centrally administered orexin-A.

DOI： 10.1007/s00535-007-2007-2

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Authorship：Lead author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER IRELAND LTD  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER IRELAND LTD  

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Language：English   Publisher：Elsevier  

This chapter argues that a basal ganglia-brainstem system throughout the mesopontine tegmentum contributes to an automatic control of movement that operates in conjunction with voluntary control processes. Activity of a muscle tone inhibitory system and the locomotion executing system can be steadily balanced by a net excitatory cortical input and a net inhibitory basal ganglia input to these systems. We further propose that dysfunction of the basal ganglia-brainstem system, together with that of the cortico-basal ganglia loop, underlies the pathogenesis of motor disturbances expressed in basal ganglia diseases.

DOI： 10.1016/S0079-6123(03)43023-9

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Language：English   Publisher：ASSOC RESEARCH VISION OPHTHALMOLOGY INC  

PURPOSE. To investigate whether nitric oxide (NO) contributes to the regulation of retinal circulation during hypercapnia in cats.
METHODS. N-G-nitro-L-arginine-methylester (L-NAME; n = 8), a NOS inhibitor; N-G-nitro-D-arginine-methylester (D-NAME; n = 6), the inactive isomer; or phosphate-buffered saline (PBS; n = 8) was injected intravitreously into the cat's eye. A selective neuronal nitric oxide synthase (nNOS) inhibitor, 7-nitroindazole (7-NI; n = 6), was injected intraperitoneally. Hypercapnia was induced for 10 minutes by inhalation of 5% carbon dioxide with 21% oxygen and 74% nitrogen. The vessel diameter and blood velocity were measured simultaneously in large retinal arterioles in cats by laser Doppler velocimetry and the retinal blood flow (RBF) calculated. Retinal vascular resistance (RVR) was also estimated.
RESULTS. In the PBS group, the vessel diameter (9.5% +/- 2.7%, P &lt; 0.05), blood velocity (15.6% +/- 4.4%, P &lt; 0.05), and RBF (37.2% +/- 3.7%, P &lt; 0.05) increased, and the RVR decreased (-26.0% +/- 2.7%, P &lt; 0.05) during hypercapnia. In the L-NAME group, those changes were greatly suppressed in response to hypercapnia. D-NAME was inactive with regard to RBF during hypercapnia. The RBF responses to hypercapnia after the 7-NI injection were significantly attenuated compared with those before 7-NI injection (P &lt; 0.05).
CONCLUSIONS. These results indicate that NO contributes to the increase in RBF during hypercapnia. Furthermore, the NO synthesized by the action of nNOS may participate in regulation of RBF during hypercapnia.

DOI： 10.1167/iovs.03-0284

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Language：English   Publisher：BLACKWELL PUBLISHING LTD  

We investigated, in a midbrain parasagittal slice preparation of Wistar rats (postnatal day 9-17), the synaptic inhibition of neurons in the pedunculopontine tegmental nucleus (PPN), which was mediated by gamma (gamma)-amino-butyric acid (GABA). Whole-cell patch-clamp recording was used, in combination with a single-cell reverse transcription-polymerise chain reaction amplification technique, to record synaptic potentials and to identify the phenotype of the recorded PPN neuron. In the presence of the ionotropic glutamate receptor antagonists, 6-cyano-2, 3-dihydroxy-7-nitro-quinoxaline-2, 3, dione, and DL-2-amino-5-phosphonovaleric acid, single electrical stimuli were applied to the substantia nigra pars reticulata (SNr), one of the basal ganglia output nuclei. Stimulation of the SNr evoked inhibitory postsynaptic potentials (IPSPs) in 73 of the 104 neurons in the PPN. The IPSPs were abolished with a GABA(A) receptor antagonist, bicuculline. Inhibitory postsynaptic currents of the neurons were reversed in polarity at approximately -93.5 mV, which was close to the value of the equilibrium potential for chloride ions of -88.4 mV Single-cell reverse transcription-polymerise chain reactions revealed that approximately 30% (9/32) of the PPN neurons that received inhibition from the SNr expressed detectable levels of choline acetyltransferase mRNA. These findings show that output from the SNr regulates the activity of cholinergic PPN neurons through GABA(A) receptors.

DOI： 10.1046/j.1460-9568.2003.02825.x

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Language：Japanese  

著者最終原稿版基底核の疾患の一つであるパーキンソン病では,運動障害のみならず睡眠障害も出現する.これは,基底核と睡眠の神経機構の間には密な関係が存在することを示している.基底核からの出力は大脳皮質や脳幹の活動を制御する.一方,脳幹網様体から広範な大脳皮質領域への投射(上行性網様体賦活系)は,覚醒の維持や睡眠の発現に中心的な役割を果たす.視床下部や脳幹に存在する様々な神経伝達物質の働きが,基底核の機能や覚醒・睡眠を調節するうえで重要な役割を担う

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Other Link： http://search.jamas.or.jp/link/ui/2004083814

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Language：English   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

