OBJECTIVE:To investigate the mechanism of electroacupuncture of sympathetic nerve activity and blood pressure reduction in the hypothalamic paraventricular nucleus(PVN)of spontaneous hypertensive rats(SHRs).METHODS:A ...OBJECTIVE:To investigate the mechanism of electroacupuncture of sympathetic nerve activity and blood pressure reduction in the hypothalamic paraventricular nucleus(PVN)of spontaneous hypertensive rats(SHRs).METHODS:A total of 64 male SHRs were divided into four groups:model,sham-operated(Sham),electroacupuncture(EA),and N-methyl-D-aspartate receptor antagonist and electroacupuncture(NRA+EA).In addition,16 Wistar-Kyoto rats were used as controls.PVN stereotaxic surgery was performed in both the Sham and NRA+EA groups,while the EA and NRA+EA groups received 14 d of electroacupuncture.Blood pressure(BP)and heart rate(HR)were measured the day before the intervention and every other day.After 14 d of intervention,the rats in each group were tested for renal sympathetic nerve activity(RSNA).The associated factor levels were determined using Western blotting,reverse transcription-polymerase chain reaction(RTPCR),enzyme-linked immunosorbent assay(ELISA)and immunofluorescence assays.RESULTS:In comparison to the model group,the EA and NRA+EA groups had significantly lower BP,HR,and RSNA(P<0.01).The expression of N-methyl-Daspartate receptor(NMDAR),angiotensin II(Ang II),angiotensin II type 1(AT1),tumor necrosis factor-α,interleukin-1β,norepinephrine and arginine vasopressin was significantly lower in the EA and NRA+EA groups(P<0.01).Moreover,the antihypertensive effect of NRA+EA group outperformed to the EA group.CONCLUSIONS:Electroacupuncture effectively reduced the BP and sympathetic nerve excitability in SHRs.The mechanism was linked to the inhibition of NMDARmediated Ang II/AT1 and the inflammatory response in PVN.展开更多
The somatotopic representation of specific body parts is a well-established spatial organizational principle in the primary somatosensory and motor cortices.
BACKGROUND Visceral hypersensitivity is the core pathogenesis of irritable bowel syndrome(IBS)and is often accompanied by negative emotions such as anxiety or depression.Paraventricular hypothalamic nucleus(PVN)cortic...BACKGROUND Visceral hypersensitivity is the core pathogenesis of irritable bowel syndrome(IBS)and is often accompanied by negative emotions such as anxiety or depression.Paraventricular hypothalamic nucleus(PVN)corticotropin-releasing factor(CRF)is involved in the stress-related gastrointestinal dysfunction.Electroacupuncture(EA)has unique advantages for the treatment of visceral hypersensitivity and negative emotions in IBS patients.However,the underlying mechanisms remain unclear.AIM To investigate the pathological mechanisms visceral hypersensitivity and negative emotions in IBS,as well as the effect mechanism of EA.METHODS A model of diarrhoeal IBS(IBS-D)with negative emotions was prepared by chronic restraint combined with glacial acetic acid enema.The effect of EA was verified by abdominal withdrawal reflex and open-field test.PVN CRFcolonic mast cell(MC)/transient potential receptor vanilloid type 1(TRPV1)pathway was detected by immunofluorescence,Western blot,ELISA,and toluidine blue staining.Moreover,PVN CRFergic neurons were activated or inhibited by chemogenetical technique to observe the changes of effect indicator.RESULTS In the model group,IBS-D symptoms and negative emotions were successfully induced.Notably,the combination of Baihui(GV20)with Tianshu(ST25)and Dachangshu(BL25)acupoints showed the greatest efficacy in improving the negative emotions and visceral hypersensitivity in model mice.Furthermore,we found that EA inhibited overactivated PVN CRFergic neurons and the overexpression of serum CRF,colonic CRF,CRF-receptor 1(CRFR1),mast cell tryptase(MCT),protease-activated receptor 2 and TRPV1 in model mice.Moreover,we found that activating PVN CRFergic neurons induced negative emotions and visceral hypersensitivity in normal mice;however,inhibiting PVN CRFergic neurons alleviated negative emotions and intestinal symptoms in model mice and decreased the expression of colonic CRF-R1,MCT,and TRPV1.CONCLUSION This research highlights the key role of PVN CRF-MC CRF-R1 and the downstream MC/TRPV1 pathway in the pathological process of IBS-D and the mechanism of the effect of EA.展开更多
Objective:This study investigates the sleep-modulating effects of ginsenoside Rg1(Rg1,C_(42)H_(72)O_(14)),a key bioactive component of ginseng,and elucidates its underlying mechanisms.Methods:C57BL/6J mice were intrap...Objective:This study investigates the sleep-modulating effects of ginsenoside Rg1(Rg1,C_(42)H_(72)O_(14)),a key bioactive component of ginseng,and elucidates its underlying mechanisms.Methods:C57BL/6J mice were intraperitoneally administered doses of Rg1 ranging from 12.5 to100 mg/kg.Sleep parameters were assessed to determine the average duration of each sleep stage by monitoring the electrical activity of the brain and muscles.Further,orexin neurons in the lateral hypothalamus(LH)and corticotropin-releasing hormone(CRH)neurons in the paraventricular hypothalamic nucleus(PVH)were ablated using viral vector surgery and electrode embedding.The excitability of LH^(orexin)and PVH^(CRH)neurons was evaluated through the measurement of cellular Finkel-Biskis-Jinkins murine osteosarcoma viral oncogene homolog(c-Fos)expression.Results:Rg1(12.5–100 mg/kg)augmented the duration of non-rapid eye movement(NREM)sleep phases,while reducing the duration of wakefulness,in a dose dependent manner.The reduced latency from wakefulness to NREM sleep indicates an accelerated sleep initiation time.We found that these sleep-promoting effects were weakened in the LH^(orexin)and PVH^(CRH)neuron ablation groups,and disappeared in the orexin and CRH double-ablation group.Decreased c-Fos protein expression in the LH and PVH confirmed that Rg1 promoted NREM sleep by inhibiting orexin and CRH neurons.Conclusion:Rg1 increases the duration of NREM sleep,underscoring the essential roles of LH^(orexin)and PVH^(CRH)neurons in facilitating the sleep-promoting effects of Rg1.Please cite this article as:Wang YY,Wu Y,Yu KW,Xie HY,Gui Y,Chen CR,Wang NH.Ginsenoside Rg1 promotes non-rapid eye movement sleep via inhibition of orexin neurons of the lateral hypothalamus and corticotropin-releasing hormone neurons of the paraventricular hypothalamic nucleus.J Integr Med.2024;22(6):719–728.展开更多
Objective To study the central role of ginkgolide B （BN52021） in regulating cardiovascular function of nerve center by examining the effects of ginkgolide B on the electrical activity of rat paraventricular nucleus ...Objective To study the central role of ginkgolide B （BN52021） in regulating cardiovascular function of nerve center by examining the effects of ginkgolide B on the electrical activity of rat paraventricular nucleus （PVN） neurons in hypothalamic slice preparation and to elucidate the mechanism involved. Methods Extracellular single-unit discharge recording technique. Results （1） In response to the application of ginkgolide t3 （0.1, 1, 10 μmol/L; n = 27） into the perfusate for 2 rain, the spontaneous discharge rates （SDR） of 26 （26/27, 96.30%） neurons were significantly decreased in a dose-dependent manner. （2） Pretreatment with L-glutamate （L-Glu, 0.2 mmol/L） led to a marked increase in the SDR of all 8 （100%） neurons in an epileptiform pattern. The increased discharges were suppressed significantly after ginkgolide B （1 μmol/L） was applied into the perfusate for 2 min. （3） In 8 neurons, perfusion of the selective L-type calcium channel agonist, Bay K 8644 （0.1 μmol/L）, induced a significant increase in the discharge rates of 8 （8/8, 100%） neurons, while ginkgolide B （1μmol/L） applied into the perfusate, could inhibit the discharges of 8 （100%） neurons. （4） In 8 neurons, the broad potassium channels blocker, tetraethylammonium （TEA, 1 mmol/L） completely blocked the inhibitory effect of ginkgolide B （1 μmol/L）. Conclusion These results suggest that ginkgolide B can inhibit the electrical activity of paraventricular neurons. The inhibitory effect may be related to the blockade of L-type voltage-activated calcium channel and potentially concerned with delayed rectifier potassium channel （KDR）.展开更多
Intermedin/adrenomedullin-2(IMD/AM2), a member of the calcitonin gene-related peptide/AM family,plays an important role in protecting the cardiovascular system. However, its role in the enhanced sympathoexcitation in ...Intermedin/adrenomedullin-2(IMD/AM2), a member of the calcitonin gene-related peptide/AM family,plays an important role in protecting the cardiovascular system. However, its role in the enhanced sympathoexcitation in obesity-related hypertension is unknown. In this study, we investigated the effects of IMD in the paraventricular nucleus(PVN) of the hypothalamus on sympathetic nerve activity(SNA), and lipopolysaccharide(LPS)-induced sympathetic activation in obesity-related hypertensive(OH)rats induced by a high-fat diet for 12 weeks. Acute experiments were performed under anesthesia. The dynamic alterations of sympathetic outflow were evaluated as changes in renal SNA and mean arterial pressure(MAP) in response to specific drugs. Male rats were fed a control diet(12% kcal as fat) or a high-fat diet(42% kcal as fat) for 12 weeks to induce OH. The results showed that IMD protein in the PVN was downregulated, but Toll-like receptor 4(TLR4) and plasma norepinephrine(NE, indicating sympathetic hyperactivity) levels, and systolic blood pressure were increased in OH rats. LPS(0.5 lg/50 nL)-induced enhancement of renal SNA and MAP was greater in OH rats than in obese or control rats. Bilateral PVN microinjection of IMD(50 pmol)caused greater decreases in renal SNA and MAP in OH rats than in control rats, and inhibited LPS-induced sympatheticactivation, and these were effectively prevented in OH rats by pretreatment with the AM receptor antagonist AM22-52.The mitogen-activated protein kinase/extracellular signalregulated kinase(ERK) inhibitor U0126 in the PVN partially reversed the LPS-induced enhancement of SNA. However,IMD in the PVN decreased the LPS-induced ERK activation,which was also effectively prevented by AM22-52. Chronic IMD administration resulted in significant reductions in the plasma NE level and blood pressure in OH rats. Moreover,IMD lowered the TLR4 protein expression and ERK activation in the PVN, and decreased the LPS-induced sympathetic overactivity. These results indicate that IMD in the PVN attenuates SNA and hypertension, and decreases the ERK activation implicated in the LPS-induced enhancement of SNA in OH rats, and this is mediated by AM receptors.展开更多
