Tranilast alleviates visceral hypersensitivity and colonic hyperpermeability by suppressing NLRP3 inflammasome activation in irritable bowel syndrome rat models.

Visceral hypersensitivity resulting from compromised gut barrier with activated immune system is a key feature of irritable bowel syndrome (IBS). Corticotropin-releasing factor (CRF) and Toll-like receptor 4 (TLR4) activate proinflammatory cytokine signaling to induce these changes, which is one of the mechanisms of IBS. As activation of the NLRP3 inflammasome by lipopolysaccharide (LPS) or TLR4 leads to release interleukin (IL)-1ß, the NLRP3 inflammasome may be involved in the pathophysiology of IBS. Tranilast, an anti-allergic drug has been demonstrated to inhibit the NLRP3 inflammasome, and we evaluated the impact of tranilast on visceral hypersensitivity and colonic hyperpermeability induced by LPS or CRF (IBS rat model). Visceral pain threshold caused by colonic balloon distention was measured by monitoring abdominal muscle contractions electrophysiologically. Colonic permeability was determined by quantifying the absorbed Evans blue within the colonic tissue. Colonic protein levels of NLRP3 and IL-1ß were assessed by immunoblot or ELISA. Intragastric administration of tranilast (20-200 mg/kg) for 3 days inhibited LPS (1 mg/kg)-induced visceral hypersensitivity and colonic hyperpermeability in a dose-dependent manner. Simultaneously, tranilast also abolished these alterations induced by CRF (50 µg/kg). LPS increased colonic protein levels of NLRP3 and IL-1ß, and tranilast inhibited these changes. ß-hydroxy butyrate, an NLRP3 inhibitor, also abolished visceral hypersensitivity and colonic hyperpermeability caused by LPS. In contrast, IL-1ß induced similar GI alterations to LPS, which were not modified by tranilast. In conclusion, tranilast improved visceral pain and colonic barrier by suppression of the NLRP3 inflammasome in IBS rat models. Tranilast may be useful for IBS treating.

Evolutionary origin of alpha rhythms in vertebrates.

The purpose of this review extends beyond the traditional triune brain model, aiming to elucidate the evolutionary aspects of alpha rhythms in vertebrates. The forebrain, comprising the telencephalon (pallium) and diencephalon (thalamus, hypothalamus), is a common feature in the brains of all vertebrates. In mammals, evolution has prioritized the development of the forebrain, especially the neocortex, over the midbrain (mesencephalon) optic tectum, which serves as the prototype for the visual brain. This evolution enables mammals to process visual information in the retina-thalamus (lateral geniculate nucleus)-occipital cortex pathway. The origin of posterior-dominant alpha rhythms observed in mammals in quiet and dark environments is not solely attributed to cholinergic pontine nuclei cells functioning as a 10 Hz pacemaker in the brainstem. It also involves the ability of the neocortex's cortical layers to generate traveling waves of alpha rhythms with waxing and waning characteristics. The utilization of alpha rhythms might have facilitated the shift of attention from external visual inputs to internal cognitive processes as an adaptation to thrive in dark environments. The evolution of alpha rhythms might trace back to the dinosaur era, suggesting that enhanced cortical connectivity linked to alpha bands could have facilitated the development of nocturnal awakening in the ancestors of mammals. In fishes, reptiles, and birds, the pallium lacks a cortical layer. However, there is a lack of research clearly observing dominant alpha rhythms in the pallium or organized nuclear structures in fishes, reptiles, or birds. Through convergent evolution, the pallium of birds, which exhibits cortex-like fiber architecture, has not only acquired advanced cognitive and motor abilities but also the capability to generate low-frequency oscillations (4-25 Hz) resembling alpha rhythms. This suggests that the origins of alpha rhythms might lie in the pallium of a common ancestor of birds and mammals.

Analysis of the Relationship Between Muscle Tones and Abnormal Postures in a Computational Model.

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.

Analysis of abnormal posture in patients with Parkinson's disease using a computational model considering muscle tones.

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.

Phlorizin attenuates postoperative gastric ileus in rats.