The present study is designed to elucidate how basal ganglia afferents from the substantia nigra pars reticulata (SNr) to the mesopontine tegmental area of the brainstem contribute to gait control and muscle-tone regulation. We used unanesthetized and acutely decerebrated cats (n=27) in which the striatum, thalamus and cerebral cortex were removed but the SNr was preserved. Repetitive stimulation (50 Hz, 10-60 muA, for 5-20 s) applied to a mesencephalic locomotor region (MLR), which corresponded to the cuneiform nucleus, and adjacent areas, evoked locomotor movements. On the other hand, stimulation of a muscle-tone inhibitory region in the pedunculopontine tegmental nucleus (PPN) suppressed postural muscle tone. An injection of either glutamatergic agonists (N-methyl-D-aspartic acid and kainic acid) or GABA antagonists (bicuculline and picrotoxin) into the MLR and PPN also induced locomotion and muscle-tone suppression, respectively. Repetitive electrical stimuli (50-100 Hz, 20-60 muA for 5-20 s) delivered to the SNr alone did not alter muscular activity. However stimulating the lateral part of the SNr attenuated and blocked PPN-induced muscle-tone suppression. Moreover, weaker stimulation of the medial part of the SNr reduced the number of step cycles and disturbed the rhythmic alternation of limb movements of MLR-induced locomotion. The onset of locomotion was delayed as the stimulus intensity was increased. At a higher strength SNr stimulation abolished the locomotion. An injection of bicuculline into either the PPN or the MLR diminished the SNr effects noted above.
These results suggest that locomotion and postural muscle tone are subject to modulation by GABAergic nigroteg-mental projections which have a partial functional topography: a lateral and medial SNr, for regulation of postural muscle tone and locomotion, respectively. We conclude that disorders of the basal ganglia may include dysfunction of the nigrotegmental (basal ganglia-brainstem) systems, which consequently leads to the production of abnormal muscle tone and gait disturbance. (C) 2003 IBRO. Published by Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0306-4522(03)00095-2

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Language：English   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

The previous report of intracellular recording of hindlimb motoneurons in decerebrate cats [Neuroscience 103 (2001) 511] has suggested that the following mechanisms are involved in a generalized motor inhibition induced by stimulating the medullary reticular formation. First, the motor inhibition, which was prominent in the late latency (3080 ms), can be ascribed to the inhibitory effects in parallel to motoneurons and to interneuronal transmission in reflex pathways. Second, both a group of interneurons receiving inhibition from flexor reflex afferents and a group of lb interneurons mediate the late inhibitory effects upon the motoneurons. To substantiate the above mechanisms of motor inhibition we examined the medullary stimulus effects upon intracellular (n=55) and extracellular (n=136) activity of spinal interneurons recorded from the lower lumbar segments (L6-L7). Single pulses or stimulus trains (1-3) pulses, with a duration of 0.2 ms and intensity of 20-50 muA) applied to the medullary nucleus reticularis gigantocellularis evoked a mixture of excitatory and inhibitory effects with early (&lt;20 ms) and late (&gt;30 ms) latencies. The medullary stimulation excited 55 interneurons (28.8%) with a late latency. Thirty-nine of the cells, which included 10 lb interneurons, were inhibited by volleys in flexor reflex afferents (FRAs). These cells were mainly located in lamina VII of Rexed. On the other hand, the late inhibitory effects were observed in 67 interneurons (35.11%), which included cells mediating reciprocal la inhibition, non-reciprocal group I (lb) inhibition, recurrent inhibition and flexion reflexes. Intracellular recording revealed that the late inhibitory effects were due to inhibitory postsynaptic potentials with a peak latency of about 50 ms and a duration of 50-60 ms. The inhibitory effects were attenuated by volleys in FRAs. Neither excitatory nor inhibitory effects with a late latency were observed in 69 (36.1%) cells which were located in the intermediate region and dorsal horn.
These results suggest the presence of a functional organization of the spinal cord with respect to the production of the generalized motor inhibition. Lamina VII interneurons that receive inhibition from volleys in FRAs possibly mediate the postsynaptic inhibition from the medullary reticular formation in parallel to motoneurons and to interneurons in reflex pathways. (C) 2003 IBRO. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/S0306-4522(03)00542-6

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Language：English   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

We compared postsynaptic inhibitory effects on forelimb motoneurons and those on hindlimb motoneurons during generalized motor inhibition evoked by stimulating the medullary reticular formation in decerebrate cats. Here, we address two questions. First, whether the medullary inhibitory effects upon forelimb motoneurons are equivalent to those upon hindlimb motoneurons. Second, whether there is a somatotopographical organization within the medullary reticular formation in terms of inhibitory connections with motoneurons. Repetitive stimulation (20-50 muA, 50-100 Hz) delivered to the dorsomedial medullary reticular formation bilaterally suppressed muscle tone of both the forelimbs and hindlimbs. The medullary stimulation hyperpolarized the membrane potentials of the forelimb (5.4 +/- 1.8 mV, n = 46) and hindlimb (5.4 +/- 2.0 mV, n = 59) motoneurons together with a decrease in input resistance. The degree of membrane hyperpolarization and input resistance was not different in the forelimb and hindlimb motoneurons. The medullary stimulation also depressed the capability of generating antidromic and orthodromic spikes in the motoneurons. Stimuli with pulse trains (one to three pulses, 5-10-ms intervals, 20-50 muA) applied to the medullary inhibitory region induced a mixture of excitatory and inhibitory postsynaptic potentials in the motoneurons. The most noteworthy potentials were the inhibitory postsynaptic potentials with a late latency. They were observed in most forelimb (n = 57/58, 98.3%) and hindlimb (n = 63/64, 98.4%) motoneurons. The inhibitory potentials in forelimb motoneurons had a latency of 25-30 ms and a peak latency of 35-40 ms, and those in hindlimb motoneurons had a latency of 30-35 ms and a peak latency of 50-60 ms. A difference was not observed in the location of the effective sites for evoking the inhibitory effects in the forelimb and hindlimb motoneurons. These sites were homogeneously distributed in the dorsomedial part of the medullary reticular formation corresponding to the location of the nucleus reticularis gigantocellularis.
From these findings we suggest that there is an equivalent amount of the postsynaptic inhibitory effects exerted on forelimb and hindlimb motoneurons during medullary-induced generalized motor inhibition. In addition, the medullary reticular formation may be functionally organized as a homogeneous or non-specific region in terms of the medullary reticulospinal inhibitory connections with forelimb and hindlimb motoneurons. (C) 2002 IBRO. Published by Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0306-4522(02)00149-5

