Ganoderma lucidum spore extract improves sleep disturbances in a rat model of sporadic Alzheimer's disease.

Introduction: Ganoderma lucidum (G. lucidum, Lingzhi) has long been listed as a premium tonic that can be used to improve restlessness, insomnia, and forgetfulness. We previously reported that a rat model of sporadic Alzheimer's disease (sAD) that was induced by an intracerebroventricular injection of streptozotocin (ICV-STZ) showed significant learning and cognitive deficits and sleep disturbances. Treatment with a G. lucidum spore extract with the sporoderm removed (RGLS) prevented learning and memory impairments in sAD model rats. Method: The present study was conducted to further elucidate the preventive action of RGLS on sleep disturbances in sAD rats by EEG analysis, immunofluorescence staining, HPLC-MS/MS and Western blot. Results: Treatment with 720 mg/kg RGLS for 14 days significantly improved the reduction of total sleep time, rapid eye movement (REM) sleep time, and non-REM sleep time in sAD rats. The novelty recognition experiment further confirmed that RGLS prevented cognitive impairments in sAD rats. We also found that RGLS inhibited the nuclear factor-κB (NF-κB)/Nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammatory pathway in the medial prefrontal cortex (mPFC) in sAD rats and ameliorated the lower activity of γ-aminobutyric acid (GABA)-ergic neurons in the parabrachial nucleus (PBN). Discussion: These results suggest that inhibiting the neuroinflammatory response in the mPFC may be a mechanism by which RGLS improves cognitive impairment. Additionally, improvements in PBN-GABAergic activity and the suppression of neuroinflammation in the mPFC in sAD rats might be a critical pathway to explain the preventive effects of RGLS on sleep disturbances in sAD.

Sporoderm-removed Ganoderma lucidum spores ameliorated early depression-like behavior in a rat model of sporadic Alzheimer's disease.

Introduction: Ganoderma lucidum: (G. lucidum, Lingzhi) is a medicinal and edible homologous traditional Chinese medicine that is used to treat various diseases, including Alzheimer's disease and mood disorders. We previously reported that the sporoderm-removed G. lucidum spore extract (RGLS) prevented learning and memory impairments in a rat model of sporadic Alzheimer's disease (sAD), but the effect of RGLS on depression-like behaviors in this model and its underlying molecular mechanisms of action remain unclear. Method: The present study investigated protective effects of RGLS against intracerebroventricular streptozotocin (ICV-STZ)-induced depression in a rat model of sAD and its underlying mechanism. Effects of RGLS on depression- and anxiety-like behaviors in ICV-STZ rats were assessed in the forced swim test, sucrose preference test, novelty-suppressed feeding test, and open field test. Results: Behavioral tests demonstrated that RGLS (360 and 720 mg/kg) significantly ameliorated ICV-STZ-induced depression- and anxiety-like behaviors. Immunofluorescence, Western blot and enzyme-linked immunosorbent assay results further demonstrated that ICV-STZ rats exhibited microglia activation and neuroinflammatory response in the medial prefrontal cortex (mPFC), and RGLS treatment reversed these changes, reflected by the normalization of morphological changes in microglia and the expression of NF-κB, NLRP3, ASC, caspase-1 and proinflammatory cytokines. Golgi staining revealed that treatment with RGLS increased the density of mushroom spines in neurons. This increase was associated with elevated expression of brain-derived neurotrophic protein in the mPFC. Discussion: In a rat model of ICV-STZ-induced sAD, RGLS exhibits antidepressant-like effects, the mechanism of which may be related to suppression of the inflammatory response modulated by the NF-κB/NLRP3 pathway and enhancement of synaptic plasticity in the mPFC.

AIE/AEE tripodal PEGyl-melphalan supramolecules and detection of trinitrophenol in water.

Herein, the design of a novel aggregation-induced emission (AIE) supramolecular fluorescence sensor (TA-PEGn) based on a tridentate melphalan derivative and three different molecular weight PEGs is presented. The three TA-PEGn sensors could self-assemble into a supramolecular system in water and show sensitive and selective responses toward trinitrophenol.

