Persistence of post-stress blood pressure elevation requires activation of astrocytes.

The reflexive excitation of the sympathetic nervous system in response to psychological stress leads to elevated blood pressure, a condition that persists even after the stress has been alleviated. This sustained increase in blood pressure, which may contribute to the pathophysiology of hypertension, could be linked to neural plasticity in sympathetic nervous activity. Given the critical role of astrocytes in various forms of neural plasticity, we investigated their involvement in maintaining elevated blood pressure during the post-stress phase. Specifically, we examined the effects of arundic acid, an astrocytic inhibitor, on blood pressure and heart rate responses to air-jet stress. First, we confirmed that the inhibitory effect of arundic acid is specific to astrocytes. Using c-Fos immunohistology, we then observed that psychological stress activates neurons in cardiovascular brain regions, and that this stress-induced neuronal activation was suppressed by arundic acid pre-treatment in rats. By evaluating astrocytic process thickness, we also confirmed that astrocytes in the cardiovascular brain regions were activated by stress, and this activation was blocked by arundic acid pre-treatment. Next, we conducted blood pressure measurements on unanesthetized, unrestrained rats. Air-jet stress elevated blood pressure, which remained high for a significant period during the post-stress phase. However, pre-treatment with arundic acid, which inhibited astrocytic activation, suppressed stress-induced blood pressure elevation both during and after stress. In contrast, arundic acid had no significant impact on heart rate. These findings suggest that both neurons and astrocytes play integral roles in stress-induced blood pressure elevation and its persistence after stress, offering new insights into the pathophysiological mechanisms underlying hypertension.

Cellular mechanisms of synchronized rhythmic burst generation in the ventromedial hypothalamus.

The ventromedial hypothalamus (VMH) plays an important role in feeding behavior and control of the sympathetic nervous system (SNS). The VMH includes a group of neurons that exhibit strong synchronized rhythmic burst firing (so-called VMH oscillation). This VMH oscillation is glucose inhibited, responsive to feeding-related peptides, and is functionally coupled to outputs of the SNS. However, the details of its rhythm generation and synchronization mechanisms are unknown. In the present study, we investigated cellular mechanisms of VMH oscillation by means of electrophysiological recordings and calcium imaging in juvenile rat slice preparations including the VMH. In the electrophysiological study, we performed membrane potential recording from neurons in the vicinity of pipettes for field potential recording. We found that the rhythmic bursts in the VMH were preserved in low Ca2+/high Mg2+ synaptic transmission blockade solution. During membrane hyperpolarization by current injection, the action potential was largely inhibited, but fluctuation of the membrane potential remained with a frequency similar to that at resting potential level. The electric VMH oscillation disappeared after application of either a gap junction blocker, carbenoxolone (100 µM), or a persistent sodium channel blocker, riluzole (20 µM). Membrane potentials and input resistances of rhythmic burst neurons in the VMH were not significantly changed during these manipulations. A calcium imaging study revealed that all VMH cells exhibiting synchronized rhythmic activity detected by intracellular calcium increases were silenced following the application of carbenoxolone. These results suggest that VMH oscillation arises from the activation of persistent sodium channels and coupling via gap junctions.

Changes in facial appearance alter one's sensitivity not only to the self but also to the outside world.

Introduction: Changes in facial appearance due to orthognathic surgery are known to improve a patient's postoperative quality of life, however, potential changes in cognitive function are unknown. This study examined the effects of changes in facial appearance due to orthognathic surgery on the sensitivity to self and to outside objects in patients with jaw deformities. Methods: Patients with jaw deformities (n = 22) and healthy controls (n = 30) were tested at 3 months preoperatively, at 1 month preoperatively, and at 1 month postoperatively to assess their impression of objects (positive, negative, and neutral pictures) and their evaluation of their own face and body. Results: The results showed that changes in facial appearance improved self-evaluation and increased their sensitivity to emotional objects even when the objects were identical. Furthermore, the improving rating for own face was associated with the sensitivity for objects. Discussion: The changes in facial appearance in patients may have helped to clear the sensitivity to these emotional objects. These findings may provide a new indicator of efficacy in orthognathic surgery.

Ostruthin, a TWIK-Related Potassium Channel Agonist, Increases the Body Temperature in Ovariectomized Rats With or Without Progesterone Administration.