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Language：Japanese   Publisher：(一社)日本生理学会  

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Language：English   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

The present study was designed to elucidate the spinal interneuronal mechanisms of motor inhibition evoked by stimulating the medullary reticular formation. Two questions were addressed. First, whether there is a parallel motor inhibition to motoneurons and to interneurons in reflex pathways. Second, whether the inhibition is mediated by interneurons interposed in known reflex pathways. We recorded the intracellular activity of hindlimb motoneurons in decerebrate cats and examined the effects of medullary stimulation on these neurons and on interneuronal transmission in reflex pathways to them. Stimuli (three pulses at 10-60 muA and 1-10 ms intervals) delivered to the nucleus reticularis gigantocellularis evoked inhibitory postsynaptic potentials in a-motoneurons (n = 147) and gamma -motoneurons (n = 5) with both early and late latencies. The early inhibitory postsynaptic potentials were observed in 66.4% of the motoneurons and had a latency of 4.0-5.5 ms with a segmental delay of more than 1.4 ms. The late inhibitory postsynaptic potentials were observed in 98.0% of the motoneurons and had a latency of 30-35 ms, with a peak latency of 50-60 ms. Both types of inhibitory postsynaptic potentials were evoked through fibers descending in the ventrolateral quadrant. The inhibitory postsynaptic potentials were not influenced by recurrent inhibitory pathways, but both types were greatly attenuated by volleys in flexor reflex afferents. Conditioning medullary stimulation, which was subthreshold to evoke inhibitory postsynaptic potentials in the motoneurons, neither evoked primary afferent depolarization of dorsal roots nor reduced the input resistance of the motoneurons. However, the conditioning stimulation often facilitated non-reciprocal group I inhibitory pathways (Tt,inhibitory pathways) to the motoneurons in early (&lt;20 ms) and late (30-80 ms) periods. In contrast, it attenuated test postsynaptic potentials evoked through reciprocal Ia inhibitory pathways, and excitatory and inhibitory pathways from flexor reflex afferent and recurrent inhibitory pathways. The inhibitory effects were observed in both early and late periods.
The present results provide new information about a parallel inhibitory process from the medullary reticular formation that produces a generalized motor inhibition by acting on &lt;alpha&gt;- and gamma -motoneurons, and on interneurons in reflex pathways. Interneurons receiving inhibition from flexor reflex afferents and a group of Ib interneurons may mediate the inhibitory effects upon motoneurons. (C) 2001 IBRO. Published by Elsevier Science Ltd. AU rights reserved.

DOI： 10.1016/S0306-4522(00)00586-8

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Language：Japanese  

出版社版随意運動の発現には大脳皮質-基底核ループが関与する.一方,随意運動には姿勢反射や筋緊張,そして歩行リズムの調節など意識に上らない自動運動が随伴し,これらの制御に関与する基本的な神経機構は脳幹・脊髄・小脳に存在する.脳幹吻側部の中脳被蓋には歩行運動と筋緊張を調節する領域が存在し,大脳皮質由来の興奮性入力と基底核からの抑制性入力が収束する.したがって,筋緊張や歩行運動は,大脳皮質-基底核ループを経由する随意的制御と,これを経由しない基底核-脳幹系による自動的制御の双方を受ける可能性がある

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Other Link： http://search.jamas.or.jp/link/ui/2002186564

Language：English   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Two types of tegmental pedunculopontine nucleus neurons have been reported previously based on their electrophysiological characteristics: type I neurons were characterized by low-threshold Ca spikes and type II neurons displayed a transient outward current. This report describes the membrane properties, synaptic inputs, morphologies and axonal projections of two subgroups of type II neurons examined in an in vitro slice preparation. Type II neurons were divided into two groups based on their spike durations: short-duration neurons with an action potential duration of 0.7-1.5 ms and long-duration neurons with an action potential duration of 1.6-2.9 ms. Choline acetyltransferase immunohistochemistry combined with biocytin labeling indicated that 56% of short-duration neurons and 61% of long-duration neurons were immunopositive for choline acetyltransferase. Short-duration neurons had a high input resistance and the capacity to discharge with high frequency. By contrast, long-duration neurons had a low input resistance and low firing frequency and upon current injection displayed an accommodation (spike-frequency adaptation) before reaching a steady firing frequency. Microstimulation of the substantia nigra pars compacta evoked antidromic responses in both short-duration neurons (n=5/14, 36%) and long-duration neurons (n=20/39, 51%). Stimulations of the subthalamic nucleus and the substantia nigra pars reticulata induced in these neurons excitatory and inhibitory postsynaptic potentials, respectively. Short-duration neurons were dispersed equally throughout the extent of the tegmental pedunculopontine nucleus area, while long-duration neurons were located more in the rostral tegmental pedunculopontine nucleus. Short-duration neurons were small with two to four thin primary dendrites. Long-duration neurons were medium to large with three to six thick primary dendrites. Cell size was positively correlated with spike duration and axonal conduction velocity, but negatively with input resistance and spontaneous firing frequency. Both groups of neurons had ascending (toward thalamus, prerectal areas and tectum) and descending (toward pontomedullary reticular formation) axons in addition to nigropetal axons. Ascending axons were observed in 75% (6/8) of short-duration neurons and in 45% (15/33) of long-duration neurons, while nigropetal axons were observed in 50% (4/8) of short-duration neurons and in 76% (25/33) of Long-duration neurons.
These results suggest that the tegmental pedunculopontine nucleus cholinergic projection system is composed of heterogeneous populations of neurons in terms of electrophysiological and morphological characteristics as well as their distribution patterns in the nucleus. (C) 1997 IBRO. Published by Elsevier Science Ltd.