AIM: To investigate the effect and mechanism of stimulation of the hypothalamic paraventricular nucleus with glutamate acid in rats with ulcerative colitis(UC).METHODS: The rats were anesthetized with 10% chloral hydr...AIM: To investigate the effect and mechanism of stimulation of the hypothalamic paraventricular nucleus with glutamate acid in rats with ulcerative colitis(UC).METHODS: The rats were anesthetized with 10% chloral hydrate via abdominal injection and treated with an equal volume of TNBS + 50% ethanol enema, injected into the upper section of the anus with the tail facing up. Colonic damage scores were calculated after injecting a certain dose of glutamic acid into the paraventricular nucleus(p VN), and the effect of the nucleus tractus solitarius(NTS) and vagus nerve in alleviating UC injury through chemical stimulation of the p VN was observed in rats. Expression changes of C-myc, Apaf-1, caspase-3, interleukin(IL)-6, and IL-17 during the protection against UC injury through chemical stimulation of the p VN in rats were detected by Western blot. Malondialdehyde(MDA) content and superoxide dismutase(SOD) activity in colon tissues of rats were measured by colorimetric methods. RESULTS: Chemical stimulation of the PVN significantly reduced UC in rats in a dose-dependent manner. The protective effects of the chemical stimulationof the p VN on rats with UC were eliminated after chemical damage to the p VN. After glutamate receptor antagonist kynurenic acid was injected into the p VN, the protective effects of the chemical stimulation of the p VN were eliminated in rats with UC. After AVpVl receptor antagonist([Deamino-penl, val4, D-Arg8]-vasopressin) was injected into NTS or bilateral chemical damage to NTS, the protective effect of the chemical stimulation of p VN on UC was also eliminated. After chemical stimulation of the p VN, SOD activity increased, MDA content decreased, C-myc protein expression significantly increased, caspase-3 and Apaf-1 protein expression significantly decreased, and IL-6 and IL-17 expression decreased in colon tissues in rats with UC. CONCLUSION: Chemical stimulation of the hypothalamic p VN provides a protective effect against UC injury in rats. Hypothalamic p VN, NTS and vagus nerve play key roles in this process.展开更多
Metformin(MET), an antidiabetic agent, also has antioxidative effects in metabolic-related hypertension.This study was designed to determine whether MET has anti-hypertensive effects in salt-sensitive hypertensive rat...Metformin(MET), an antidiabetic agent, also has antioxidative effects in metabolic-related hypertension.This study was designed to determine whether MET has anti-hypertensive effects in salt-sensitive hypertensive rats by inhibiting oxidative stress in the hypothalamic paraventricular nucleus(PVN). Salt-sensitive rats received a highsalt(HS) diet to induce hypertension, or a normal-salt(NS)diet as control. At the same time, they received intracerebroventricular(ICV) infusion of MET or vehicle for 6 weeks. We found that HS rats had higher oxidative stress levels and mean arterial pressure(MAP) than NS rats. ICV infusion of MET attenuated MAP and reduced plasma norepinephrine levels in HS rats. It also decreased reactive oxygen species and the expression of subunits of NAD(P)H oxidase, improved the superoxide dismutase activity,reduced components of the renin-angiotensin system, and altered neurotransmitters in the PVN. Our findings suggest that central MET administration lowers MAP in saltsensitive hypertension via attenuating oxidative stress,inhibiting the renin-angiotensin system, and restoring the balance between excitatory and inhibitory neurotransmitters in the PVN.展开更多
AIM: To study the neural mechanism by which electroacupuncture(EA) at RN12(Zhongwan) and BL21(Weishu) regulates gastric motility.METHODS: One hundred and forty-four adult Sprague Dawley rats were studied in four separ...AIM: To study the neural mechanism by which electroacupuncture(EA) at RN12(Zhongwan) and BL21(Weishu) regulates gastric motility.METHODS: One hundred and forty-four adult Sprague Dawley rats were studied in four separate experiments. Intragastric pressure was measured using custommade rubber balloons, and extracellular neuron firing activity, which is sensitive to gastric distention in the dorsal vagal complex(DVC), was recorded by an electrophysiological technique. The expression levels of c-fos, motilin(MTL) and gastrin(GAS) in the paraventricular hypothalamic nucleus(PVN) were assayed by immunohistochemistry, and the expression levels of motilin receptor(MTL-R) and gastrin receptor(GAS-R) in both the PVN and the gastric antrum were assayed by western blotting.RESULTS: EA at RN12 + BL21(gastric Shu and Mu points), BL21(gastric Back-Shu point), RN12(gastric Front-Mu point), resulted in increased neuron-activating frequency in the DVC(2.08 ± 0.050, 1.17 ± 0.023, 1.55 ± 0.079 vs 0.75 ± 0.046, P < 0.001) compared with a model group. The expression of c-fos(36.24 ± 1.67, 29.41 ± 2.55, 31.79 ± 3.00 vs 5.73 ± 2.18, P < 0.001), MTL(22.48 ± 2.66, 20.76 ± 2.41, 19.17 ± 1.71 vs 11.68 ± 2.52, P < 0.001), GAS(24.99 ± 2.95, 21.69 ± 3.24, 23.03 ± 3.09 vs 12.53 ± 2.15, P < 0.001), MTL-R(1.39 ± 0.05, 1.22 ± 0.05, 1.17 ± 0.12 vs 0.84 ± 0.06, P < 0.001), and GAS-R(1.07 ± 0.07, 0.91 ± 0.06, 0.78 ± 0.05 vs 0.45 ± 0.04, P < 0.001) increased in the PVN after EA compared with the model group. The expression of MTL-R(1.46 ± 0.14, 1.26 ± 0.11, 0.99 ± 0.07 vs 0.65 ± 0.03, P < 0.001), and GAS-R(1.63 ± 0.11, 1.26 ± 0.16, 1.13 ± 0.02 vs 0.80 ± 0.11, P < 0.001) increased in the gastric antrum after EA compared with the model group. Damaging the PVN resulted in reduced intragastric pressure(13.67 ± 3.72 vs 4.27 ± 1.48, P < 0.001). These data demonstrate that the signals induced by EA stimulation of acupoints RN12 and BL21 are detectable in the DVC and the PVN, and increase the levels of gastrointestinal hormones and their receptors in the PVN and gastric antrum to regulate gastric motility. CONCLUSION: EA at RN12 and BL21 regulates gastric motility, which may be achieved through the PVN-DVCvagus-gastric neural pathway.展开更多
AIM： To investigate the effects of electrical stimulation of hypothalamic paraventricular nuclei （PVN） on gastric mucosal cellular apoptosis and proliferation induced by gastric ischemia/reperfusion （I/R） injury....AIM： To investigate the effects of electrical stimulation of hypothalamic paraventricular nuclei （PVN） on gastric mucosal cellular apoptosis and proliferation induced by gastric ischemia/reperfusion （I/R） injury. METHODS： For different experimental purposes, stimulating electrode plantation or electrolytic destruction of the PVN was applied, then the animals＇ GI/R injury model was established by clamping the celiac artery for 30 min and allowing reperfusing the artery for 30 rain, 1 h, 3 h or 6 h respectively. Then histological, immunohistochemistry methods were used to assess the gastric mucosal damage index, the gastric mucosal cellular apoptosis and proliferation at different times. RESULTS： The electrical stimulation of PVN significantly attenuated the GI/R injury at 30 min, i h and 3 h after reperfusion. The electrical stimulation of PVN decreased gastric mucosal apoptosis and increased gastric mucosal proliferation. The electrolytic destruction of the PVN could eliminate the protective effects of electrical stimulation of PVN on GI/R injury. These results indicated that the PVN participated in the regulation of GI/R injury as a specific area in the brain, exerting protective effects against the GI/R injury, and the protection was associated with the inhibition of cellular apoptosis and the promotion of gastric mucosal proliferation. CONCLUSION： Stimulating PVN significantly inhibits the gastric mucosal cellular apoptosis and promots gastric mucosal cellular proliferation. This may explain the protective mechanisms of electrical stimulation of PVN against GI/R injury.展开更多
Angiotensin(Ang)-(1–7) is an important biologically-active peptide of the renin-angiotensin system. This study was designed to determine whether inhibition of Ang-(1–7) in the hypothalamic paraventricular nucleus(PV...Angiotensin(Ang)-(1–7) is an important biologically-active peptide of the renin-angiotensin system. This study was designed to determine whether inhibition of Ang-(1–7) in the hypothalamic paraventricular nucleus(PVN) attenuates sympathetic activity and elevates blood pressure by modulating pro-inflammatory cytokines(PICs)and oxidative stress in the PVN in salt-induced hypertension. Rats were fed either a high-salt(8% NaCl) or a normal salt diet(0.3% NaCl) for 10 weeks, followed by bilateral microinjections of the Ang-(1–7) antagonist A-779 or vehicle into the PVN. We found that the mean arterial pressure(MAP), renal sympathetic nerve activity(RSNA), and plasma norepinephrine(NE) were significantly increased in salt-induced hypertensive rats. The high-salt diet also resulted in higher levels of the PICs interleukin-6, interleukin-1 beta, tumor necrosis factor alpha, and monocyte chemotactic protein-1, as well as higher gp91 phoxexpression and superoxide production in the PVN. Microinjection of A-779(3 nmol/50 nL) into the bilateral PVN of hypertensive rats not only attenuated MAP, RSNA, and NE, but also decreased the PICs and oxidative stress in the PVN. These results suggest that the increased MAP and sympathetic activity in salt-induced hypertension can be suppressed by blockade of endogenous Ang-(1–7) in the PVN, through modulation of PICs and oxidative stress.展开更多