BACKGROUND AND OBJECTIVES: The TWIK-related potassium (TREK) channel subfamily, including TREK1 and TREK2, is a novel cold receptor. Ostruthin, a TREK1 and TREK2 agonist, is a component found in the plant Paramignya trimera and is traditionally used as an anticancer medicine in Vietnam, with its stems and roots treating various ailments. The female hormone progesterone (P4) influences body temperature in women; however, the effect of P4 on thermoregulation via TREK has not been examined. This study aims to investigate the effects of P4 on thermoregulatory responses in ostruthin-administered ovariectomized rats, which are animal models of human menopause. METHODS: Wistar rats were ovariectomized and implanted with silastic tubes with or without P4 (P4(+) and P4(-) groups). The TREK agonist or vehicle was injected intraperitoneally. Body temperature, locomotor activity, tail skin temperature, and thermoregulatory behavior (assessed by tail-hiding behavior) were continuously measured. Plasma concentrations of catecholamines, triiodothyronine, and thyroxine were also measured. RESULTS: In both the P4(+) and P4(-) groups, the change in body temperature was greater among the rats administered the TREK agonist compared to the vehicle. No significant differences were observed between the groups in locomotor activity, tail skin temperature, or tail-hiding behavior. The dopamine concentration in the P4(+) group was lower than that in the P4(-) group. CONCLUSIONS: Ostruthin, the TREK agonist, increases body temperature in ovariectomized rats; however, P4 may not affect these responses in ovariectomized rats.

Effects of linalool on respiratory neuron activity in the brainstem-spinal cord preparation from newborn rats.

Linalool and linalyl acetate are major components of lavender essential oil. These substances possess many biological activities, such as anti-inflammatory activity, analgesic and anxiolytic effects, and anticonvulsant properties, and they also induce modulation of neuronal activity in the autonomic nervous system. However, there are no reports of the direct effects of linalool on respiratory activity. In the present study, we analyzed the effects of linalool and linalyl acetate on central respiratory activity in the brainstem-spinal cord preparation isolated from newborn rats. Linalool dose-dependently decreased the rate of respiratory activity. This effect was reversed by bicuculline, suggesting that linalool enhanced inhibitory synaptic connections via GABAA receptors. In addition, linalool reduced the coefficient of variation of inspiratory burst intervals and thus could work to stabilize the respiratory rhythm. Linalyl acetate did not cause inhibitory effects as observed in linalool treatment. Linalool depressed burst activity of pre-inspiratory neurons in the medullary respiratory networks and increased the amplitude of inspiratory inhibitory postsynaptic potentials of pre-inspiratory neurons. We concluded that linalool caused inhibitory effects on respiratory rhythm generation mainly through activation of presynaptic GABAA receptors of pre-inspiratory neurons.

The right amygdala and migraine: Analyzing volume reduction and its relationship with symptom severity.

This study aimed to explore the relationship between gray matter volume changes and various clinical parameters in patients with migraine, focusing on symptom severity, quality of life, and states of depression and anxiety. Using a case-control design, we examined 33 patients with migraine, with or without aura, and 27 age-matched healthy subjects. We used magnetic resonance imaging to assess the volumes of 140 bilateral brain regions. Clinical evaluations included the Migraine Disability Assessment, the Migraine Specific Quality of Life Questionnaire, the Center for Epidemiologic Studies Depression scale, Spielberger's State and Trait Anxiety scales, and the Japanese version of the Montreal Cognitive Assessment. We compared the scores of these measures between migraine patients and healthy controls to examine the interplay between brain structure and clinical symptoms. Significant volumetric differences were observed in the pallidum and amygdala between migraine patients and healthy individuals. The reduction in the right amygdala volume correlated significantly with migraine severity as measured by the Migraine Disability Assessment. Path analysis revealed a model where Migraine Disability Assessment scores were influenced by Migraine Specific Quality of Life Questionnaire outcomes, which were further affected by depression, anxiety, and a low right pallidum volume. Our findings suggest that the chronicity and severity of migraine headaches specifically affect the right amygdala. Our path model suggests a complex relationship whereby migraine disability is strongly influenced by quality of life, which is, in turn, affected by psychological states, such as anxiety and depression.

Involvement of cannabinoid receptors in depression of the putative nociceptive response in spinal cord preparations isolated from neonatal rats.