DOI： 10.1016/S0306-4522(97)00019-5

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Language：English   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Two types of tegmental pedunculopontine nucleus neurons have been reported previously based on their electrophysiological characteristics: type I neurons were characterized by low-threshold Ca spikes and type II neurons displayed a transient outward current. This report describes the membrane properties, synaptic inputs, morphologies and axonal projections of two subgroups of type II neurons examined in an in vitro slice preparation. Type II neurons were divided into two groups based on their spike durations: short-duration neurons with an action potential duration of 0.7-1.5 ms and long-duration neurons with an action potential duration of 1.6-2.9 ms. Choline acetyltransferase immunohistochemistry combined with biocytin labeling indicated that 56% of short-duration neurons and 61% of long-duration neurons were immunopositive for choline acetyltransferase. Short-duration neurons had a high input resistance and the capacity to discharge with high frequency. By contrast, long-duration neurons had a low input resistance and low firing frequency and upon current injection displayed an accommodation (spike-frequency adaptation) before reaching a steady firing frequency. Microstimulation of the substantia nigra pars compacta evoked antidromic responses in both short-duration neurons (n=5/14, 36%) and long-duration neurons (n=20/39, 51%). Stimulations of the subthalamic nucleus and the substantia nigra pars reticulata induced in these neurons excitatory and inhibitory postsynaptic potentials, respectively. Short-duration neurons were dispersed equally throughout the extent of the tegmental pedunculopontine nucleus area, while long-duration neurons were located more in the rostral tegmental pedunculopontine nucleus. Short-duration neurons were small with two to four thin primary dendrites. Long-duration neurons were medium to large with three to six thick primary dendrites. Cell size was positively correlated with spike duration and axonal conduction velocity, but negatively with input resistance and spontaneous firing frequency. Both groups of neurons had ascending (toward thalamus, prerectal areas and tectum) and descending (toward pontomedullary reticular formation) axons in addition to nigropetal axons. Ascending axons were observed in 75% (6/8) of short-duration neurons and in 45% (15/33) of long-duration neurons, while nigropetal axons were observed in 50% (4/8) of short-duration neurons and in 76% (25/33) of Long-duration neurons.
These results suggest that the tegmental pedunculopontine nucleus cholinergic projection system is composed of heterogeneous populations of neurons in terms of electrophysiological and morphological characteristics as well as their distribution patterns in the nucleus. (C) 1997 IBRO. Published by Elsevier Science Ltd.

DOI： 10.1016/S0306-4522(97)00019-5

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Language：English   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

We have previously defined three types of tegmental pedunculopontine nuclei neurons based on their electrophysiological characteristics: Type I neurons characterized by low-threshold Ca2+ spikes, Type II neurons which displayed a transient outward current (A-current), and Type III neurons having neither low-threshold spikes nor A-current [Kang: Y. and Kitai S. T. (1990) Brain Res. 535, 79-95]. In this report, ionic mechanisms underlying repetitive firing of Type I (n = 15) and Type II (n = 69) neurons were studied in in vitro slice preparations. Type I neurons did not fire rhythmically but their spontaneous firing frequency ranged From 0 to 19.5 spikes/s (mean 9.7 spikes/s). The spontaneous firing of Type II neurons was rhythmic, with a mean frequency of 9.6 spikes/s (range 3.5-16.0 spikes/s). Choline acetyltransferase immunohistochemistry combined with biocytin labeling indicated that none of the Type I neurons were immunopositive to choline acetyltransferase, while 60% (42 of 69) of Type II neurons were immunopositive. There was no apparent difference in the electrophysiological membrane properties of immunopositive and immunonegative Type II neurons. At membrane potentials subthreshold for Na+ spikes (- 50 mV), spontaneous membrane oscillations (11.6 Hz) were observed: these underlie the spontaneous repetitive firing of Type I neurons. The subthreshold membrane oscillation was tetrodotoxin sensitive but was not affected by Ca2+-free medium. A similar tetrodotoxin-sensitive subthreshold membrane oscillation (10.5 Hz) was also observed in Type II neurons. However, in Type II neurons a membrane oscillation was also observed at higher membrane potentials (-50 mV). This high-threshold oscillation was insensitive to tetrodotoxin and Na+-free medium, but was eliminated in Ca2+-free conditions. The amplitude and frequency of the high-threshold oscillation was increased upon membrane depolarization. Ar the most prominent oscillatory level (around -40 mV), the high-threshold oscillation had a mean frequency of 8.8 Hz. The high-threshold Ca2+ spike was triggered from the peak potential (- 35 to - 30 mV) of the high-threshold oscillation. Application of tetraethylammonium chloride (&lt;5 mM) increased the amplitude of the high-threshold oscillation, while nifedipine greatly attenuated the high-threshold oscillation without changing the shape of the high-threshold Ca2+ spike. Application of Cd2+ eliminated both the high-threshold oscillation and the high-threshold Ca2+ spike, and omega-conotoxin reduced the size of the high-threshold Ca2+ spike without affecting the frequency of the high-threshold oscillation. Nickel did not have any effect on either the high-threshold oscillation or the high-threshold Ca2+ spike.
These data suggest an involvement of N- and L-type Ca2+ channels in the generation of the high-threshold oscillation and the high-threshold Ca2+ spike, respectively. The results indicate that a persistent Na+ conductance plays a crucial role in the subthreshold membrane oscillation, which underlies spontaneous repetitive firing in Type I neurons. On the other hand, in addition to a persistent Na+ conductance for subthreshold membrane oscillation, a voltage-dependent Ca2+ conductance with Ca2+ dependent K+ conductance (for the high-threshold oscillation) may be responsible for rhythmic firing of Type II neurons. (C) 1997 IBRO.