Analysis of coping capacities and cognitive biases of novice drivers-A questionnaire-based study.

Coping capacity is a key aspect of driver-vehicle interaction when drivers observe and make decisions, and is of great importance for drivers. However, different drivers have different self-cognition and assess their driving abilities differently, especially for novice drivers. Based on questionnaire data, this study has investigated the coping capacities of drivers in both static environments and dynamic environments. With the ANOVA analysis method and the structural equation model (SEM), this study has verified the effects of gender and driving factors (driving years, driving frequency, driving time) on drivers' coping capacities based on drivers' self-assessment scores and mutual assessment scores. Drivers' self-assessment scores show significant effects of all factors on drivers' coping capacities, and drivers' mutual assessment scores show significant effects of all factors, excluding driving time, on drivers' coping capacities. Also, it has been found that all drivers in the driving year group have cognitive biases. It seems that first-year drivers are always overconfident with their driving skills, while drivers with a driving experience of more than three years usually score driving skills of themselves and other drivers most conservatively. With increased exposure to various traffic conditions, experienced drivers are more aware of their limitations in dealing with complex traffic situations, while novice drivers do not know their lack of capability to properly respond to any unexpected situation they could encounter.

Chronic Stress-Induced Elevation of Melanin-Concentrating Hormone in the Locus Coeruleus Inhibits Norepinephrine Production and Associated With Depression-Like Behaviors in Rats.

BACKGROUND: Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that projects throughout the central nervous system, including the noradrenergic locus coeruleus (LC). Our previous study suggested that MCH/MCH receptor 1 (MCHR1) in the LC may be involved in the regulation of depression. The present study investigated whether the role of MCH/MCHR1 in the LC in depression-like behaviors is associated with the regulation of norepinephrine. METHOD: Chronic unpredictable stress (CUS) and an acute intra-LC microinjection of MCH induced depression-like behaviors in rats. The MCHR1 antagonist SNAP-94847 was also microinjected in the LC in rats that were suffering CUS or treated with MCH. The sucrose preference, forced swim, and locomotor tests were used for behavioral evaluation. Immunofluorescence staining, enzyme-linked immunosorbent assay, western blot, and high-performance liquid chromatography with electrochemical detection were used to explore the mechanism of MCH/MCHR1 in the regulation of depression-like behaviors. RESULTS: CUS induced an abnormal elevation of MCH levels and downregulated MCHR1 in the LC, which was highly correlated with the formation of depression-like behaviors. SNAP-94847 exerted antidepressant effects in CUS-exposed rats by normalizing tyrosine hydroxylase, dopamine ß hydroxylase, and norepinephrine in the LC. An acute microinjection of MCH induced depression-like behaviors through its action on MCHR1. MCHR1 antagonism in the LC significantly reversed the MCH-induced downregulation of norepinephrine production by normalizing MCHR1-medicated cAMP-PKA signaling. CONCLUSIONS: Our study confirmed that the MCH/MCHR1 system in the LC may be involved in depression-like behaviors by downregulating norepinephrine production. These results improve our understanding of the pathogenesis of depression that is related to the MCH/MCHR1 system in the LC.

Reduction of BDNF Levels and Biphasic Changes in Glutamate Release in the Prefrontal Cortex Correlate with Susceptibility to Chronic Stress-Induced Anhedonia.

Chronic stress has been considered to induce depressive symptoms, such as anhedonia, particularly in susceptible individuals. Synaptic plasticity in the prefrontal cortex (PFC) is closely associated with susceptibility or resilience to chronic stress-induced anhedonia. However, effects of chronic stress with different durations on the neurobiological mechanisms that underlie susceptibility to anhedonia remain unclear. The present study investigated effects of chronic mild stress (CMS) for 14, 21, and 35 d on anhedonia-like behavior and glutamate synapses in the PFC. We found that brain-derived neurotrophic factor (BDNF) levels in the PFC significantly decreased only in anhedonia-susceptible rats that were exposed to CMS for 14, 21, and 35 d. Additionally, 14 d of CMS increased prefrontal glutamate release, and 35 d of CMS decreased glutamate release, in addition to reducing synaptic proteins and spine density in the PFC. Moreover, we found that anhedonia-like behavior in a subset of rats spontaneously decreased, accompanied by the restoration of BDNF levels and glutamate release, on day 21 of CMS. Ketamine treatment restored the reduction of BDNF levels and biphasic changes in glutamate release that were induced by CMS. Our findings revealed a progressive reduction of synaptic plasticity and biphasic changes in glutamate release in the PFC during CMS. Reductions of BDNF levels may be key neurobiological markers of susceptibility to stress-induced anhedonia.