A metabolite of acetaminophen, AM404, which is an anandamide transporter inhibitor, induces analgesia mainly via activation of transient receptor potential channel 1 in the spinal cord, although the role of cannabinoid receptors remains to be studied. The ventral root reflex response induced by stimulation of the dorsal root in in vitro preparations of rat spinal cord is useful to assess the effect of analgesics. We analyzed the effects of AM404 and cannabinoid receptor antagonist AM251 on reflex responses in lumbar spinal cord preparations from newborn rats and found that the amplitude of the slow ventral root potential after administration of 10 µM AM404 was not significantly changed, whereas 10 µM AM251 significantly increased the amplitude. Administration of the cannabinoid receptor 1 agonist WIN55,212-2 (10 µM) did not significantly affect the reflex response. We suggest that endogenous cannabinoids in the spinal cord are involved in the antinociceptive mechanism through suppressive effects.

Effects of aconitine on the respiratory activity of brainstem-spinal cord preparations isolated from newborn rats.

Aconitine is a sodium channel opener, but its effects on the respiratory center are not well understood. We investigated the dose-dependent effects of aconitine on central respiratory activity in brainstem-spinal cord preparations isolated from newborn rats. Bath application of 0.5-5 µM aconitine caused an increase in respiratory rhythm and decrease in the inspiratory burst amplitude of the fourth cervical ventral root (C4). Separate application of aconitine revealed that medullary neurons were responsible for the respiratory rhythm increase, and neurons in both the medulla and spinal cord were involved in the decrease of C4 amplitude by aconitine. A local anesthetic, lidocaine (100 µM), or a voltage-dependent sodium channel blocker, tetrodotoxin (0.1 µM), partially antagonized the C4 amplitude decrease by aconitine. Tetrodotoxin treatment tentatively decreased the respiratory rhythm, but lidocaine tended to further increase the rhythm. Treatment with 100 µM riluzole or 100 µM flufenamic acid, which are known to inhibit respiratory pacemaker activity, did not reduce the respiratory rhythm enhanced by aconitine + lidocaine. The application of 1 µM aconitine depolarized the preinspiratory, expiratory, and inspiratory motor neurons. The facilitated burst rhythm of inspiratory neurons after aconitine disappeared in a low Ca2+/high Mg2+ synaptic blockade solution. We showed the dose-dependent effects of aconitine on respiratory activity. The antagonists reversed the depressive effects of aconitine in different manners, possibly due to their actions on different sites of sodium channels. The burst-generating pacemaker properties of neurons may not be involved in the generation of the facilitated rhythm after aconitine treatment.

Exercise evaluation with metabolic and ventilatory responses and blood lactate concentration in mice.

This study aimed to clarify the differential exercise capacity between 2-month-old and 10-month-old mice using an incremental running test. Metabolic and ventilatory responses and blood lactate concentration were measured to evaluate exercise capacity. We examined whether incremental running test results reflected metabolic and ventilatory responses and blood lactate concentration observed during the steady-state running test. Metabolic response significantly declined with age, whereas ventilatory response was similar between the groups. A low-intensity/moderate exercise load of 10/min in an incremental running test was performed on both mice for 30 min. They showed a characteristic pattern in ventilatory response in 10-month mice. The results of incremental running tests didn't necessarily reflect the steady-state metabolic and ventilatory responses because some parameters showed an approximation and others did not in incremental and steady-state tests, which changed with age. Our study suggests metabolic and ventilatory responses depending on age and provides basic knowledge regarding the objective and quantitative assessment of treadmill running in an animal model.

Cell Responses of the Ventrolateral Medulla to PAR1 Activation and Changes in Respiratory Rhythm in Newborn Rat En Bloc Brainstem-Spinal Cord Preparations.