DOI： 10.1016/S0306-4522(96)00540-4

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Language：English   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

We have previously defined three types of tegmental pedunculopontine nuclei neurons based on their electrophysiological characteristics: Type I neurons characterized by low-threshold Ca2+ spikes, Type II neurons which displayed a transient outward current (A-current), and Type III neurons having neither low-threshold spikes nor A-current [Kang: Y. and Kitai S. T. (1990) Brain Res. 535, 79-95]. In this report, ionic mechanisms underlying repetitive firing of Type I (n = 15) and Type II (n = 69) neurons were studied in in vitro slice preparations. Type I neurons did not fire rhythmically but their spontaneous firing frequency ranged From 0 to 19.5 spikes/s (mean 9.7 spikes/s). The spontaneous firing of Type II neurons was rhythmic, with a mean frequency of 9.6 spikes/s (range 3.5-16.0 spikes/s). Choline acetyltransferase immunohistochemistry combined with biocytin labeling indicated that none of the Type I neurons were immunopositive to choline acetyltransferase, while 60% (42 of 69) of Type II neurons were immunopositive. There was no apparent difference in the electrophysiological membrane properties of immunopositive and immunonegative Type II neurons. At membrane potentials subthreshold for Na+ spikes (- 50 mV), spontaneous membrane oscillations (11.6 Hz) were observed: these underlie the spontaneous repetitive firing of Type I neurons. The subthreshold membrane oscillation was tetrodotoxin sensitive but was not affected by Ca2+-free medium. A similar tetrodotoxin-sensitive subthreshold membrane oscillation (10.5 Hz) was also observed in Type II neurons. However, in Type II neurons a membrane oscillation was also observed at higher membrane potentials (-50 mV). This high-threshold oscillation was insensitive to tetrodotoxin and Na+-free medium, but was eliminated in Ca2+-free conditions. The amplitude and frequency of the high-threshold oscillation was increased upon membrane depolarization. Ar the most prominent oscillatory level (around -40 mV), the high-threshold oscillation had a mean frequency of 8.8 Hz. The high-threshold Ca2+ spike was triggered from the peak potential (- 35 to - 30 mV) of the high-threshold oscillation. Application of tetraethylammonium chloride (&lt;5 mM) increased the amplitude of the high-threshold oscillation, while nifedipine greatly attenuated the high-threshold oscillation without changing the shape of the high-threshold Ca2+ spike. Application of Cd2+ eliminated both the high-threshold oscillation and the high-threshold Ca2+ spike, and omega-conotoxin reduced the size of the high-threshold Ca2+ spike without affecting the frequency of the high-threshold oscillation. Nickel did not have any effect on either the high-threshold oscillation or the high-threshold Ca2+ spike.
These data suggest an involvement of N- and L-type Ca2+ channels in the generation of the high-threshold oscillation and the high-threshold Ca2+ spike, respectively. The results indicate that a persistent Na+ conductance plays a crucial role in the subthreshold membrane oscillation, which underlies spontaneous repetitive firing in Type I neurons. On the other hand, in addition to a persistent Na+ conductance for subthreshold membrane oscillation, a voltage-dependent Ca2+ conductance with Ca2+ dependent K+ conductance (for the high-threshold oscillation) may be responsible for rhythmic firing of Type II neurons. (C) 1997 IBRO.

DOI： 10.1016/S0306-4522(96)00540-4

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Language：English   Publisher：WILEY-BLACKWELL  

To characterize the fine morphology of individual reticulospinal axons at multiple spinal segments, localized injections of the anterograde neural tracer, Phaseolus vulgaris ris leucoagglutinin (PHA-L), were made into the nucleus reticularis pontis oralis (NRPo) of the cat. Following survival periods of 6-8 weeks, labelled axons, between 1 and 8 mu m in diameter, were found throughout the cervical and upper thoracic segments. Thick axons (diameter greater than or equal to 3 mu m) were found to descend beyond the upper thoracic spinal cord, while most thin axons (diameter &lt; 3 mu m) ended in the upper cervical cord. From serial transverse sections (50 mu m) of segments C3 to T2, in four cats, the trajectories of 23 single, thick reticulospinal axons were traced in continuity over distances of between 21.8 and 59.4 mm, corresponding to 3 and 8 segments, respectively. Most axons gave off at least one, and as many as four collaterals per segment, some preferentially in the cervical enlargement. The remainder gave off collaterals almost but not all segments. Detailed reconstruction of the collateralization and arborization in the spinal gray matter showed two major termination types, one where terminals remained ipsilateral to the stem axon, the other where additional collaterals extended across the midline from the ipsilateral gray matter to terminate in the contralateral gray matter. Axons tended to have collaterals of one type or the other, irrespective of the rostrocaudal level. Both ipsilateral and bilateral projections terminated mainly in laminae VII and VIII although the branching patterns varied from axon to axon. Individual stem axons, in general, showed similar termination patterns at each level. (C)) 1997 Wiley-Liss, Inc.

DOI： 10.1002/(SICI)1096-9861(19970113)377:2<234::AID-CNE6>3.0.CO;2-4

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Other Link： http://search.jamas.or.jp/link/ui/1997211050

Language：English   Publisher：RAPID SCIENCE PUBLISHERS  

REPETITIVE electrical stimulation of the midbrain periaqueductal grey (FAG) terminates quiet breathing and initiates inspiration that precedes vocalization. To understand the neuronal mechanisms underlying this phenomenon, activities of expiratory neurones (n=39) of the Botzinger complex (BOT) were examined in decerebrate cats. Most augmenting expiratory (E-aug) neurones (20/22) of the BOT, including 15 bulbospinal neurones, decreased their activities (9/20) or ceased to discharge (11/20) after the onset of stimulation of the FAG. This suggests that suppression of E-aug neurones of the BOT, which project to phrenic motoneurones, results in disinhibition of these neurones, and, in turn, terminates expiration and initiates inspiration preceding vocalization.