Toll-like receptor 4 (TLR4) and cellular Src (cSrc) are closely associated with inflammatory cytokines and oxidative stress in hypertension, so we designed this study to explore the exact role of c-Src in the mechanis...Toll-like receptor 4 (TLR4) and cellular Src (cSrc) are closely associated with inflammatory cytokines and oxidative stress in hypertension, so we designed this study to explore the exact role of c-Src in the mechanism of action of the TLR4 signaling pathway in salt-induced hypertension. Salt-sensitive rats were given a high salt diet for 10 weeks to induce hypertension. This resulted in higher levels of TLR4, activated c-Src, pro-inflammatory cytokines, oxidative stress, and arterial pressure. Infusion of a TLR4 blocker into the hypothalamic paraventricular nucleus (PVN) decreased the activated c-Src, while microinjection of a c-Src inhibitor attenuated the PVN levels of nuclear factor-kappa B, pro-inflammatory cytokines, and oxidative stress. Our findings suggest that a longterm high-salt diet increases TLR4 expression in the PVN and this promotes the activation of c-Src, which upregulates the expression of pro-inflammatory cytokines and results in the overproduction of reactive oxygen species.Therefore, inhibiting central c-Src activity may be a new target for treating hypertension.展开更多
Differences in intravaginal ejaculation latency reflect normal biological variation, but the causes are poorly understood. Here, we investigated whether variation in ejaculation latency in an experimental rat model is...Differences in intravaginal ejaculation latency reflect normal biological variation, but the causes are poorly understood. Here, we investigated whether variation in ejaculation latency in an experimental rat model is related to altered sympathetic nervous system （SNS） activity and expression of N-methyI-D-aspartic acid （NMDA） receptors in the paraventricular nucleus of the hypothalamus （PVN）. Male rats were classified as ＂sluggish,＂ ＂normal,＂ and ＂rapid＂ ejaculators on the basis of ejaculation frequency during copulatory behavioral testing. The lumbar splanchnic nerve activity baselines in these groups were not significantly different at 1460±480 mV, 1660±600 mV, and 1680±490 mV, respectively （P = 0.71）. However, SNS sensitivity was remarkably different between the groups （P 〈 0.01）, being 28.9% ± 8.1% in ＂sluggish,＂ 48.4%±7.5% in ＂normal,＂ and 88.7% ~ 7.4% in ＂rapid＂ groups. Compared with ＂normal＂ ejaculators, the percentage of neurons expressing NMDA receptors in the PVN of ＂rapid＂ ejaculators was significantly higher, whereas it was significantly lower in ＂sluggish＂ ejaculators （P = 0.01）. In addition, there was a positive correlation between the expression of NMDA receptors in the PVN and SNS sensitivity （r = 0.876, P = 0.02）. This study shows that intravaginal ejaculatory latency is associated with SNS activity and is mediated by NMDA receptors in the PVN.展开更多
OBJECTIVE:To explore whether the paraventricular nucleus(PVN)participates in regulation of the antimyocardial ischemia-reperfusion injury(MIRI)effect of electroacupuncture(EA)and whether this is achieved through the P...OBJECTIVE:To explore whether the paraventricular nucleus(PVN)participates in regulation of the antimyocardial ischemia-reperfusion injury(MIRI)effect of electroacupuncture(EA)and whether this is achieved through the PVN-interposed nucleus(IN)neural pathway.METHODS:The modeling method of myocardial ischemia reperfusion injury was achieved by ligating the left anterior descending coronary artery in SpragueDawley rats.We used the Powerlab multi-channel physiological recorder system to record electrocardiograms and analyze the changes in ST segment displacement;2,3,5-Triphenyltetrazolium chloride staining was used to observe the percentage of myocardial infarction areas.Detecting cardiac troponin I(cTnI),lactate dehydrogenase(LDH)in serum was done with an enzyme-linked immunosorbent assay kit.Morphological changes in the myocardium were detected in each group with hematoxylin-eosin staining of paraffin sections.Detection of c-fos protein expression in the PVN of the hypothalamus was done with the immuneofluorescence method.The Plexon multi-channel acquisition system recorded PVN neuron discharges and local field potentials in each group of rats.Offline Sorter software was used for cluster analysis.Neuro Explorer software was used to perform autocorrelation,raster and frequency characteristics and spectral energy analysis of neuron signals in each group.RESULTS:Compared with the MIRI model group,the areas of myocardial infarction in the EA group were significantly reduced;the expression of cTnI,LDH in serum was decreased significantly.The firing frequency of pyramidal cells in the PVN was significantly increased and the spectrum energy map showed energy was reduced,c-fos expression in PVN was reduced,this indicated that neuronal activity in the PVN participates in the effect of EA improving myocardial injury.In addition,we used the kainic acid method to lesion the IN and observed that the effect of EA was weakened.For example,the area of myocardial infarction of lesion IN+EA group in rats was significantly increased compared with that resulting from EA group,the expression of cTnI,LDH in serum was significantly increased,the firing frequency of pyramidal cells in the PVN was significantly reduced.A spectral energy diagram shows that the energy after damage was higher than that of EA group.At the same time,the expression of c-fos in the PVN increased again.CONCLUSION:Our results indicated that the PVN-IN nerve pathway may participate as an effective pathway of EA to improve the effect of myocardial injury.展开更多
Sympathetic activation and the kidney play critical roles in hypertension and chronic heart failure.The role of the kidney in sympathetic activation is still not well known.In this study,we revealed an excitatory rena...Sympathetic activation and the kidney play critical roles in hypertension and chronic heart failure.The role of the kidney in sympathetic activation is still not well known.In this study,we revealed an excitatory renal reflex(ERR)in rats induced by chemical stimulation of the kidney that regulated sympathetic activity and blood pressure.The ERR was induced by renal infusion of capsaicin,and evaluated by the changes in renal sympathetic outflow,blood pressure,and heart rate.Renal infusion of capsaicin dose-dependently increased the contralateral renal sympathetic nerve activity,mean arterial pressure,and heart rate.Capsaicin in the corticomedullary border had greater effects than in the cortex or medulla.Intravenous infusion of capsaicin had no significant effects.The effects of renal infusion of capsaicin were abolished by ipsilateral renal denervation,but were not affected by bilateral sinoaortic denervation.Renal infusion of capsaicin increased the ipsilateral renal afferent activity.The ERR was also induced by renal infusion of bradykinin,adenosine,and angiotensin II,but not by ATP.Renal infusion of capsaicin increased c-Fos expression in the paraventricular nucleus(PVN)of hypothalamus.Lesion of neurons in the PVN with kainic acid abolished the capsaicin-induced ERR.These findings indicate that chemical stimulation of kidney causes an excitatory reflex,leading to sympathetic activation,pressor response,and accelerated heart rate.The PVN is an important central nucleus in the pathway of the ERR.展开更多
AIM To determine whether medullary catecholaminergic neurons expressing Fos induced by chemical stimulation of the stomach project to the paraventricular nucleus of hypothalamus (PVH) in rats. METHODS A triple labe...AIM To determine whether medullary catecholaminergic neurons expressing Fos induced by chemical stimulation of the stomach project to the paraventricular nucleus of hypothalamus (PVH) in rats. METHODS A triple labeling method of horseradish peroxidase (HRP) retrograde tracing combined with Fos (ABC method) and tyrosin hydroxylase (TH) (PAP method) immunohistochemical stainings was used in the present study. RESULTS Seven kinds of labeled neurons were found in the nucleus tractus solitarii (NTS), the ventrolateral medulla (VLM) and the reticular formation of the medulla (RF): Fos like immunoreactive (LI) neurons, TH LI neurons and HRP retrogradely single labeled neurons, Fos/HRP, Fos/TH and HRP/TH double labeled neurons, and Fos/HRP/TH triple labeled neurons. CONCLUSION Ascending projections from the NTS, VLM and RF to the PVH might be involved in the transmitting process of the visceral noxious stimulation.展开更多
Experimental autoimmune prostatitis(EAP)-induced persistent inflammatory immune response can significantly upregulate the expression of N-methyl-D-aspartic acid(NMDA)receptors in the paraventricular nucleus(PVN).Howev...Experimental autoimmune prostatitis(EAP)-induced persistent inflammatory immune response can significantly upregulate the expression of N-methyl-D-aspartic acid(NMDA)receptors in the paraventricular nucleus(PVN).However,the mechanism has not yet been elucidated.Herein,we screened out the target prostate-derived inflammation cytokines(PDICs)by comparing the inflammatory cytokine levels in peripheral blood and cerebrospinal fluid(CSF)between EAP rats and their controls.After identifying the target PDIC,qualified males in initial copulatory behavior testing(CBT)were subjected to implanting tubes onto bilateral PVN.Next,they were randomly divided into four subgroups(EAP-1,EAP-2,Control-1,and Control-2).After 1-week recovery,EAP-1 rats were microinjected with the target PDIC inhibitor,Control-1 rats were microinjected with the target PDIC,while the EAP-2 and Control-2 subgroups were only treated with the same amount of artificial CSF(aCSF).Results showed that only interleukin-1β(IL-1β)had significantly increased mRNA-expression in the prostate of EAP rats compared to the controls(P<0.001)and significantly higher protein concentrations in both the serum(P=0.001)and CSF(P<0.001)of the EAP groups compared to the Control groups.Therefore,IL-1βwas identified as the target PDIC which crosses the blood-brain barrier,thereby influencing the central nervous system.Moreover,the EAP-1 subgroup displayed a gradually prolonged ejaculation latency(EL)in the last three CBTs(all P<0.01)and a significantly lower expression of NMDA NR1 subunit in the PVN(P=0.043)compared to the respective control groups after a 10-day central administration of IL-1βinhibitors.However,the Control-1 subgroup showed a gradually shortened EL(P<0.01)and a significantly higher NR1 expression(P=0.004)after homochronous IL-1βadministration.Therefore,we identified IL-1βas the primary PDIC which shortens EL in EAP rats.However,further studies should be conducted to elucidate the specific molecular mechanisms through which IL-1βupregulates NMDA expression.展开更多