Proteinase-activated receptor-1 (PAR1) is expressed in astrocytes of various brain regions, and its activation is involved in the modulation of neuronal activity. Here, we report effects of PAR1 selective agonist TFLLR on respiratory rhythm generation in brainstem-spinal cord preparations. Preparations were isolated from newborn rats (P0-P4) under deep isoflurane anesthesia and were transversely cut at the rostral medulla. Preparations were superfused with artificial cerebrospinal fluid (25-26 °C), and inspiratory C4 ventral root activity was monitored. The responses to TFLLR of cells close to the cut surface were detected by calcium imaging or membrane potential recordings. Application of 10 µM TFLLR (4 min) induced a rapid and transient increase of calcium signal in cells of the ventrolateral respiratory regions of the medulla. More than 88% of responding cells (223/254 cells from 13 preparations) were also activated by low (0.2 mM) K+ solution, suggesting that they were astrocytes. Immunohistochemical examination demonstrated that PAR1 was expressed on many astrocytes. Respiratory-related neurons in the medulla were transiently hyperpolarized (-1.8 mV) during 10 µM TFLLR application, followed by weak membrane depolarization after washout. C4 burst rate decreased transiently in response to application of TFLLR, followed by a slight increase. The inhibitory effect was partially blocked by 50 µM theophylline. In conclusion, activation of astrocytes via PAR1 resulted in a decrease of inspiratory C4 burst rate in association with transient hyperpolarization of respiratory-related neurons. After washout, slow and weak excitatory responses appeared. Adenosine may be partially involved in the inhibitory effect of PAR1 activation.

Preoperative state anxiety predicts postoperative health-related quality of life: A prospective observational study on patients undergoing lung cancer surgery.

Objective: Improving quality of life (QOL) after surgery is very important. Recently, preoperative anxiety has been suggested to predict postoperative health-related (HR) QOL, however the accuracy of anxiety measurement remains problematic. We examined the relationship between preoperative anxiety level and postoperative HRQOL using qualitative and quantitative assessment of anxiety. Method: We used a detailed anxiety assessment to quantitatively investigate preoperative anxiety as a predictor of postoperative HRQOL in lung cancer patients. Fifty one patients who underwent surgery for lung cancer were included. They were assessed four times: on admission, on discharge, 1 month after surgery, and 3 months after surgery. Anxiety was measured separately as "state anxiety" and "trait anxiety" using the State-Trait Anxiety Inventory, and HRQOL was measured using the EuroQol 5 dimension 5-level. Results: The HRQOL decreased at discharge and gradually recovered over time, reaching the same level at 3 months after surgery as at admission. HRQOL score was lower at discharge than at pre-surgery and 3 months after the surgery (p < 0.0001 each), and the score at 1 month after the surgery was lower than at pre-surgery (p = 0.007). In addition, multiple regression analysis showed that HRQOL at discharge was associated with "state anxiety" rather than "trait anxiety" at admission (p = 0.004). Conclusion: This study identifies the types of anxiety that affect postoperative HRQOL. We suggest that postoperative HRQOL on discharge may be improved by interventions such as psychological or medication treatment for preoperative state anxiety if identified preoperative state anxiety can be managed appropriately.

Modulation of acyl and des-acyl ghrelin on autonomic and behavioral thermoregulation in various ambient temperatures.

Maintenance of body temperature (Tb) at various ambient temperatures (Ta) during fasting is important for homeotherms. Fasting decreases Tb in thermoneutral and cold conditions and facilitates thermoregulatory behavior in the cold in rats; however, the mechanism is unknown. We focused on ghrelin, a hormone secreted by the stomach during fasting, in two circulatory forms: acyl ghrelin (AG) and des-acyl ghrelin (DAG). AG is called active ghrelin, while DAG, the non-active ghrelin, was unknown for a long time before its many functions were recently clarified. In the present review, we present the modulation of AG and DAG on autonomic and behavioral thermoregulation at various Ta and discuss the differences between their modulation on thermoregulation. AG decreases Tb in thermoneutral and cold conditions but does not affect the thermoregulatory behavior of rodents in cold conditions. The DAG decreases Tb in thermoneutral and hot conditions, but it does not affect Tb and facilitates the thermoregulatory behavior of rodents in the cold. These findings indicate that the actions of AG and DAG on thermoregulation are similar in thermoneutral conditions but are different in cold conditions.

Continuous positive airway pressure treatment reduces renal tubular damage in patients with obstructive sleep apnea: A retrospective single-center cohort study.