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Morphological features of rat pedunculopontine projection neurons were investigated in in vitro preparation by using intracellular labeling with biocytin combined with choline acetyltransferase (ChAT) immunohistochemistry. These neurons were classified into two types (Type I and II), based on their electrical membrane properties: Type I had low-threshold Ca2+ spikes, and Type II had A-current. All Type I neurons (n = 17) were ChAT immunonegative (ChAT(-)). Type II neurons were either ChAT immunopositive (ChAT(+); n = 49) or ChAT(-) (n = 20). In terms of topography in the tegmental pedunculopontine nucleus (PPN), Type I neurons were dispersed throughout the extent of the nucleus, whereas Type II neurons tended to be located more in the rostral and middle sections. Both Type I and II neurons consisted of small (long axis &lt;20 mu m), medium (20-35 mu m), and large (&gt;35 mu m) cells. The small cells were round or oval; medium cells were round, triangular, or fusiform; and the large cells were primarily fusiform in shape. In terms of the soma size, there was a difference in Type I (15-38 mu m) and Type II (11-50 mu m) neurons, but no significant difference was found between Type II ChAT(+) and ChAT(-) cells. Both types of neurons had three to six primary dendrites, but the dendritic field was more prominent in Type II neurons. Most of the axons originated from one of the primary dendrites, which gave off axon collaterals, some of which projected out of the nucleus. The intrinsic collaterals were thin and branched partly within the dendritic field of the parent cell. The extrinsic collaterals were thicker and could be grouped into three categories: 1) collaterals arborizing in the substantia nigra, 2) collaterals ascending mainly toward the thalamus, pretectal, and tectal area; and 3) collaterals descending toward the mesencephalic and/or pontine reticular formation. It was noted that the collaterals of both ChAT(+) and ChAT neurons were traced into the substantia ni;ya. There was no significant difference in antidromic latencies between Type I (m = 1.47 msec) and Type II (m = 1.36 msec) neurons following electrical stimulation of the substantia nigra. (C) 1996 Wiley-Liss, Inc.

DOI： 10.1002/(SICI)1096-9861(19960729)371:3<345::AID-CNE1>3.0.CO;2-2

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Language：English   Publisher：ELSEVIER SCI PUBL IRELAND LTD  

In acute decerebrate cats, medial pontine reticular formation (MLR) and the mesencephalic locomotor region (MLR) were stimulated and their stimulus effects upon 250 medullary reticulospinal neurons (RSNs) were studied. One hundred and twenty-six RSNs were mono- and disynaptically activated. From the response patterns of the RSNs, they were divided into the mPRF-activated RSNs (n = 67) and the MLR-activated RSNs (n = 59). The former group of RSNs was located in the nucleus reticularis gigantocellularis (NRGc), while the latter group of RSNs was distributed in both the NRGc and the nucleus reticularis magnocellularis (NRMc). The activity of MLR-excited 12 RSNs was suppressed with the preceding mPRF stimulation. These RSNs were mainly located in the NRMc. Most mPRF-excited RSNs increased their discharge rates during mPRF-evoked suppression of postural muscle tone, and most MLR-excited RSNs increased their discharge rates during MLR-evoked locomotion. With mPRF stimulation, MLR-evoked locomotion was suppressed with cessation of MLR-excited RSNs activity. These results suggest that mPRF stimulation suppresses the activity of the locomotor rhythm generating system at the levels of not only the spinal cord but also the medullary output cells.

DOI： 10.1016/0168-0102(95)00924-I

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Postsynaptic responses of dopamine (DA) neurons in the substantia nigra pars compacta (SNc) to stimulation of the pedunculopontine tegmental nuclei (PPN) were studied in in vitro slice preparations in the rat. The recorded neurons were intracellularly injected with biocytin and also identified as DA neurons by an immunocytochemical technique. PPN stimulation induced in DA neurons monosynaptic excitatory postsynaptic potentials (EPSPs) that consisted of early transient and slow components. An application of anti-glutamatergic agents (1 mM kynurenic acid and/or 30 mu M 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)) in the bathing media partially suppressed the EPSPs, indicating that PPN inputs to SNc DA neurons are glutamatergic and non-glutamatergic. Anti-glutamatergic resistant EPSPs were suppressed by applications of anti-cholinergic agents such as atropine, mecamylamine, and pirenzepine. These data indicate a convergence of glutamatergic and cholinergic excitatory inputs from the PPN to SNc DA neurons and that both nicotinic and muscarinic receptors are involved in the cholinergic transmission.

DOI： 10.1016/0168-0102(94)00869-H

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Postsynaptic responses of dopamine (DA) neurons in the substantia nigra pars compacta (SNc) to stimulation of the pedunculopontine tegmental nuclei (PPN) were studied in in vitro slice preparations in the rat. The recorded neurons were intracellularly injected with biocytin and also identified as DA neurons by an immunocytochemical technique. PPN stimulation induced in DA neurons monosynaptic excitatory postsynaptic potentials (EPSPs) that consisted of early transient and slow components. An application of anti-glutamatergic agents (1 mM kynurenic acid and/or 30 mu M 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)) in the bathing media partially suppressed the EPSPs, indicating that PPN inputs to SNc DA neurons are glutamatergic and non-glutamatergic. Anti-glutamatergic resistant EPSPs were suppressed by applications of anti-cholinergic agents such as atropine, mecamylamine, and pirenzepine. These data indicate a convergence of glutamatergic and cholinergic excitatory inputs from the PPN to SNc DA neurons and that both nicotinic and muscarinic receptors are involved in the cholinergic transmission.