Study on the preparation and mechanical properties of purple ceramics.

This paper aims at preparing a smart wearable purple ceramic that meet the color requirements of purple smart wear in the market after using zirconate neodymium as a chromogenic agent. However, the mechanical performance of zirconate neodymium purple ceramic is not satisfactory, especially it has an extremely low fracture toughness. To solve this, a 3 mol% yttria-stabilized zirconia (3YSZ) is added to zirconate neodymium in the preparation of multiphase ceramics to improve its mechanical properties. In this experiment, a series of ceramic samples with addition of increasing amount of 3YSZ 0, 20, 40, 50, 60, 70 and 80% were prepared in the 1400-1500 °C sintering temperature range. It was found that at the same temperature, the mechanical properties of the ceramic samples gradually improved with the increase in the 3YSZ content. Moreover, with the same content, the mechanical properties of the ceramic samples gradually improved with the decrease in temperature. The results show that when 3YSZ has a mass fraction of 80% and is sintered at 1400 °C, the fracture toughness of the prepared ceramic samples reaches 8.15 MPa‧m1/2, which is nearly two times higher than that of the monolithic neodymium zirconate 2.57 MPa‧m1/2. The Vickers hardness of the prepared ceramic samples reached 12.93 GPa, which is nearly 88% higher than the undoped neodymium zirconate. This indicates that the samples can be applied in smart wearables, such as mobile phone backplane, with a certain practical significance for engineering toughening of zirconate ceramics.

Total tubeless percutaneous nephrolithotomy without artificial hydronephrosis in preschool children: Three case reports.

RATIONALE: Indwelling ureteral catheter, double J tube, or nephrostomy tube are routine procedures for percutaneous nephrolithotomy (PCNL) in children. There are a few cases in which PCNL has been performed in children without any additional instruments being left in place. PATIENT CONCERNS: In this study, 3 children were treated for hematuria and complicated with different degrees of urinary tract infection. All of them were diagnosed as upper urinary tract calculi by abdominal computed tomography. DIAGNOSIS: Three preschoolers were diagnosed with upper urinary tract calculi before surgery, one with no hydronephrosis and the other 2 with different degrees of hydronephrosis. INTERVENTIONS: After preoperative evaluation, all the children successfully completed PCNL without indwelling ureteral catheter, double J tube, or nephrostomy tube. OUTCOMES: The operation was successful and there were no residual stones observed during postoperative review. The operating times for the children were 33 minutes, 17 minutes, and 20 minutes, and the intraoperative bleeding volumes were 1 mL, 2 mL, and 2 mL. The catheter was removed on the second day after the operation, the postoperative review of the abdominal computed tomography or ultrasound did not indicate any stone residue, and there were no fever, bleeding, and other related complications after the operation. LESSONS: We believe that total tubeless PCNL without artificial hydronephrosis can be achieved in the preschool population.

SIRT1 Interacts with Prepro-Orexin in the Hypothalamus in SOD1G93A Mice.

The participation of silent mating type information regulation 2 homolog 1 (SIRT1) in amyotrophic lateral sclerosis (ALS) has been reported in many studies. However, the role of the expression and function of SIRT1 in the hypothalamus in ALS remains unknown. In the current study, we performed western blot, co-immunoprecipitation and immunofluorescence analyses to determine the expression and in-depth mechanism of SIRT1 in the hypothalamus in SOD1G93A transgenic mice. We found that SIRT1 was overexpressed in the hypothalamus after motor symptom onset. In addition, SIRT1 interacted with prepro-orexin, a molecule involved in energy balance and the sleep/wake cycle, in both preclinical and clinical ALS regardless of whether SIRT1 levels were elevated. These findings indicate that SIRT1 might participate in sleep and metabolic changes in ALS, suggesting that SIRT1 is a new target for ALS treatment.