BACKGROUND: Chronic intermittent hypoxia (IH) plays a significant role in the pathogenesis of obstructive sleep apnea (OSA) comorbidities. The prevalence of chronic kidney disease is higher in patients with OSA than the general population, and renal function decline is well correlated with renal tubular injury. However, little is known about the impact of OSA-induced chronic IH on the renal tubules. METHODS: We conducted a retrospective survey of clinical records performing multiple regression analysis and cluster analysis with particular attention to the 3% oxygen desaturation index (ODI) and urinary N-acetyl-ß-d-glucosaminidase (NAG). RESULTS: In patients with suspicion of OSA, urinary NAG creatinine ratio (UNCR) was elevated as their 3% ODI increased (n = 197, p < 0.001), and the elevated UNCR decreased following CPAP treatment in patients with OSA (n = 46, p = 0.014). Multiple regression analysis showed that 3% ODI was associated with UNCR. Cluster analysis identified three clusters of patients with OSA, including two younger age clusters, one of which was characterized by high BMI, high 3% ODI, and high prevalence of major comorbidities. In a comparative analysis of younger age cases (age ≤ 55, n = 82), the UNCR level was higher in patients with severe 3% ODI (3% ODI > 40 events/h, n = 24) (p = 0.014). CONCLUSIONS: Our results indicate that even at younger ages, OSA patients with severe chronic IH and major comorbidities are susceptible to renal tubular damage. Early treatment with CPAP may attenuate renal tubular injury and progression toward end-stage renal disease.

Cannabinoid receptors involved in descending inhibition on spinal seizure-like activity in the phrenic output.

Seizure-like burst activities are induced by blockade of GABAA and/or glycine receptors in various spinal ventral roots of brainstem-spinal cord preparation from neonatal rodents. We found that this is not applicable to the phrenic nerve and that a new inhibitory descending pathway may suppress seizure-like activity in the phrenic nerve. Experiments were performed in brainstem-spinal cord preparation from newborn rats (age: 0-1 day). Left phrenic nerve and right C4 activities were recorded simultaneously. When GABAA and glycine receptors were blocked by 10 µM bicuculline and 10 µM strychnine (Bic+Str), seizure-like burst activities appeared in the fourth cervical ventral root (C4) but not the phrenic nerve. After making a transverse section at C1, the inspiratory burst activity disappeared from both C4 and the phrenic nerve, whereas seizure-like activity appeared in both nerves. We hypothesized that inhibitory descending pathways other than those via GABAA and/or glycine receptors (from the medulla to the spinal cord) work to avoid disturbance of regular respiratory-related diaphragm contraction by seizure-like activity. We found that cannabinoid receptor antagonist, AM251 was effective for the induction of seizure-like activity by Bic+Str in the phrenic nerve in brainstem-spinal cord preparation. Cannabinoid receptors may be involved in this descending inhibitory system.

Cerebral white matter lesions and regional blood flow are associated with reduced cognitive function in early-stage cognitive impairment.

Background: Differences in the extent of cerebral white matter lesions (WML) and regional cerebral blood flow (rCBF) in early-stage cognitive impairment (ESCI) contribute to the prognosis of cognitive decline; however, it is unclear precisely how WML and rCBF affect cognitive decline in ESCI. Objective: We examined the association between WML, rCBF, and cognitive impairment in the ESCI, using path analysis to clarify how these variables affect each other. Methods: Eighty-three patients who consulted our memory clinic regarding memory loss were included in this study based on the Clinical Dementia Rating. Participants underwent the Mini-Mental State Examination (MMSE), brain magnetic resonance imaging (MRI) for voxel-based morphometry analysis, and brain perfusion single-photon emission computed tomography (SPECT) for rCBF evaluation in cortical regions, using 3D stereotactic surface projection (3D-SSP) analysis. Results: Path analysis was performed on the MRI voxel-based morphometry and SPECT 3D-SSP data, showing a significant correlation between both and MMSE scores. In the most suitable model (GFI = 0.957), correlations were observed between lateral ventricular (LV-V) and periventricular WML (PvWML-V) volumes [standardized coefficient (SC) = 0.326, p = 0.005], LV-V and rCBF of the anterior cingulate gyrus (ACG-rCBF; SC = 0.395, p < 0.0001), and ACG-rCBF and PvWML-V (SC = 0.231, p = 0.041). Furthermore, a direct relationship between PvWML-V and MMSE scores was identified (SC = -0.238, p = 0.026). Conclusion: Significant interrelationships were observed among the LV-V, PvWML-V, and ACG-rCBF that directly affected the MMSE score in the ESCI. The mechanisms behind these interactions and the impact of PvWML-V on cognitive function require further investigation.