DOI： 10.1016/0168-0102(94)00869-H

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Extracellular levels of serotonin (5-HT) and 5-hydroxyindolacetic acid (5-HIAA) were measured in the medial pontine reticular formation of acute decerebrate cats. The mean basal levels of 5-HT and 5-HIAA were 26 fmol/20 mu l and 15 pmol/20 mu l. Perfusion of the dialysis probe with high K+ and Ca2+-free Ringer solution for 60 min resulted in 4.8-8.5 x increase and 25-48% decrease in the extracellular levels of 5-HT, respectively, in comparison to the basal 5-HT levels. Perfusion with TTX-added Rinaer solution for 60 min resulted in a consistent decrease in the extracellular levels of 5-HT.

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Language：English   Publisher：SPRINGER VERLAG  

The present study was aimed at elucidating the pontomedullary and spinal cord mechanisms of postural atonia induced by microinjection of carbachol and restored by microinjections of serotonin or atropine sulfate into the nucleus reticularis pontis oralis (NRPo). Medullary reticulospinal neurons (n = 132) antidromically activated by stimulating the L1 spinal cord segment were recorded extracellularly. Seventy-eight of them were orthodromically activated with mono- or disynaptic latencies by stimulating the NRPo area at the site where carbachol injections effectively induced postural atonia. Most of these reticulospinal neurons (71 of 78) were located in the nucleus reticularis gigantocellularis (NRGc). Following carbachol injection into the NRPo, discharge rates of the NRGc reticulospinal neurons (29 of 34) increased, while the activity of soleus muscles decreased bilaterally. Serotonin or atropine injections into the same NRPo area resulted in a decrease in the discharge rates of the reticulospinal neurons with a concomitant increase in the levels of hindlimb muscle tone. Membrane potentials of hindlimb extensor and flexor alpha motoneurons (MNs) were hyperpolarized and depolarized by carbachol and serotonin or atropine injections, respectively. In all pairs of reticulospinal neurons and MNs (n = 11), there was a high correlation between the increase in the discharge rates and the degree of membrane hyperpolarization of the MNs. Spike-triggered averaging during carbachol-induced atonia revealed that inhibitory postsynaptic potentials (IPSPs) were evoked in 15 MNs by the discharges of nine reticulospinal neurons. Four of them evoked IPSPs in more than one MN. The mean segmental delay and the mean time to the peak of IPSPs were 1.6 ms and 2.0 ms, respectively. Axonal trajectories of reticulospinal neurons (n = 6), which evoked IPSPs in MNs, were investigated in the lumbosacral segments (L1-S1) by antidromic threshold mapping. The stem axons descended through the ventral (n = 2) and ventrolateral (n = 4) funiculi in the lumbar segments. All axons projected their collaterals to the intermediate region (laminae V, VI) and ventromedial part (laminae VII, VIII) of the gray matter. All these results suggest that the reticulospinal pathway originating from the NRGc is involved in postural atonia induced by pontine microinjection of carbachol, and that the pathway is inactivated during the postural restoration induced by subsequent injections of serotonin or atropine. It is further suggested that the pontine inhibitory effect is mediated via segmental inhibitory interneurons projecting to MNs.

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By utilizing an anterograde neural tracer, Phaseolus vulgaris leucoagglutinin (PHA-L), pontomedullary reticuloreticular connections and reticulospinal connections were studied, including their fiber trajectories and distribution of PHA-L labeled terminals in close apposition to target reticular and spinal neurons, and branching patterns of axon collaterals at the levels of the cervical and upper thoracic cord. PHA-L was focally microinjected into the medial pontine reticular formation corresponding to the nucleus reticularis pontis oralis. A great number of PHA-L labeled thin fibers descended bilaterally coursing through the medial part of the pontine and medullary reticular formation with an ipsilateral predominance. Labeled terminal boutons were closely apposed to somata of various sized pontomedullary reticular neurons. Labeled thick fibers descended ipsilaterally coursing through the ventral half of the medial longitudinal fasciculus, and further descended through the ventral funiculus of the spinal cord. At the levels of the cervical and upper thoracic cord, these reticulospinal fibers gave off axon collaterals sending terminal fibers to small- to large-sized neurons in Rexed's laminae VII and VIII. Some of the axon collaterals innervated not only ipsilateral but also contralateral gray matter. By reconstructing branching patterns of axon collaterals, each axon collateral was found to innervate spinal neurons located in a disk-like spinal segment with a width less than 1 mm.

DOI： 10.1016/0168-0102(93)90024-K

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Pontine carbachol injection sites critically related to the induction of postural atonia were explored in reflexively standing acute decerebrate cats. Carbachol (4.0 mug/0.25 mu]) and atropine (2.0 mug/0.25 mul) were focally injected into the pontomedullary reticular formation, and their effects on hindlimb extensor muscle tone were studied. The effective carbachol injection sites were concentrated in the region between P 1.5 and P 3.5, H -3.0 and H -5.0, and LR 1.2 and LR 2.5 (Horsley-Clarke coordinates). The effective sites corresponded to the dorsomedial part of both the nucleus reticularis pontis oralis (NRPo) and the rostral portion of the nucleus reticularis pontis caudalis (NRPc). The mean latency to the beginning of carbachol-induced postural atonia was about 90 s (92 +/- 28 s; n=24).

DOI： 10.1016/0304-3940(93)90318-F

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Pontine carbachol injection sites critically related to the induction of postural atonia were explored in reflexively standing acute decerebrate cats. Carbachol (4.0 mug/0.25 mu]) and atropine (2.0 mug/0.25 mul) were focally injected into the pontomedullary reticular formation, and their effects on hindlimb extensor muscle tone were studied. The effective carbachol injection sites were concentrated in the region between P 1.5 and P 3.5, H -3.0 and H -5.0, and LR 1.2 and LR 2.5 (Horsley-Clarke coordinates). The effective sites corresponded to the dorsomedial part of both the nucleus reticularis pontis oralis (NRPo) and the rostral portion of the nucleus reticularis pontis caudalis (NRPc). The mean latency to the beginning of carbachol-induced postural atonia was about 90 s (92 +/- 28 s; n=24).