BACKGROUND: Postoperative ileus (POI) is a major complication of abdominal surgery (AS). Impaired gut barrier mediated via Toll-like receptor 4 (TLR4) and interleukin-1 (IL-1) receptor is involved in the development of POI. Phlorizin is a nonselective inhibitor of sodium-linked glucose transporters (SGLTs) and is known to improve lipopolysaccharide (LPS)-induced impaired gut barrier. This study aimed to clarify our hypothesis that AS-induced gastric ileus is mediated via TLR4 and IL-1 signaling, and phlorizin improves the ileus. METHODS: AS consisted of a celiotomy and manipulation of the cecum for 1 min. Gastric emptying (GE) in 20 min with liquid meal was determined 3 h after the surgery in rats. The effect of subcutaneous (s.c.) injection of LPS (1 mg kg-1 ) was also determined 3 h postinjection. KEY RESULTS: AS delayed GE, which was blocked by TAK-242, an inhibitor of TLR4 signaling and anakinra, an IL-1 receptor antagonist. LPS delayed GE, which was also mediated via TLR4 and IL-1 receptor. Phlorizin (80 mg kg-1 , s.c.) significantly improved delayed GE induced by both AS and LPS. However, intragastrical (i.g.) administration of phlorizin did not alter it. As gut mainly expresses SGLT1, SGLT2 may not be inhibited by i.g. phlorizin. The effect of phlorizin was blocked by ghrelin receptor antagonist in the LPS model. CONCLUSIONS & INFERENCES: AS-induced gastric ileus is mediated via TLR4 and IL-1 signaling, which is simulated by LPS. Phlorizin improves the gastric ileus via activation of ghrelin signaling, possibly by inhibition of SGLT2. Phlorizin may be useful for the treatment of POI.

Gait control by the frontal lobe.

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.

Imeglimin prevents visceral hypersensitivity and colonic hyperpermeability in irritable bowel syndrome rat model.

Visceral hypersensitivity and leaky gut, which are mediated via corticotropin-releasing factor (CRF) and Toll-like receptor 4 are key pathophysiology of irritable bowel syndrome (IBS). Metformin was reported to improve these gastrointestinal (GI) changes. In this study, we attempted to determine the effects of imeglimin, which was synthesized from metformin on GI function in IBS rat models. Imeglimin blocked lipopolysaccharide- or CRF-induced visceral hypersensitivity and colonic hyperpermeability. These effects were prevented by compound C or naloxone. These results suggest that imeglimin may be effective for the treatment of IBS by improved visceral sensation and colonic barrier via AMPK and opioid receptor.

[Control of Posture and Gait by the Basal Ganglia: Pathophysiological Mechanisms Implicated in Parkinson's Disease].

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.

Peripheral apelin mediates visceral hypersensitivity and impaired gut barrier in a rat irritable bowel syndrome model.

Growing evidence indicates that visceral hypersensitivity and impaired gut barrier play an important role in the pathophysiology of irritable bowel syndrome (IBS). In animal models, these changes are known to be mediated via corticotropin-releasing factor (CRF)-Toll like receptor 4 (TLR4)-proinflammatory cytokine signaling. Apelin, an endogenous ligand of APJ, was reported to modulate CRF-induced enhanced colonic motility. In this context, we hypothesized that apelin also modulates visceral sensation and gut barrier, and tested this hypothesis. We measured visceral pain threshold in response to colonic balloon distention by abdominal muscle contractions assessed by electromyogram in rats. Colonic permeability was estimated by quantifying the absorbed Evans blue in colonic tissue. Intraperitoneal (ip) administration of [Ala13]-apelin-13, an APJ antagonist, blocked lipopolysaccharide (LPS)- or CRF-induced visceral hypersensitivity and colonic hyperpermeability (IBS model) in a dose-response manner. These inhibitory effects were blocked by compound C, an AMPK inhibitor, NG-nitro-L-arginine methyl ester, a nitric oxide (NO) synthesis inhibitor or naloxone in the LPS model. On the other hand, ip [Pyr1]-apelin-13, an APJ agonist, caused visceral hypersensitivity and colonic hyperpermeability, and these effects were reversed by astressin, a CRF receptor antagonist, TAK-242, a TLR4 antagonist or anakinra, an interleukin-1 receptor antagonist. APJ system modulated CRF-TLR4-proinflammatory cytokine signaling to cause visceral hypersensitivity and colonic hyperpermeability. APJ antagonist blocked these GI changes in IBS models, which were mediated via AMPK, NO and opioid signaling. Apelin may contribute to the IBS pathophysiology, and the inhibition of apelinergic signaling may be a promising therapeutic option for IBS.