BACKGROUND:It has been confirmed that c-fos expression increased markedly in hypothalamic paraventricular nucleus(PVN)during asthmatic attack in rats,and PVN has extensive physiological functions,involving in the regu...BACKGROUND:It has been confirmed that c-fos expression increased markedly in hypothalamic paraventricular nucleus(PVN)during asthmatic attack in rats,and PVN has extensive physiological functions,involving in the regulation of respiratory system,etc.OBJECTIVE:To observe the alteration of electroencephalogram(EEG)and power spectra in PVN during the asthmatic attack,and the alteration of lung function and diaphragmatic muscle discharge after bilateral PVN lesion in asthmatic rats.DESIGN:A randomized control study.SETTING:Laboratory of Physiology and Pharmacology,School of Basic Medical Sciences,Southeast University.MATERIALS:Forty-eight male adult SD rats of 260-300 g were used.The rats were randomly divided into 6 groups(n=8):control group,asthma group,electrolytic lesion of PVN group,KA-induced lesion of PVN group,sham electrolytic lesion of PVN group and sham kainic acid(KA)-induced lesion of PVN group.KA,chicken ovalbumin and aluminum hydroxide were purchased from American Sigma Company.Bordetella pertussis vaccine(Institute of Biological Products of Shanghai);stereotaxic apparatus(JiangwanⅡ,China);lesion-producing device(YC-2 programmable stimulato,Chengdu Instrument Company);MD2000 signal processing system(Nanjing Medical School);data acquisition system(RM6240B,Chengdu Instrument Company).METHODs:The experiments were carried out in the Laboratory of Physiology and Pharmacology,School of Basic Medical Sciences,Southeast University from January to August in 2006.①Rats except for control group were sensitized with an intraperitoneal injection of 100 mg chicken ovalbumin and 100 mg aluminum hydroxide and Bordetella pertussis vaccine containing 5×10^(9) heat-killed in 1 mL of sterile saline.From the fifteenth to seventeenth days rats received three times aerosolized ovalbumin challenge.In rats of the control group and asthma group three steel electrodes were placed into the left PVN(AP-1.8 mm,LR 0.4 mm,OH-7.9 mm),parietal cortex and subcutaneous tissue in lower limb.Lung function tests were carried out simultaneously.Small holes were drilled in the skull to introduce a concentric bipolar electrode in the direction of the PVN in order to perform electrolytic lesion.The electrodes were connected to a lesion-producing device and a current of 1.0-1.5 mA was passed over a period of 10-15 s on each side of the PVN.The rats received 0.5μg/0.5μL of KA in phosphate buffer(0.1 mol/L,pH 7.4),and the speed of infusion was 0.1μL per minute in order to perform KA-induced lesion of PVN.②Three days after operation of lesion,lung function tests were carried out.All the electrode and transducer were connected with data acquisition system.This technique yielded airway resistance(Raw),dynamic compliance(Cdyn),the expiratory time(Te)/the inspiratory time(Ti),minute ventilation volume(MVV),EMGdi frequency and EMGdi integral.③The differences of the measurement data were compared using the t test.MAIN OUTCOME MEASURES:①The alteration of EEG and power spectrum of PVN during asthmatic attack in sensitized rats;②The effects of electrolytic lesion or KA-induced lesion of PVN on lung function in asthmatic rats.RESULTS:All the 48 rats were involved in the analysis of results.①Alteration of EEG and power spectrum:Five minutes after injection of ovalbumin into caudal vena,the breathing rate of the rat was obviously speeded up and the total power spectrum was increased[(18476.71±2140.94),(13838.75±2983.26)mV^(2),P<0.01],the percentage of theδpower andθpower decreased significantly(P<0.01),while the percentage ofαpower andβ1 power were enhanced(P<0.05,0.01).Ten minutes after injection,the EEG power spectrum of PVN further shifted rightward,the total power gradually increased(P<0.01)which suggesting that the intensive hypersynchrony activities of PVN neurons.The percentage ofδpower was decreased significantly(P<0.01),but theα,β1 andβ2 were increased(P<0.01).Twenty-five minutes later,the breathing movements became steady,and the EEG power spectrum of PVN returned to the control level step by step.②The alteration of lung function was detected during asthmatic attack after electrolytic lesion or KA-induced lesions of PVN respectively.It was found that EMGdi frequency,Te/Ti and RL were all decreased(P<0.01),EMGdi integral,MVV and Cdyn were all enhanced(P<0.01),while there were no significant changes in the sham surgery group(P>0.05).CONCLUSION:The excitability of PVN is increased during the asthmatic attack.PVN plays a key role in the regulation of asthma.Both electrolytic and KA lesions of PVN can significantly relieve the asthmatic symptoms of rats,and improve their lung function.展开更多
The paraventricular nucleus of the thalamus(PVT),which serves as a hub,receives dense projections from the medial prefrontal cortex(mPFC)and projects to the lateral division of central amygdala(CeL).The infralimbic(IL...The paraventricular nucleus of the thalamus(PVT),which serves as a hub,receives dense projections from the medial prefrontal cortex(mPFC)and projects to the lateral division of central amygdala(CeL).The infralimbic(IL)cortex plays a crucial role in encoding and recalling fear extinction memory.Here,we found that neurons in the PVT and IL were strongly activated during fear extinction retrieval.Silencing PVT neurons inhibited extinction retrieval at recent time point(24 h after extinction),while activating them promoted extinction retrieval at remote time point(7 d after extinction),suggesting a critical role of the PVT in extinction retrieval.In the mPFC-PVT circuit,projections from IL rather than prelimbic cortex to the PVT were dominant,and disrupting the IL-PVT projection suppressed extinction retrieval.Moreover,the axons of PVT neurons preferentially projected to the CeL.Silencing the PVT-CeL circuit also suppressed extinction retrieval.Together,our findings reveal a new neural circuit for fear extinction retrieval outside the classical IL-amygdala circuit.展开更多
The thalamus is the gate of the cerebral cortex, the ultimate target for the neural networks controlling behavioral states and cognitive functions. According to the reticular theory initially proposed by Moruzzi and M...The thalamus is the gate of the cerebral cortex, the ultimate target for the neural networks controlling behavioral states and cognitive functions. According to the reticular theory initially proposed by Moruzzi and Magoun, excitatory inputs from large reticular zones of the brainstem via widespread intra- and extra-thalamocortical systems finally activate the cerebral cortex to cause generalized cortical activation and wakefulness [1]. This theory proposes a central relay role to the thalamus for cortical activation as supported by early studies using neurodegeneration techniques and by the elegant work of Steriade’s group and other investigators illustrating the electrophysiological mechanisms of the thalamocortical system at the cellular level during wakefulness, rapid eye-movement sleep (REMs) and non-REM sleep (NREMs)[2].展开更多
基金Doctoral Research Fund Project of Qilu Hospital of Shandong University(Qingdao):Mechanistic Study on the Improvement of Vertigo Caused by Posterior Circulation Ischemia by Acupuncture through Regulating Cerebral Blood Flow in Rats with Posterior Circulation Ischemia Vertigo(No.QDKY2023BS19)National Natural Science Foundation of China:From Microrna 9 Regulate P2X7 Receptor of Microglia in Paraventricular Nucleus of Hypothalamus to Explore the Effect of Electroacupuncture on Sympathetic Nerve Excitability in Spontaneously Hypertensive Rats(No.82074553)。
文摘OBJECTIVE:To investigate the mechanism of electroacupuncture of sympathetic nerve activity and blood pressure reduction in the hypothalamic paraventricular nucleus(PVN)of spontaneous hypertensive rats(SHRs).METHODS:A total of 64 male SHRs were divided into four groups:model,sham-operated(Sham),electroacupuncture(EA),and N-methyl-D-aspartate receptor antagonist and electroacupuncture(NRA+EA).In addition,16 Wistar-Kyoto rats were used as controls.PVN stereotaxic surgery was performed in both the Sham and NRA+EA groups,while the EA and NRA+EA groups received 14 d of electroacupuncture.Blood pressure(BP)and heart rate(HR)were measured the day before the intervention and every other day.After 14 d of intervention,the rats in each group were tested for renal sympathetic nerve activity(RSNA).The associated factor levels were determined using Western blotting,reverse transcription-polymerase chain reaction(RTPCR),enzyme-linked immunosorbent assay(ELISA)and immunofluorescence assays.RESULTS:In comparison to the model group,the EA and NRA+EA groups had significantly lower BP,HR,and RSNA(P<0.01).The expression of N-methyl-Daspartate receptor(NMDAR),angiotensin II(Ang II),angiotensin II type 1(AT1),tumor necrosis factor-α,interleukin-1β,norepinephrine and arginine vasopressin was significantly lower in the EA and NRA+EA groups(P<0.01).Moreover,the antihypertensive effect of NRA+EA group outperformed to the EA group.CONCLUSIONS:Electroacupuncture effectively reduced the BP and sympathetic nerve excitability in SHRs.The mechanism was linked to the inhibition of NMDARmediated Ang II/AT1 and the inflammatory response in PVN.