One-stage tubeless percutaneous nephrolithotomy for asymptomatic calculous pyonephrosis.

BACKGROUND: In recent years, the safety and effectiveness of one-stage percutaneous nephrolithotomy (PCNL) for the treatment of calculous pyonephrosis have been proven. In order to further reduce postoperative pain and hospital stay, we first proposed and practiced the idea of one-stage tubeless percutaneous nephrolithotomy for calculous pyonephrosis. METHODS: A retrospective analysis was performed of case data of 30 patients with asymptomatic calculous pyonephrosis treated in our center with one-stage PCNL from January 2016 to January 2021. Patients were routinely given 20 mg of furosemide and 10 mg of dexamethasone sodium phosphate injection intravenously at the beginning of anesthesia. Among them, 27 patients successfully underwent one-stage tubeless percutaneous nephrolithotomy, while 3 cases were given indwelling nephrostomy tubes because of proposed second-stage surgery or the number of channels was greater than or equal to 3. All patients were operated on by the same surgeon. RESULTS: Preoperatively, 11 of 30 patients (8 men and 22 women) had positive urine bacterial cultures, and all were given appropriate antibiotics based on drug sensitivity tests. All patients completed the surgery successfully. The mean operative time was 66.6 ± 34.7 min, the mean estimated blood loss was 16.67 ± 14.34 mL and the mean postoperative hospital stay was 5.0 ± 3.1 days. The mean postoperative hospital stay was 4.6 ± 2.5 days among the 27 patients with one-stage tubeless percutaneous nephrolithotomy. Of the 3 patients with postoperative fever, 2 had the tubeless technique applied. One patient with 3 channels was given renal artery interventional embolization for control of postoperative bleeding. None of the 30 patients included in the study developed sepsis. The final stone-free rate was 93.3% (28/30) on repeat computed tomography at 1 month postoperatively. The final stone-free rate was 92.6% in the 27 patients undergoing one-stage tubeless percutaneous nephrolithotomy (25/27). CONCLUSIONS: One-stage tubeless PCNL is an available and safe option in carefully evaluated and selected calculous pyonephrosis patients.

An autofocus algorithm considering wavelength changes for large scale microscopic hyperspectral pathological imaging system.

Microscopic hyperspectral imaging technology has been widely used to acquire pathological information of tissue sections. Autofocus is one of the most important steps in microscopic hyperspectral imaging systems to capture large scale or even whole slide images of pathological slides with high quality and high speed. However, there are quite few autofocus algorithm put forward for the microscopic hyperspectral imaging system. Therefore, this article proposes a Laplace operator based autofocus algorithm for microscopic hyperspectral imaging system which takes the influence of wavelength changes into consideration. Through the proposed algorithm, the focal length for each wavelength can be adjusted automatically to ensure that each single band image can be autofocused precisely with adaptive image sharpness evaluation method. In addition, to increase the capture speed, the relationship of wavelength and focal length is derived and the focal offsets among different single band images are calculated for pre-focusing. We have employed the proposed method on our own datasets and the experimental results show that it can capture large-scale microscopic hyperspectral pathology images with high precise.