A Neural Controller Model Considering the Vestibulospinal Tract in Human Postural Control.

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.

Knee dynamics during take-off and landing in spike jumps performed by volleyball players with patellar tendinopathy.

[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.

Discussion of Research Priorities for Gait Disorders in Parkinson's Disease.

Gait and balance abnormalities develop commonly in Parkinson's disease and are among the motor symptoms most disabling and refractory to dopaminergic or other treatments, including deep brain stimulation. Efforts to develop effective therapies are challenged by limited understanding of these complex disorders. There is a major need for novel and appropriately targeted research to expedite progress in this area. The Scientific Issues Committee of the International Parkinson and Movement Disorder Society has charged a panel of experts in the field to consider the current knowledge gaps and determine the research routes with highest potential to generate groundbreaking data. © 2021 International Parkinson and Movement Disorder Society.

Evaluation of Postural Sway in Post-stroke Patients by Dynamic Time Warping Clustering.

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 t s long data slots. Then, we clustered the t-s data slots into K 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 post-hoc 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.

Increase in muscle tone promotes the use of ankle strategies during perturbed stance.

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.

Phlorizin attenuates visceral hypersensitivity and colonic hyperpermeability in a rat model of irritable bowel syndrome.

Visceral hypersensitivity and impaired gut barrier are crucial contributors to the pathophysiology of irritable bowel syndrome (IBS), and those are mediated via corticotropin-releasing factor (CRF)-Toll like receptor 4-pro-inflammatory cytokine signaling. Phlorizin is an inhibitor of sodium-linked glucose transporters (SGLTs), and known to have anti-cytokine properties. Thus, we hypothesized that phlorizin may improve these gastrointestinal changes in IBS, and tested this hypothesis in rat IBS models, i.e., lipopolysaccharide (LPS) or CRF-induced visceral hypersensitivity and colonic hyperpermeability. The visceral pain threshold in response to colonic balloon distention was estimated by abdominal muscle contractions by electromyogram, and colonic permeability was measured by quantifying the absorbed Evans blue in colonic tissue. Subcutaneous (s.c.) injection of phlorizin inhibited visceral hypersensitivity and colonic hyperpermeability induced by LPS in a dose-dependent manner. Phlorizin also blocked CRF-induced these gastrointestinal changes. Phlorizin is known to inhibit both SGLT1 and SGLT2, but intragastric administration of phlorizin may only inhibit SGLT1 because gut mainly expresses SGLT1. We found that intragastric phlorizin did not display any effects, but ipragliflozin, an orally active and selective SGLT2 inhibitor improved the gastrointestinal changes in the LPS model. Compound C, an adenosine monophosphate-activated protein kinase (AMPK) inhibitor, NG-nitro-L-arginine methyl ester, a nitric oxide (NO) synthesis inhibitor and naloxone, an opioid receptor antagonist reversed the effects of phlorizin. In conclusions, phlorizin improved visceral hypersensitivity and colonic hyperpermeability in IBS models. These effects may result from inhibition of SGLT2, and were mediated via AMPK, NO and opioid pathways. Phlorizin may be effective for the treatment of IBS.

EMA401, an angiotensin II type 2 receptor antagonist blocks visceral hypersensitivity and colonic hyperpermeability in rat model of irritable bowel syndrome.