文摘The somatotopic representation of specific body parts is a well-established spatial organizational principle in the primary somatosensory and motor cortices.
基金Supported by the Excellent Youth Project of Anhui Universities,No.2022AH030065National Natural Science Foundation of China,No.82474224 and No.82405244+3 种基金Anhui Provincial Natural Science Foundation,No.2408085MH223Open Projects of Anhui Province Key Laboratory of Meridian Viscera Correlationship,No.2024AHMVC04Research Project of Xin’an Medical and Chinese Medicine Modernization Research Institute,No.2023CXMMTCM016the Anhui Province Scientific Research Planning Project,No.2022AH050438.
文摘BACKGROUND Visceral hypersensitivity is the core pathogenesis of irritable bowel syndrome(IBS)and is often accompanied by negative emotions such as anxiety or depression.Paraventricular hypothalamic nucleus(PVN)corticotropin-releasing factor(CRF)is involved in the stress-related gastrointestinal dysfunction.Electroacupuncture(EA)has unique advantages for the treatment of visceral hypersensitivity and negative emotions in IBS patients.However,the underlying mechanisms remain unclear.AIM To investigate the pathological mechanisms visceral hypersensitivity and negative emotions in IBS,as well as the effect mechanism of EA.METHODS A model of diarrhoeal IBS(IBS-D)with negative emotions was prepared by chronic restraint combined with glacial acetic acid enema.The effect of EA was verified by abdominal withdrawal reflex and open-field test.PVN CRFcolonic mast cell(MC)/transient potential receptor vanilloid type 1(TRPV1)pathway was detected by immunofluorescence,Western blot,ELISA,and toluidine blue staining.Moreover,PVN CRFergic neurons were activated or inhibited by chemogenetical technique to observe the changes of effect indicator.RESULTS In the model group,IBS-D symptoms and negative emotions were successfully induced.Notably,the combination of Baihui(GV20)with Tianshu(ST25)and Dachangshu(BL25)acupoints showed the greatest efficacy in improving the negative emotions and visceral hypersensitivity in model mice.Furthermore,we found that EA inhibited overactivated PVN CRFergic neurons and the overexpression of serum CRF,colonic CRF,CRF-receptor 1(CRFR1),mast cell tryptase(MCT),protease-activated receptor 2 and TRPV1 in model mice.Moreover,we found that activating PVN CRFergic neurons induced negative emotions and visceral hypersensitivity in normal mice;however,inhibiting PVN CRFergic neurons alleviated negative emotions and intestinal symptoms in model mice and decreased the expression of colonic CRF-R1,MCT,and TRPV1.CONCLUSION This research highlights the key role of PVN CRF-MC CRF-R1 and the downstream MC/TRPV1 pathway in the pathological process of IBS-D and the mechanism of the effect of EA.
基金supported by grants from the National Natural Science Foundation of China(No.82174496,No.82374574)Shanghai Key Discipline of Traditional Chinese Medicine Construction Project(No.shzyyzdxk–2024113)。
文摘Objective:This study investigates the sleep-modulating effects of ginsenoside Rg1(Rg1,C_(42)H_(72)O_(14)),a key bioactive component of ginseng,and elucidates its underlying mechanisms.Methods:C57BL/6J mice were intraperitoneally administered doses of Rg1 ranging from 12.5 to100 mg/kg.Sleep parameters were assessed to determine the average duration of each sleep stage by monitoring the electrical activity of the brain and muscles.Further,orexin neurons in the lateral hypothalamus(LH)and corticotropin-releasing hormone(CRH)neurons in the paraventricular hypothalamic nucleus(PVH)were ablated using viral vector surgery and electrode embedding.The excitability of LH^(orexin)and PVH^(CRH)neurons was evaluated through the measurement of cellular Finkel-Biskis-Jinkins murine osteosarcoma viral oncogene homolog(c-Fos)expression.Results:Rg1(12.5–100 mg/kg)augmented the duration of non-rapid eye movement(NREM)sleep phases,while reducing the duration of wakefulness,in a dose dependent manner.The reduced latency from wakefulness to NREM sleep indicates an accelerated sleep initiation time.We found that these sleep-promoting effects were weakened in the LH^(orexin)and PVH^(CRH)neuron ablation groups,and disappeared in the orexin and CRH double-ablation group.Decreased c-Fos protein expression in the LH and PVH confirmed that Rg1 promoted NREM sleep by inhibiting orexin and CRH neurons.Conclusion:Rg1 increases the duration of NREM sleep,underscoring the essential roles of LH^(orexin)and PVH^(CRH)neurons in facilitating the sleep-promoting effects of Rg1.Please cite this article as:Wang YY,Wu Y,Yu KW,Xie HY,Gui Y,Chen CR,Wang NH.Ginsenoside Rg1 promotes non-rapid eye movement sleep via inhibition of orexin neurons of the lateral hypothalamus and corticotropin-releasing hormone neurons of the paraventricular hypothalamic nucleus.J Integr Med.2024;22(6):719–728.
文摘Objective To study the central role of ginkgolide B （BN52021） in regulating cardiovascular function of nerve center by examining the effects of ginkgolide B on the electrical activity of rat paraventricular nucleus （PVN） neurons in hypothalamic slice preparation and to elucidate the mechanism involved. Methods Extracellular single-unit discharge recording technique. Results （1） In response to the application of ginkgolide t3 （0.1, 1, 10 μmol/L; n = 27） into the perfusate for 2 rain, the spontaneous discharge rates （SDR） of 26 （26/27, 96.30%） neurons were significantly decreased in a dose-dependent manner. （2） Pretreatment with L-glutamate （L-Glu, 0.2 mmol/L） led to a marked increase in the SDR of all 8 （100%） neurons in an epileptiform pattern. The increased discharges were suppressed significantly after ginkgolide B （1 μmol/L） was applied into the perfusate for 2 min. （3） In 8 neurons, perfusion of the selective L-type calcium channel agonist, Bay K 8644 （0.1 μmol/L）, induced a significant increase in the discharge rates of 8 （8/8, 100%） neurons, while ginkgolide B （1μmol/L） applied into the perfusate, could inhibit the discharges of 8 （100%） neurons. （4） In 8 neurons, the broad potassium channels blocker, tetraethylammonium （TEA, 1 mmol/L） completely blocked the inhibitory effect of ginkgolide B （1 μmol/L）. Conclusion These results suggest that ginkgolide B can inhibit the electrical activity of paraventricular neurons. The inhibitory effect may be related to the blockade of L-type voltage-activated calcium channel and potentially concerned with delayed rectifier potassium channel （KDR）.