Long-acting versus short-acting granulocyte colony-stimulating factors among cancer patients after chemotherapy in China: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Granulocyte colony-stimulating factors (G-CSFs) include long-acting ones and short-acting ones. They have been mainly applied in Chinese clinical practice for years to prevent neutropenia. However, which type of G-CSF is more superior has not been conclusively determined. METHODS: A systematic literature search was conducted using the PubMed, Embase, Cochrane Library, clinical trials.gov, China National Knowledge Infrastructure, and WAN FANG databases for related studies published till August 2021. Revman 5.3 software was used to assess the effectiveness and safety of these 2 types of G-CSFs in patients undergoing chemotherapy. RESULTS: Ten studies involving 1916 patients were included in our meta-analysis to compare the effectiveness and safety of long-acting G-CSFs and short-acting G-CSFs. We found that the incidence of febrile neutropenia (relative risk [RR] 0.82; 95% confidence interval [CI] 0.57-1.17), the recovery time of the absolute neutrophil count (mean difference -0.23; 95% CI -0.49 to 0.03), and the fatigue rate (RR 0.82; 95% CI 0.62-1.07) were similar between the long- and the short-acting G-CSFs. However, the long-acting G-CSFs significantly decreased the incidence (RR 0.86; 95% CI 0.76-0.96) and shortened the duration (mean difference -0.19; 95% CI -0.38 to 0.00) of severe (grade ≥3) neutropenia, and decreased the rate of bone and/or muscle pain (RR 0.75; 95% CI 0.58-0.98). CONCLUSION: Primary prophylaxis with long-acting G-CSFs was more effective and safer than primary prophylaxis with short-acting G-CSFs in Chinese adults undergoing chemotherapy.

Hierarchical nano-to-molecular disassembly of boron dipyrromethene nanoparticles for enhanced tumor penetration and activatable photodynamic therapy.

The development of activatable photosensitizers (PSs) is of particular interest for achieving tumor photodynamic therapy (PDT) with minimal side effects. However, the in vivo applications of PSs are limited by complex physiological and biological delivery barriers. Herein, boron dipyrromethene (BDP)-based nanoparticles are developed through the self-assembly of a multifunctional "one-for-all" building block for enhanced tumor penetration and activatable PDT. The nanoparticles show excellent colloidal stability and long circulation lifetime in blood. Once they reach the tumor site, the first-stage size reduction occurs due to the hydrolysis of the Schiff base bond between polyethylene glycol and the cyclic Arg-Gly-Asp peptide in the acidic tumor microenvironment (pH~6.5), facilitating tumor penetration and specific recognition by cancer cells overexpressing integrin ανß3 receptors. Upon the endocytosis by cancer cells, the second-stage size reduction is triggered by more acidic pH in lysosomes (pH~4.5). Importantly, the protonated diethylamino groups can block photoinduced electron transfer from the amine donor to the excited PSs and accelerate complete disassembly of the nanoparticles into single PS molecule, with the recovery of the fluorescence and photoactivity for efficient PDT. This study presents a smart PS delivery strategy involving acidity-triggered hierarchical disassembly from the nano to molecular scale for precise tumor PDT.

Anti-stress effects of combined block of glucocorticoid and mineralocorticoid receptors in the paraventricular nucleus of the hypothalamus.

BACKGROUND AND PURPOSE: Mineralocorticoid receptors (MRs), glucocorticoid receptors (GRs) and corticotropin-releasing factor (CRF) in the paraventricular nucleus of hypothalamus (PVN) are involved in the response to stress. The present study investigated the role of GRs and MRs in the PVN in regulating depressive and anxiety-like behaviours. EXPERIMENTAL APPROACH: To model chronic stress, rats were exposed to corticosterone treatment via drinking water for 21 days, and GR antagonist RU486 and MR antagonist spironolactone, alone and combined, were directly injected in the PVN daily for the last 7 days of corticosterone treatment. Behavioural tests were run on days 22 and 23. Depressive- and anxiety-like behaviours were evaluated in forced swim test, sucrose preference test, novelty-suppressed feeding test and social interaction test. The expression of GRs, MRs and CRF were detected by western blot. KEY RESULTS: Rats exposed to corticosterone exhibited depressive- and anxiety-like behaviours. The expression of GRs and MRs decreased, and CRF levels increased in the PVN. The intra-PVN administration of RU486 increased the levels of GRs and CRF without influencing depressive- or anxiety-like behaviours. The spironolactone-treated group exhibited an increase in MRs without influencing GRs and CRF in the PVN and improved anxiety-like behaviours. Interestingly, the intra-PVN administration of RU486 and spironolactone combined restored expression of GRs, MRs and CRF and improved depressive- and anxiety-like behaviours. CONCLUSION AND IMPLICATIONS: In this rat model of stress, the simultaneous restoration of GRs, MRs and CRF in the PVN might play an important role in the treatment of depression and anxiety.