Visceral hypersensitivity and impaired gut barrier are crucial pathophysiology of irritable bowel syndrome (IBS), and injection of lipopolysaccharide or corticotropin-releasing factor, and repeated water avoidance stress simulate these gastrointestinal changes in rat (IBS models). We previously demonstrated that losartan, an angiotensin II type 1 (AT1) receptor antagonist prevented these changes, and we attempted to determine the effects of EMA401, an AT2 receptor antagonist in the current study. EMA401 blocked visceral hypersensitivity and colonic hyperpermeability in these models, and naloxone reversed the effects by EMA401. These results suggest that EMA401 may improve gut function via opioid signaling in IBS.

Activation of central adenosine A2B receptors mediate brain ghrelin-induced improvement of intestinal barrier function through the vagus nerve in rats.

Leaky gut that is a condition reflecting intestinal barrier dysfunction has been attracting attention for its relations with many diseases such as irritable bowel syndrome or Alzheimer dementia. We have recently demonstrated that ghrelin acts in the brain to improve leaky gut via the vagus nerve. In the present study, we tried to clarify the precise central mechanisms by which ghrelin improves intestinal barrier function through the vagus nerve. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Adenosine receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), blocked the intracisternal ghrelin-induced improvement of intestinal hyperpermeability while dopamine, cannabinoid or opioid receptor antagonist failed to prevent it. Since DPCPX can block adenosine A1 and adenosine A2B receptors, we examined which subtype is involved in the mechanism. Intracisternal injection of adenosine A2B agonist but not adenosine A1 agonist improved colonic hyperpermeability, while peripheral injection of adenosine A2B agonist failed to improve it. Intracisternal adenosine A2B agonist-induced improvement of colonic hyperpermeability was blocked by vagotomy. Adenosine A2B specific antagonist, alloxazine blocked the ghrelin- or central vagal stimulation by 2-deoxy-d-glucose-induced improvement of intestinal hyperpermeability. These results suggest that activation of adenosine A2B receptors in the central nervous system is capable of improving intestinal barrier function through the vagal pathway, and the adenosine A2B receptors may mediate the ghrelin-induced improvement of leaky gut in a vagal dependent fashion. These findings may help us understand the pathophysiology in not only gastrointestinal diseases but also non-gastrointestinal diseases associated with the altered intestinal permeability.

Preceding Postural Control in Forelimb Reaching Movements in Cats.

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.

Imipramine improves visceral sensation and gut barrier in rat models of irritable bowel syndrome.

An impaired gut barrier, possibly leading to visceral hypersensitivity has been recently recognized to be one of the pivotal pathophysiology of irritable bowel syndrome (IBS). We previously showed that lipopolysaccharide (LPS), corticotropin-releasing factor (CRF), and repeated water avoidance stress (WAS) induce visceral hypersensitivity and colonic hyperpermeability via pro-inflammatory cytokine signaling (rat IBS models). Although the precise mechanisms of action are unclear, imipramine, a tricyclic antidepressant, improves IBS symptoms, and also has anticytokine properties. In this study, we hypothesized that imipramine improves the gut barrier to ameliorate IBS symptoms. To test this hypothesis, we determined its effects on visceral hypersensitivity and colonic hyperpermeability in rat IBS models. The visceral pain threshold in response to colonic balloon distention was electrophysiologically estimated by abdominal muscle contractions, and colonic permeability was measured by quantifying the absorbed Evans blue in colonic tissue in vivo. Subcutaneous imipramine injection (7, 20, 50 mg/kg) dose-dependently inhibited LPS-induced (1 mg/kg, subcutaneously) visceral hypersensitivity and colonic hyperpermeability. Imipramine also blocked these gastrointestinal (GI) changes induced by CRF (50 µg/kg, intraperitoneally) or repeated WAS (1 h daily for 3 days). Yohimbine (an α2-adrenoceptors antagonist), sulpiride (a dopamine D2 receptor antagonist), and naloxone hydrochloride (an opioid receptor antagonist) reversed these effects of imipramine in the LPS model. Therefore, imipramine may block GI changes in IBS via α2-adrenoceptors, dopamine D2, and opioid signaling. The improvement in the gut barrier resulting in inhibition of visceral pain is considered a valid mechanism of imipramine to ameliorate IBS symptoms.