基金supported by the National Natural Science Foundation of China(81000106 and81470539)
文摘Intermedin/adrenomedullin-2(IMD/AM2), a member of the calcitonin gene-related peptide/AM family,plays an important role in protecting the cardiovascular system. However, its role in the enhanced sympathoexcitation in obesity-related hypertension is unknown. In this study, we investigated the effects of IMD in the paraventricular nucleus(PVN) of the hypothalamus on sympathetic nerve activity(SNA), and lipopolysaccharide(LPS)-induced sympathetic activation in obesity-related hypertensive(OH)rats induced by a high-fat diet for 12 weeks. Acute experiments were performed under anesthesia. The dynamic alterations of sympathetic outflow were evaluated as changes in renal SNA and mean arterial pressure(MAP) in response to specific drugs. Male rats were fed a control diet(12% kcal as fat) or a high-fat diet(42% kcal as fat) for 12 weeks to induce OH. The results showed that IMD protein in the PVN was downregulated, but Toll-like receptor 4(TLR4) and plasma norepinephrine(NE, indicating sympathetic hyperactivity) levels, and systolic blood pressure were increased in OH rats. LPS(0.5 lg/50 nL)-induced enhancement of renal SNA and MAP was greater in OH rats than in obese or control rats. Bilateral PVN microinjection of IMD(50 pmol)caused greater decreases in renal SNA and MAP in OH rats than in control rats, and inhibited LPS-induced sympatheticactivation, and these were effectively prevented in OH rats by pretreatment with the AM receptor antagonist AM22-52.The mitogen-activated protein kinase/extracellular signalregulated kinase(ERK) inhibitor U0126 in the PVN partially reversed the LPS-induced enhancement of SNA. However,IMD in the PVN decreased the LPS-induced ERK activation,which was also effectively prevented by AM22-52. Chronic IMD administration resulted in significant reductions in the plasma NE level and blood pressure in OH rats. Moreover,IMD lowered the TLR4 protein expression and ERK activation in the PVN, and decreased the LPS-induced sympathetic overactivity. These results indicate that IMD in the PVN attenuates SNA and hypertension, and decreases the ERK activation implicated in the LPS-induced enhancement of SNA in OH rats, and this is mediated by AM receptors.
文摘AIM: To investigate the effect and mechanism of stimulation of the hypothalamic paraventricular nucleus with glutamate acid in rats with ulcerative colitis(UC).METHODS: The rats were anesthetized with 10% chloral hydrate via abdominal injection and treated with an equal volume of TNBS + 50% ethanol enema, injected into the upper section of the anus with the tail facing up. Colonic damage scores were calculated after injecting a certain dose of glutamic acid into the paraventricular nucleus(p VN), and the effect of the nucleus tractus solitarius(NTS) and vagus nerve in alleviating UC injury through chemical stimulation of the p VN was observed in rats. Expression changes of C-myc, Apaf-1, caspase-3, interleukin(IL)-6, and IL-17 during the protection against UC injury through chemical stimulation of the p VN in rats were detected by Western blot. Malondialdehyde(MDA) content and superoxide dismutase(SOD) activity in colon tissues of rats were measured by colorimetric methods. RESULTS: Chemical stimulation of the PVN significantly reduced UC in rats in a dose-dependent manner. The protective effects of the chemical stimulationof the p VN on rats with UC were eliminated after chemical damage to the p VN. After glutamate receptor antagonist kynurenic acid was injected into the p VN, the protective effects of the chemical stimulation of the p VN were eliminated in rats with UC. After AVpVl receptor antagonist([Deamino-penl, val4, D-Arg8]-vasopressin) was injected into NTS or bilateral chemical damage to NTS, the protective effect of the chemical stimulation of p VN on UC was also eliminated. After chemical stimulation of the p VN, SOD activity increased, MDA content decreased, C-myc protein expression significantly increased, caspase-3 and Apaf-1 protein expression significantly decreased, and IL-6 and IL-17 expression decreased in colon tissues in rats with UC. CONCLUSION: Chemical stimulation of the hypothalamic p VN provides a protective effect against UC injury in rats. Hypothalamic p VN, NTS and vagus nerve play key roles in this process.
基金supported by the National Natural Science Foundation of China(81600333,81770426,81800372,91439120,and 91639105)the Postdoctoral Science Foundation of China(2016M602835,2017M620457)the Postdoctoral Science Foundation of Shaanxi Province,China(2016BSHEDZZ91)
文摘Metformin(MET), an antidiabetic agent, also has antioxidative effects in metabolic-related hypertension.This study was designed to determine whether MET has anti-hypertensive effects in salt-sensitive hypertensive rats by inhibiting oxidative stress in the hypothalamic paraventricular nucleus(PVN). Salt-sensitive rats received a highsalt(HS) diet to induce hypertension, or a normal-salt(NS)diet as control. At the same time, they received intracerebroventricular(ICV) infusion of MET or vehicle for 6 weeks. We found that HS rats had higher oxidative stress levels and mean arterial pressure(MAP) than NS rats. ICV infusion of MET attenuated MAP and reduced plasma norepinephrine levels in HS rats. It also decreased reactive oxygen species and the expression of subunits of NAD(P)H oxidase, improved the superoxide dismutase activity,reduced components of the renin-angiotensin system, and altered neurotransmitters in the PVN. Our findings suggest that central MET administration lowers MAP in saltsensitive hypertension via attenuating oxidative stress,inhibiting the renin-angiotensin system, and restoring the balance between excitatory and inhibitory neurotransmitters in the PVN.
基金Supported by The National Nature Science Foundation Council of ChinaNo.81473784+3 种基金the Natural Science Foundation of Anhui ProvinceNo.1408085MH166the Natural Science Foundation of Anhui University of Traditional Chinese MedicineNo.2013qn002
文摘AIM: To study the neural mechanism by which electroacupuncture(EA) at RN12(Zhongwan) and BL21(Weishu) regulates gastric motility.METHODS: One hundred and forty-four adult Sprague Dawley rats were studied in four separate experiments. Intragastric pressure was measured using custommade rubber balloons, and extracellular neuron firing activity, which is sensitive to gastric distention in the dorsal vagal complex(DVC), was recorded by an electrophysiological technique. The expression levels of c-fos, motilin(MTL) and gastrin(GAS) in the paraventricular hypothalamic nucleus(PVN) were assayed by immunohistochemistry, and the expression levels of motilin receptor(MTL-R) and gastrin receptor(GAS-R) in both the PVN and the gastric antrum were assayed by western blotting.RESULTS: EA at RN12 + BL21(gastric Shu and Mu points), BL21(gastric Back-Shu point), RN12(gastric Front-Mu point), resulted in increased neuron-activating frequency in the DVC(2.08 ± 0.050, 1.17 ± 0.023, 1.55 ± 0.079 vs 0.75 ± 0.046, P < 0.001) compared with a model group. The expression of c-fos(36.24 ± 1.67, 29.41 ± 2.55, 31.79 ± 3.00 vs 5.73 ± 2.18, P < 0.001), MTL(22.48 ± 2.66, 20.76 ± 2.41, 19.17 ± 1.71 vs 11.68 ± 2.52, P < 0.001), GAS(24.99 ± 2.95, 21.69 ± 3.24, 23.03 ± 3.09 vs 12.53 ± 2.15, P < 0.001), MTL-R(1.39 ± 0.05, 1.22 ± 0.05, 1.17 ± 0.12 vs 0.84 ± 0.06, P < 0.001), and GAS-R(1.07 ± 0.07, 0.91 ± 0.06, 0.78 ± 0.05 vs 0.45 ± 0.04, P < 0.001) increased in the PVN after EA compared with the model group. The expression of MTL-R(1.46 ± 0.14, 1.26 ± 0.11, 0.99 ± 0.07 vs 0.65 ± 0.03, P < 0.001), and GAS-R(1.63 ± 0.11, 1.26 ± 0.16, 1.13 ± 0.02 vs 0.80 ± 0.11, P < 0.001) increased in the gastric antrum after EA compared with the model group. Damaging the PVN resulted in reduced intragastric pressure(13.67 ± 3.72 vs 4.27 ± 1.48, P < 0.001). These data demonstrate that the signals induced by EA stimulation of acupoints RN12 and BL21 are detectable in the DVC and the PVN, and increase the levels of gastrointestinal hormones and their receptors in the PVN and gastric antrum to regulate gastric motility. CONCLUSION: EA at RN12 and BL21 regulates gastric motility, which may be achieved through the PVN-DVCvagus-gastric neural pathway.
基金grants from the National Natural Science Foundation of China, No. 30370533, 30570671the Educational Department Science Research Foundation of Jiangsu Province, No. 99KJB310005,05KJB310134
文摘AIM： To investigate the effects of electrical stimulation of hypothalamic paraventricular nuclei （PVN） on gastric mucosal cellular apoptosis and proliferation induced by gastric ischemia/reperfusion （I/R） injury. METHODS： For different experimental purposes, stimulating electrode plantation or electrolytic destruction of the PVN was applied, then the animals＇ GI/R injury model was established by clamping the celiac artery for 30 min and allowing reperfusing the artery for 30 rain, 1 h, 3 h or 6 h respectively. Then histological, immunohistochemistry methods were used to assess the gastric mucosal damage index, the gastric mucosal cellular apoptosis and proliferation at different times. RESULTS： The electrical stimulation of PVN significantly attenuated the GI/R injury at 30 min, i h and 3 h after reperfusion. The electrical stimulation of PVN decreased gastric mucosal apoptosis and increased gastric mucosal proliferation. The electrolytic destruction of the PVN could eliminate the protective effects of electrical stimulation of PVN on GI/R injury. These results indicated that the PVN participated in the regulation of GI/R injury as a specific area in the brain, exerting protective effects against the GI/R injury, and the protection was associated with the inhibition of cellular apoptosis and the promotion of gastric mucosal proliferation. CONCLUSION： Stimulating PVN significantly inhibits the gastric mucosal cellular apoptosis and promots gastric mucosal cellular proliferation. This may explain the protective mechanisms of electrical stimulation of PVN against GI/R injury.