Role of the amygdala-medial orbitofrontal relationship in odor recognition in the elderly.

INTRODUCTION: In patients with mild cognitive impairment, pathological changes begin in the amygdala (AMG) and hippocampus (HI), especially in the parahippocampal gyrus and entorhinal cortex (ENT). These areas play an important role in olfactory detection and recognition. It is important to understand how subtle signs of olfactory disability relate to the functions of the above-mentioned regions, as well as the orbitofrontal cortex (OFC). In this study, we evaluated brain activation using functional magnetic resonance imaging (fMRI), performed during the presentation of olfactory stimuli (classified as "normal odors" not inducing memory retrieval), and investigated the relationships of the blood oxygen level-dependent (BOLD) signal with olfactory detection and recognition abilities in healthy elderly subjects. METHODS: Twenty-four healthy elderly subjects underwent fMRI during olfaction, and raw mean BOLD signals were extracted from regions of interest, including bilateral regions (AMG, HI, parahippocampus, and ENT) and orbitofrontal subregions (frontal inferior OFC, frontal medial OFC, frontal middle OFC, and frontal superior OFC). Multiple regression and path analyses were conducted to understand the roles of these areas in olfactory detection and recognition. RESULTS: Activation of the left AMG had the greatest impact on olfactory detection and recognition, while the ENT, parahippocampus, and HI acted as a support system for AMG activation. Less activation of the right frontal medial OFC was associated with good olfactory recognition. These findings improve our understanding of the roles of limbic and prefrontal regions in olfactory awareness and identification in elderly individuals. CONCLUSION: Functional decline of the ENT and parahippocampus crucially impacts olfactory recognition. However, AMG function may compensate for deficits through connections with frontal regions.

Respiratory rhythm affects recalibration of body ownership.

Change in body perception requires recalibration of various sensory inputs. However, it is less known how information other than sensations relates to the recalibration of body perception. Here, we focused on the relationship between respiration and cognition and investigated whether respiratory rhythms are related to the recalibration of hand perception. We built a visual feedback environment, in which a mannequin hand moved in conjunction with its own respiratory rhythm, and participants performed an experiment under conditions in congruency/incongruency for spatial and temporal factors. The temporal and spatial congruency between own respiratory rhythm and the mannequin hand markedly facilitated the phenomenon of hand ownership sense transfer to the mannequin hand, while incongruency had little effect on the change in hand ownership. The finding suggests that an internal model in the brain allows respiratory rhythms to be involved in the adaptation of the body's neural representations.

Mild-intensity running exercise recovered motor function by improvement of ankle mobility after unilateral brain injury of mice using three-dimensional kinematic analysis techniques.

Motor dysfunction, such as gait impairment, is a major disability induced by traumatic brain injury or stroke. Treadmill running is often used as a physical exercise (Ex) clinically and experimentally for the recovery of patients. In animal experiments, although dynamic behavioral deficits can be evaluated using scoring systems, local and minor behaviors are difficult to determine. This study aims to evaluate motor dysfunction and recovery after brain damage (BD) with/without mild-intensity running Ex in mice using three-dimensional (3D) kinematic analysis. To determine exercise intensity, C57/BL6-strain male young adult mice were examined in an incremental running test while the pulmonary gas exchange of O2 and CO2 were measured. The animals were then subjected to left hemidecortication as BD, and some mice performed Ex (10 m/min for 30 min 5 times/wk) for 4 weeks. The BD with Ex and BD or sham-operated mice (sham) without (w/o) Ex had their gait recorded by four synchronized cameras, and gait was evaluated via 3D-kinematic analysis. The BD w/o Ex mice significantly differed in stride, step, and stride width for both limbs compared to the sham w/o Ex mice. The BD with Ex mice showed improvement. The BD w/o Ex mice had restricted ankle movements and impairment in dorsal/planter flexing using trajectory analysis. Consistent with these impairments, the nonaffected side also exhibited a different trajectory, suggesting compensatory movements. These results suggest that the appropriate Ex after BD recovered motor function. Furthermore, the present study suggested that 3D-kinematic analysis is a powerful tool for detecting minor behavioral alterations owing to the impairment of the affected side and the compensation of the unaffected side.