Prophylactic effects of sporoderm-removed Ganoderma lucidum spores in a rat model of streptozotocin-induced sporadic Alzheimer's disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Ganoderma lucidum (G. lucidum, Lingzhi), also known as "immortality mushroom" has been broadly used to improve health and longevity for thousands of years in Asia. G. lucidum and its spores have been used to promote health, based on its broad pharmacological and therapeutic activity. This species is recorded in Chinese traditional formula as a nootropic and has been suggested to improve cognitive dysfunction in Alzheimer's disease. However, little is known about the nootropic effects and molecular mechanism of action of G. lucidum spores. AIM OF THE STUDY: The present study investigated the protective effects of sporoderm-deficient Ganoderma lucidum spores (RGLS) against learning and memory impairments and its mechanism of action. MATERIALS AND METHODS: In the Morris water maze, the effects of RGLS on learning and memory impairments were evaluated in a rat model of sporadic Alzheimer's disease that was induced by an intracerebroventricular injection of streptozotocin (STZ). Changes in amyloid ß (Aß) expression, Tau expression and phosphorylation, brain-derived neurotrophic factor (BDNF), and the BDNF receptor tropomyosin-related kinase B (TrkB) in the hippocampus were evaluated by Western blot. RESULTS: Treatment with RGLS (360 and 720 mg/kg) significantly enhanced memory in the rat model of STZ-induced sporadic Alzheimer's disease and reversed the STZ-induced increases in Aß expression and Tau protein expression and phosphorylation at Ser199, Ser202, and Ser396. The STZ-induced decreases in neurotrophic factors, including BDNF, TrkB and TrkB phosphorylation at Tyr816, were reversed by treatment with RGLS. CONCLUSION: These findings indicate that RGLS prevented learning and memory impairments in the present rat model of STZ-induced sporadic Alzheimer's disease, and these effects depended on a decrease in Aß expression and Tau hyperphosphorylation and the modulation of BDNF-TrkB signaling in the hippocampus.

VAMP3 and SNAP23 as Potential Targets for Preventing the Disturbed Flow-Accelerated Thrombus Formation.

Disturbed blood flow has been recognized to promote platelet aggregation and thrombosis via increasing accumulation of von Willebrand factor (VWF) at the arterial post-stenotic sites. The mechanism underlying the disturbed-flow regulated endothelial VWF production remains elusive. Here we described a mouse model, in which the left external carotid artery (LECA) is ligated to generate disturbed flow in the common carotid artery. Ligation of LECA increased VWF accumulation in the plasma. Carotid arterial thrombosis was induced by ferric chloride (FeCl3) application and the time to occlusion in the ligated vessels was reduced in comparison with the unligated vessels. In vitro, endothelial cells were subjected to oscillatory shear (OS, 0.5 ± 4 dynes/cm2) or pulsatile shear (PS, 12 ± 4 dynes/cm2). OS promoted VWF secretion as well as the cell conditioned media-induced platelet aggregation by regulating the intracellular localization of vesicle-associated membrane protein 3 (VAMP3) and synaptosomal-associated protein 23 (SNAP23). Disruption of vimentin intermediate filaments abolished the OS-induced translocation of SNAP23 to the cell membrane. Knockdown of VAMP3 and SNAP23 reduced the endothelial secretion of VWF. Systemic inhibition of VAMP3 and SNAP23 by treatment of mice with rapamycin significantly ameliorated the FeCl3-induced thrombogenesis, whereas intraluminal overexpression of VAMP3 and SNAP23 aggravated it. Our findings demonstrate VAMP3 and SNAP23 as potential targets for preventing the disturbed flow-accelerated thrombus formation.

Multifunctional nanoparticles as photosensitizer delivery carriers for enhanced photodynamic cancer therapy.