基金supported by the National Natural Science Foundation of China(81600333,81770426,91439120,and 91639105)the China Postdoctoral Science Foundation(2016M602835 and 2016M592802)the Shaanxi Postdoctoral Science Foundation(2016BSHEDZZ91)
文摘Angiotensin(Ang)-(1–7) is an important biologically-active peptide of the renin-angiotensin system. This study was designed to determine whether inhibition of Ang-(1–7) in the hypothalamic paraventricular nucleus(PVN) attenuates sympathetic activity and elevates blood pressure by modulating pro-inflammatory cytokines(PICs)and oxidative stress in the PVN in salt-induced hypertension. Rats were fed either a high-salt(8% NaCl) or a normal salt diet(0.3% NaCl) for 10 weeks, followed by bilateral microinjections of the Ang-(1–7) antagonist A-779 or vehicle into the PVN. We found that the mean arterial pressure(MAP), renal sympathetic nerve activity(RSNA), and plasma norepinephrine(NE) were significantly increased in salt-induced hypertensive rats. The high-salt diet also resulted in higher levels of the PICs interleukin-6, interleukin-1 beta, tumor necrosis factor alpha, and monocyte chemotactic protein-1, as well as higher gp91 phoxexpression and superoxide production in the PVN. Microinjection of A-779(3 nmol/50 nL) into the bilateral PVN of hypertensive rats not only attenuated MAP, RSNA, and NE, but also decreased the PICs and oxidative stress in the PVN. These results suggest that the increased MAP and sympathetic activity in salt-induced hypertension can be suppressed by blockade of endogenous Ang-(1–7) in the PVN, through modulation of PICs and oxidative stress.
基金supported by the National Natural Science Foundation of China (81770426, 81600333, 81600330, and 81800373)China Postdoctoral Science Foundation (2016M602835)Shaanxi Postdoctoral Science Foundation (2016BSHEDZZ91).
文摘Toll-like receptor 4 (TLR4) and cellular Src (cSrc) are closely associated with inflammatory cytokines and oxidative stress in hypertension, so we designed this study to explore the exact role of c-Src in the mechanism of action of the TLR4 signaling pathway in salt-induced hypertension. Salt-sensitive rats were given a high salt diet for 10 weeks to induce hypertension. This resulted in higher levels of TLR4, activated c-Src, pro-inflammatory cytokines, oxidative stress, and arterial pressure. Infusion of a TLR4 blocker into the hypothalamic paraventricular nucleus (PVN) decreased the activated c-Src, while microinjection of a c-Src inhibitor attenuated the PVN levels of nuclear factor-kappa B, pro-inflammatory cytokines, and oxidative stress. Our findings suggest that a longterm high-salt diet increases TLR4 expression in the PVN and this promotes the activation of c-Src, which upregulates the expression of pro-inflammatory cytokines and results in the overproduction of reactive oxygen species.Therefore, inhibiting central c-Src activity may be a new target for treating hypertension.
文摘Differences in intravaginal ejaculation latency reflect normal biological variation, but the causes are poorly understood. Here, we investigated whether variation in ejaculation latency in an experimental rat model is related to altered sympathetic nervous system （SNS） activity and expression of N-methyI-D-aspartic acid （NMDA） receptors in the paraventricular nucleus of the hypothalamus （PVN）. Male rats were classified as ＂sluggish,＂ ＂normal,＂ and ＂rapid＂ ejaculators on the basis of ejaculation frequency during copulatory behavioral testing. The lumbar splanchnic nerve activity baselines in these groups were not significantly different at 1460±480 mV, 1660±600 mV, and 1680±490 mV, respectively （P = 0.71）. However, SNS sensitivity was remarkably different between the groups （P 〈 0.01）, being 28.9% ± 8.1% in ＂sluggish,＂ 48.4%±7.5% in ＂normal,＂ and 88.7% ~ 7.4% in ＂rapid＂ groups. Compared with ＂normal＂ ejaculators, the percentage of neurons expressing NMDA receptors in the PVN of ＂rapid＂ ejaculators was significantly higher, whereas it was significantly lower in ＂sluggish＂ ejaculators （P = 0.01）. In addition, there was a positive correlation between the expression of NMDA receptors in the PVN and SNS sensitivity （r = 0.876, P = 0.02）. This study shows that intravaginal ejaculatory latency is associated with SNS activity and is mediated by NMDA receptors in the PVN.
基金Supported by National Natural Science Foundation of China:Mechanism of GABA/Glu Neural Circuit in Lateral HypothalamusParietal Nucleus in Alleviating Myocardial Ischemia-Reperfusion Injury by Acupuncture Preconditioning(82074536)Study on the Protective Effect of Acupuncture Pretreatment on Myocardial Ischemia-Reperfusion Injury Based on Hypothalamic-Cerebellar Neural Circuit(81774414)+2 种基金Mechanism of GABA Neural Circuit in the Paraventricular Nucleus of Hypothalamus and Ventrolateral Region of Medulla Oblongata in Alleviating Myocardial Ischemia-Reperfusion Injury Induced by Acupuncture Pretreatment(82104999)Natural Science Foundation of Anhui Province the Central Regulatory Mechanism of Acupuncture Regulating Cardiac Function(2108085Y30)Anhui Province University Outstanding Top Talent Cultivation Funding Project(gxgwfx2019025)
文摘OBJECTIVE:To explore whether the paraventricular nucleus(PVN)participates in regulation of the antimyocardial ischemia-reperfusion injury(MIRI)effect of electroacupuncture(EA)and whether this is achieved through the PVN-interposed nucleus(IN)neural pathway.METHODS:The modeling method of myocardial ischemia reperfusion injury was achieved by ligating the left anterior descending coronary artery in SpragueDawley rats.We used the Powerlab multi-channel physiological recorder system to record electrocardiograms and analyze the changes in ST segment displacement;2,3,5-Triphenyltetrazolium chloride staining was used to observe the percentage of myocardial infarction areas.Detecting cardiac troponin I(cTnI),lactate dehydrogenase(LDH)in serum was done with an enzyme-linked immunosorbent assay kit.Morphological changes in the myocardium were detected in each group with hematoxylin-eosin staining of paraffin sections.Detection of c-fos protein expression in the PVN of the hypothalamus was done with the immuneofluorescence method.The Plexon multi-channel acquisition system recorded PVN neuron discharges and local field potentials in each group of rats.Offline Sorter software was used for cluster analysis.Neuro Explorer software was used to perform autocorrelation,raster and frequency characteristics and spectral energy analysis of neuron signals in each group.RESULTS:Compared with the MIRI model group,the areas of myocardial infarction in the EA group were significantly reduced;the expression of cTnI,LDH in serum was decreased significantly.The firing frequency of pyramidal cells in the PVN was significantly increased and the spectrum energy map showed energy was reduced,c-fos expression in PVN was reduced,this indicated that neuronal activity in the PVN participates in the effect of EA improving myocardial injury.In addition,we used the kainic acid method to lesion the IN and observed that the effect of EA was weakened.For example,the area of myocardial infarction of lesion IN+EA group in rats was significantly increased compared with that resulting from EA group,the expression of cTnI,LDH in serum was significantly increased,the firing frequency of pyramidal cells in the PVN was significantly reduced.A spectral energy diagram shows that the energy after damage was higher than that of EA group.At the same time,the expression of c-fos in the PVN increased again.CONCLUSION:Our results indicated that the PVN-IN nerve pathway may participate as an effective pathway of EA to improve the effect of myocardial injury.
基金supported by the National Natural Science Foundation of China(31871148,91639105,31571167,and 31571168).
文摘Sympathetic activation and the kidney play critical roles in hypertension and chronic heart failure.The role of the kidney in sympathetic activation is still not well known.In this study,we revealed an excitatory renal reflex(ERR)in rats induced by chemical stimulation of the kidney that regulated sympathetic activity and blood pressure.The ERR was induced by renal infusion of capsaicin,and evaluated by the changes in renal sympathetic outflow,blood pressure,and heart rate.Renal infusion of capsaicin dose-dependently increased the contralateral renal sympathetic nerve activity,mean arterial pressure,and heart rate.Capsaicin in the corticomedullary border had greater effects than in the cortex or medulla.Intravenous infusion of capsaicin had no significant effects.The effects of renal infusion of capsaicin were abolished by ipsilateral renal denervation,but were not affected by bilateral sinoaortic denervation.Renal infusion of capsaicin increased the ipsilateral renal afferent activity.The ERR was also induced by renal infusion of bradykinin,adenosine,and angiotensin II,but not by ATP.Renal infusion of capsaicin increased c-Fos expression in the paraventricular nucleus(PVN)of hypothalamus.Lesion of neurons in the PVN with kainic acid abolished the capsaicin-induced ERR.These findings indicate that chemical stimulation of kidney causes an excitatory reflex,leading to sympathetic activation,pressor response,and accelerated heart rate.The PVN is an important central nucleus in the pathway of the ERR.
文摘AIM To determine whether medullary catecholaminergic neurons expressing Fos induced by chemical stimulation of the stomach project to the paraventricular nucleus of hypothalamus (PVH) in rats. METHODS A triple labeling method of horseradish peroxidase (HRP) retrograde tracing combined with Fos (ABC method) and tyrosin hydroxylase (TH) (PAP method) immunohistochemical stainings was used in the present study. RESULTS Seven kinds of labeled neurons were found in the nucleus tractus solitarii (NTS), the ventrolateral medulla (VLM) and the reticular formation of the medulla (RF): Fos like immunoreactive (LI) neurons, TH LI neurons and HRP retrogradely single labeled neurons, Fos/HRP, Fos/TH and HRP/TH double labeled neurons, and Fos/HRP/TH triple labeled neurons. CONCLUSION Ascending projections from the NTS, VLM and RF to the PVH might be involved in the transmitting process of the visceral noxious stimulation.