DOI： 10.1016/0304-3940(93)90318-F

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Language：English   Publisher：SPRINGER VERLAG  

Intrapontine microinjections of serotonin in acutely decerebrated cats resulted in the bilateral augmentation of the postural muscle tone of the hindlimbs. Optimal injection sites were located in the dorsomedial part of the rostral pontine reticular formation corresponding to the nucleus reticularis pontis oralis (NRPo). In this study, attempts were made to elucidate the cellular basis for the serotoninergically induced augmentation of postural muscle tone by recording the electromyographic (EMG) activity of hindlimb extensor muscles, the monosynaptic reflex responses evoked by electrical stimulation of group la muscle afferent fibres and the membrane potentials of hindlimb alpha-motoneurons (MNs). Serotonin injections resulted not only in the augmentation of the EMG activity of gastrocnemius soleus muscles, but also in the restoration of EMG suppression, which was induced by previous injection of carbachol into the NRPo. Extensor and flexor monosynaptic reflex responses were facilitated by serotonin injections into the NRPo. Such reflex facilitation was not induced by serotonin injections into the mesencephalic or the medullary reticular formation. Intrapontine serotonin injections resulted in membrane depolarization of extensor and flexor MNs with decreases in input resistance and rheobase. Spontaneous depolarizing synaptic potentials (EPSPs) increased in both frequency and amplitude. Peak voltage of la monosynaptic EPSPs also increased. Serotonin injections which followed carbachol injections resulted in membrane depolarization of MNs along with an increase in the frequency of spontaneous EPSPs and a decrease in carbachol-induced inhibitory postsynaptic potentials. Following pontine carbachol injections, antidromic and orthodromic responses in MNs were suppressed. Discharges of MNs evoked by intracellular current injections were also suppressed, but were restored following serotonin injections. These results indicate that postsynaptic excitation, presynaptic facilitation and disinhibition (withdrawal of postsynaptic inhibition) simultaneously act on the hindlimb MNs during serotonin-induced postural augmentation and restoration.

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By utilizing an anterograde neural tracer, Phaseolus vulgaris leucoagglutinin (PHA-L), pontomedullary reticuloreticular connections and reticulospinal connections were studied, including their fiber trajectories and distribution of PHA-L labeled terminals in close apposition to target reticular and spinal neurons, and branching patterns of axon collaterals at the levels of the cervical and upper thoracic cord. PHA-L was focally microinjected into the medial pontine reticular formation corresponding to the nucleus reticularis pontis oralis. A great number of PHA-L labeled thin fibers descended bilaterally coursing through the medial part of the pontine and medullary reticular formation with an ipsilateral predominance. Labeled terminal boutons were closely apposed to somata of various sized pontomedullary reticular neurons. Labeled thick fibers descended ipsilaterally coursing through the ventral half of the medial longitudinal fasciculus, and further descended through the ventral funiculus of the spinal cord. At the levels of the cervical and upper thoracic cord, these reticulospinal fibers gave off axon collaterals sending terminal fibers to small- to large-sized neurons in Rexed's laminae VII and VIII. Some of the axon collaterals innervated not only ipsilateral but also contralateral gray matter. By reconstructing branching patterns of axon collaterals, each axon collateral was found to innervate spinal neurons located in a disk-like spinal segment with a width less than 1 mm. © 1993.

DOI： 10.1016/0168-0102(93)90024-K

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Language：English   Publisher：ELSEVIER SCIENCE BV  

Studies in both decerebrate, and intact cats have already established the presence of specific areas in the brainstem that subserve control of posture and locomotion. They are the subthalamic locomotor region (SLR) in the lateral hypothalamic area (LHA), the mesencephalic locomotor region (MLR) in the posterior midbrain, the dorsal tegmental field (DTF) and the ventral tegmental field (VTF) of caudal pons along its midline. These areas can be stimulates either electrically or chemically to induce site-specific changes in posture and locomotor synergies. Our observations indicate that the postural and locomotor synergies are structured in a hierarchy within rostro-caudal axis of the brainstem, and that the command routing through the brainstem relies on interactions with the SLR, the MLR, the DTF area and the VTF area. These results and our concepts for postural and locomotor control and their interactions are discussed with the concepts of command hierarchies for motor control.

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Reflex micturition was evoked in both non-immobilized (n = 5) and immobilized (n = 5) decerebrate cats by filling the bladder with physiological saline. Intracellular recordings were made from pudendal motoneurons (PU-MNs; n = 14) throughout the periods of before, during and after reflex micturition. The changes in the activity of PU-MNs were correlated with those in the intravesical pressure. Our results support the proposition that coordination of the sphincters and the detrusors is established by a gating mechanism, which is activated by the supraspinal source such as the pontine micturition center.

DOI： 10.1016/0304-3940(92)90430-F

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Reflex micturition was evoked in both non-immobilized (n = 5) and immobilized (n = 5) decerebrate cats by filling the bladder with physiological saline. Intracellular recordings were made from pudendal motoneurons (PU-MNs; n = 14) throughout the periods of before, during and after reflex micturition. The changes in the activity of PU-MNs were correlated with those in the intravesical pressure. Our results support the proposition that coordination of the sphincters and the detrusors is established by a gating mechanism, which is activated by the supraspinal source such as the pontine micturition center.

DOI： 10.1016/0304-3940(92)90430-F

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Event date： 2021.9

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