Photodynamic therapy (PDT) is an emerging cancer treatment combining light, oxygen, and a photosensitizer (PS) to produce highly cytotoxic reactive oxygen species that cause cancer cell death. However, most PSs are hydrophobic molecules that have poor water solubility and cannot target tumor tissues, causing damage to normal tissues and cells during PDT. Thus, there is a substantial demand for the development of nanocarrier systems to achieve targeted delivery of PSs into tumor tissues and cells. This review summarizes the research progress in PS delivery systems for PDT treatment of tumors and focuses on the recent design and development of multifunctional nanoparticles as PS delivery carriers for enhanced PDT. These multifunctional nanoparticles possess unique properties, including tunable particle size, changeable shape, stimuli-responsive PS activation, controlled PS release, and hierarchical targeting capability. These properties can increase tumor accumulation, penetration, and cellular internalization of nanoparticles to achieve PS activation and/or release in cancer cells for enhanced PDT. Finally, recent developments in multifunctional nanoparticles for tumor-targeted PS delivery and their future prospects in PDT are discussed.

A common neuronal mechanism of hypertension and sleep disturbances in spontaneously hypertensive rats: Role of orexinergic neurons.

Epidemiologic studies have shown that sleep disorders are associated with the development of hypertension. The present study investigated dynamic changes in sleep patterns during the development of hypertension across the lifespan in spontaneously hypertensive rats (SHRs) and the neural mechanism that underlies these comorbidities, with a focus on the orexinergic system. Blood pressure in rats was measured using a noninvasive blood pressure tail cuff. Sleep was monitored by electroencephalographic and electromyographic recordings. Immunohistochemistry was used to detect the density and activity of orexinergic neurons in the perifornical nucleus. Hcrt2-SAP (400 or 800 ng) was microinjected in the lateral hypothalamus to lesion orexinergic neurons. Compared with Wistar-Kyoto rats, SHRs exhibited various patterns of sleep disturbances. In SHRs, dynamic changes in hypersomnia in the rats' active phase was not synchronized with the development of hypertension, but hyperarousal in the inactive phase and difficulties in falling asleep were observed concurrently with the development of hypertension. Furthermore, the density and activity of orexinergic neurons in the perifornical nucleus were significantly higher in SHRs than in age-matched Wistar-Kyoto rats. The reduction of orexinergic neurons in the lateral hypothalamus partially ameliorated the development of hypertension and prevented difficulties in falling asleep in SHRs. These results indicate that although the correlation between sleep disturbances and hypertension is very complex, common mechanisms may underlie these comorbidities in SHRs. Overactivity of the orexin system may be one such common mechanism.

Serotonergic system may be involved in alterations of sleep homeostasis in spontaneously hypertensive rats.

Hypertension is associated with sleep disorders. Spontaneously hypertensive rats are derived from Wistar-Kyoto rats and widely used in research on hypertension. The present study investigated the propensity to sleep and electroencephalographic spectrum changes over 24 hr in spontaneously hypertensive rats, and proposed the involvement of the serotonergic system in these alterations. Time-course analysis showed that spontaneously hypertensive rats exhibit hyperarousal during the light phase but hypersomnia during the dark phase. Spontaneously hypertensive rats also exhibited less slight fluctuation in electroencephalographic delta power density over 24 hr as compared with Wistar-Kyoto rats, suggesting that the accumulation or elimination of sleep pressure was disrupted. Sleep deprivation disrupted the regulation of sleep homeostasis in spontaneously hypertensive rats, reflected by less sleep time and poor sleep quality during the recovery period. The density and activity of serotonergic neurons in the dorsal raphe nucleus were higher in spontaneously hypertensive rats compared with Wistar-Kyoto rats. Interestingly, we observed the absence of fluctuations in 5-hydroxytryptamine and 5-hydroxyindoleacetic acid across the sleep, wake, sleep deprivation and sleep recovery stages in spontaneously hypertensive rats, which were dramatically different from Wistar-Kyoto rats. These results indicate that the disruption of sleep-wake pattern and sleep homeostasis in spontaneously hypertensive rats might be related to abnormalities of the serotonergic system.