基金This work was supported by the National Natural Science Foundation of China(Grant No.81501245 and No.81971377)Fellowship of China Postdoctoral Science Foundation(Grant No.2020M671393)Jiangsu Province Postdoctoral Research Support Project(Grant No.2020Z134).
文摘Experimental autoimmune prostatitis(EAP)-induced persistent inflammatory immune response can significantly upregulate the expression of N-methyl-D-aspartic acid(NMDA)receptors in the paraventricular nucleus(PVN).However,the mechanism has not yet been elucidated.Herein,we screened out the target prostate-derived inflammation cytokines(PDICs)by comparing the inflammatory cytokine levels in peripheral blood and cerebrospinal fluid(CSF)between EAP rats and their controls.After identifying the target PDIC,qualified males in initial copulatory behavior testing(CBT)were subjected to implanting tubes onto bilateral PVN.Next,they were randomly divided into four subgroups(EAP-1,EAP-2,Control-1,and Control-2).After 1-week recovery,EAP-1 rats were microinjected with the target PDIC inhibitor,Control-1 rats were microinjected with the target PDIC,while the EAP-2 and Control-2 subgroups were only treated with the same amount of artificial CSF(aCSF).Results showed that only interleukin-1β(IL-1β)had significantly increased mRNA-expression in the prostate of EAP rats compared to the controls(P<0.001)and significantly higher protein concentrations in both the serum(P=0.001)and CSF(P<0.001)of the EAP groups compared to the Control groups.Therefore,IL-1βwas identified as the target PDIC which crosses the blood-brain barrier,thereby influencing the central nervous system.Moreover,the EAP-1 subgroup displayed a gradually prolonged ejaculation latency(EL)in the last three CBTs(all P<0.01)and a significantly lower expression of NMDA NR1 subunit in the PVN(P=0.043)compared to the respective control groups after a 10-day central administration of IL-1βinhibitors.However,the Control-1 subgroup showed a gradually shortened EL(P<0.01)and a significantly higher NR1 expression(P=0.004)after homochronous IL-1βadministration.Therefore,we identified IL-1βas the primary PDIC which shortens EL in EAP rats.However,further studies should be conducted to elucidate the specific molecular mechanisms through which IL-1βupregulates NMDA expression.
基金the Scientific Foundation of the Ministry of Railway,No.6747600045
文摘BACKGROUND:It has been confirmed that c-fos expression increased markedly in hypothalamic paraventricular nucleus(PVN)during asthmatic attack in rats,and PVN has extensive physiological functions,involving in the regulation of respiratory system,etc.OBJECTIVE:To observe the alteration of electroencephalogram(EEG)and power spectra in PVN during the asthmatic attack,and the alteration of lung function and diaphragmatic muscle discharge after bilateral PVN lesion in asthmatic rats.DESIGN:A randomized control study.SETTING:Laboratory of Physiology and Pharmacology,School of Basic Medical Sciences,Southeast University.MATERIALS:Forty-eight male adult SD rats of 260-300 g were used.The rats were randomly divided into 6 groups(n=8):control group,asthma group,electrolytic lesion of PVN group,KA-induced lesion of PVN group,sham electrolytic lesion of PVN group and sham kainic acid(KA)-induced lesion of PVN group.KA,chicken ovalbumin and aluminum hydroxide were purchased from American Sigma Company.Bordetella pertussis vaccine(Institute of Biological Products of Shanghai);stereotaxic apparatus(JiangwanⅡ,China);lesion-producing device(YC-2 programmable stimulato,Chengdu Instrument Company);MD2000 signal processing system(Nanjing Medical School);data acquisition system(RM6240B,Chengdu Instrument Company).METHODs:The experiments were carried out in the Laboratory of Physiology and Pharmacology,School of Basic Medical Sciences,Southeast University from January to August in 2006.①Rats except for control group were sensitized with an intraperitoneal injection of 100 mg chicken ovalbumin and 100 mg aluminum hydroxide and Bordetella pertussis vaccine containing 5×10^(9) heat-killed in 1 mL of sterile saline.From the fifteenth to seventeenth days rats received three times aerosolized ovalbumin challenge.In rats of the control group and asthma group three steel electrodes were placed into the left PVN(AP-1.8 mm,LR 0.4 mm,OH-7.9 mm),parietal cortex and subcutaneous tissue in lower limb.Lung function tests were carried out simultaneously.Small holes were drilled in the skull to introduce a concentric bipolar electrode in the direction of the PVN in order to perform electrolytic lesion.The electrodes were connected to a lesion-producing device and a current of 1.0-1.5 mA was passed over a period of 10-15 s on each side of the PVN.The rats received 0.5μg/0.5μL of KA in phosphate buffer(0.1 mol/L,pH 7.4),and the speed of infusion was 0.1μL per minute in order to perform KA-induced lesion of PVN.②Three days after operation of lesion,lung function tests were carried out.All the electrode and transducer were connected with data acquisition system.This technique yielded airway resistance(Raw),dynamic compliance(Cdyn),the expiratory time(Te)/the inspiratory time(Ti),minute ventilation volume(MVV),EMGdi frequency and EMGdi integral.③The differences of the measurement data were compared using the t test.MAIN OUTCOME MEASURES:①The alteration of EEG and power spectrum of PVN during asthmatic attack in sensitized rats;②The effects of electrolytic lesion or KA-induced lesion of PVN on lung function in asthmatic rats.RESULTS:All the 48 rats were involved in the analysis of results.①Alteration of EEG and power spectrum:Five minutes after injection of ovalbumin into caudal vena,the breathing rate of the rat was obviously speeded up and the total power spectrum was increased[(18476.71±2140.94),(13838.75±2983.26)mV^(2),P<0.01],the percentage of theδpower andθpower decreased significantly(P<0.01),while the percentage ofαpower andβ1 power were enhanced(P<0.05,0.01).Ten minutes after injection,the EEG power spectrum of PVN further shifted rightward,the total power gradually increased(P<0.01)which suggesting that the intensive hypersynchrony activities of PVN neurons.The percentage ofδpower was decreased significantly(P<0.01),but theα,β1 andβ2 were increased(P<0.01).Twenty-five minutes later,the breathing movements became steady,and the EEG power spectrum of PVN returned to the control level step by step.②The alteration of lung function was detected during asthmatic attack after electrolytic lesion or KA-induced lesions of PVN respectively.It was found that EMGdi frequency,Te/Ti and RL were all decreased(P<0.01),EMGdi integral,MVV and Cdyn were all enhanced(P<0.01),while there were no significant changes in the sham surgery group(P>0.05).CONCLUSION:The excitability of PVN is increased during the asthmatic attack.PVN plays a key role in the regulation of asthma.Both electrolytic and KA lesions of PVN can significantly relieve the asthmatic symptoms of rats,and improve their lung function.
基金This work was supported by the National Natural Science Foundation of China(31530091 and 81870912)the National Key Research and Development Program of China(2016YFC1306703)+1 种基金the Science and Technology Program of Guangdong Province,China(2018B030334001)the Collaborative Innovation Center for Cardiovascular Disease Translational Medicine,China.
文摘The paraventricular nucleus of the thalamus(PVT),which serves as a hub,receives dense projections from the medial prefrontal cortex(mPFC)and projects to the lateral division of central amygdala(CeL).The infralimbic(IL)cortex plays a crucial role in encoding and recalling fear extinction memory.Here,we found that neurons in the PVT and IL were strongly activated during fear extinction retrieval.Silencing PVT neurons inhibited extinction retrieval at recent time point(24 h after extinction),while activating them promoted extinction retrieval at remote time point(7 d after extinction),suggesting a critical role of the PVT in extinction retrieval.In the mPFC-PVT circuit,projections from IL rather than prelimbic cortex to the PVT were dominant,and disrupting the IL-PVT projection suppressed extinction retrieval.Moreover,the axons of PVT neurons preferentially projected to the CeL.Silencing the PVT-CeL circuit also suppressed extinction retrieval.Together,our findings reveal a new neural circuit for fear extinction retrieval outside the classical IL-amygdala circuit.
基金supported by grants from the National Natural Science Foundation of China (81471347, 81771426, and 31500853)the Talent-Introducing Project of State Administration of Foreign Experts Affairs of China (X2017008)
文摘The thalamus is the gate of the cerebral cortex, the ultimate target for the neural networks controlling behavioral states and cognitive functions. According to the reticular theory initially proposed by Moruzzi and Magoun, excitatory inputs from large reticular zones of the brainstem via widespread intra- and extra-thalamocortical systems finally activate the cerebral cortex to cause generalized cortical activation and wakefulness [1]. This theory proposes a central relay role to the thalamus for cortical activation as supported by early studies using neurodegeneration techniques and by the elegant work of Steriade’s group and other investigators illustrating the electrophysiological mechanisms of the thalamocortical system at the cellular level during wakefulness, rapid eye-movement sleep (REMs) and non-REM sleep (NREMs)[2].
