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Hypertension is usually accompanied by elevated sympathetic tonicity, but how sympathetic hyperactivity is triggered is not clear. Recent advances revealed that microglia-centered neuroinflammation contributes to sympathetic excitation in hypertension. In this study, we performed a temporospatial analysis of microglia at both morphological and transcriptomic levels and found that microglia in the hypothalamic paraventricular nucleus (PVN), a sympathetic center, were early responders to hypertensive challenges. Vasculature analyses revealed that the PVN was characterized by high capillary density, thin vessel diameter, and complex vascular topology relative to other brain regions. As such, the PVN was susceptible to the penetration of ATP released from the vasculature in response to hemodynamic disturbance after blood pressure increase. Mechanistically, ATP ligation to microglial P2Y12 receptor was responsible for microglial inflammatory activation and the eventual sympathetic overflow. Together, these findings identified a distinct vasculature pattern rendering vulnerability of PVN pre-sympathetic neurons to hypertension-associated microglia-mediated inflammatory insults.
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Although many studies have addressed the regulatory circuits affecting neuronal activities, local non-synaptic mechanisms that determine neuronal excitability remain unclear. Here, we found that microglia prevented overactivation of pre-sympathetic neurons in the hypothalamic paraventricular nucleus (PVN) at steady state. Microglia constitutively released platelet-derived growth factor (PDGF) B, which signaled via PDGFRα on neuronal cells and promoted their expression of Kv4.3, a key subunit that conducts potassium currents. Ablation of microglia, conditional deletion of microglial PDGFB, or suppression of neuronal PDGFRα expression in the PVN elevated the excitability of pre-sympathetic neurons and sympathetic outflow, resulting in a profound autonomic dysfunction. Disruption of the PDGFBMG-Kv4.3Neuron pathway predisposed mice to develop hypertension, whereas central supplementation of exogenous PDGFB suppressed pressor response when mice were under hypertensive insult. Our results point to a non-immune action of resident microglia in maintaining the balance of sympathetic outflow, which is important in preventing cardiovascular diseases.
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Hipertensão , Microglia , Animais , Hipertensão/metabolismo , Camundongos , Neurônios/fisiologia , Potássio/metabolismo , Proteínas Proto-Oncogênicas c-sis/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismoRESUMO
We previously showed that orexin neurons are activated by hypoxia and facilitate the peripheral chemoreflex (PCR)-mediated hypoxic ventilatory response (HVR), mostly by promoting the respiratory frequency response. Orexin neurons project to the nucleus of the solitary tract (nTS) and the paraventricular nucleus of the hypothalamus (PVN). The PVN contributes significantly to the PCR and contains nTS-projecting corticotropin-releasing hormone (CRH) neurons. We hypothesized that in male rats, orexin neurons contribute to the PCR by activating nTS-projecting CRH neurons. We used neuronal tract tracing and immunohistochemistry (IHC) to quantify the degree that hypoxia activates PVN-projecting orexin neurons. We coupled this with orexin receptor (OxR) blockade with suvorexant (Suvo, 20â mg/kg, i.p.) to assess the degree that orexin facilitates the hypoxia-induced activation of CRH neurons in the PVN, including those projecting to the nTS. In separate groups of rats, we measured the PCR following systemic orexin 1 receptor (Ox1R) blockade (SB-334867; 1â mg/kg) and specific Ox1R knockdown in PVN. OxR blockade with Suvo reduced the number of nTS and PVN neurons activated by hypoxia, including those CRH neurons projecting to nTS. Hypoxia increased the number of activated PVN-projecting orexin neurons but had no effect on the number of activated nTS-projecting orexin neurons. Global Ox1R blockade and partial Ox1R knockdown in the PVN significantly reduced the PCR. Ox1R knockdown also reduced the number of activated PVN neurons and the number of activated tyrosine hydroxylase neurons in the nTS. Our findings suggest orexin facilitates the PCR via nTS-projecting CRH neurons expressing Ox1R.
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Hormônio Liberador da Corticotropina , Neurônios , Antagonistas dos Receptores de Orexina , Receptores de Orexina , Orexinas , Ratos Sprague-Dawley , Núcleo Solitário , Animais , Masculino , Hormônio Liberador da Corticotropina/metabolismo , Orexinas/metabolismo , Ratos , Neurônios/metabolismo , Neurônios/fisiologia , Neurônios/efeitos dos fármacos , Núcleo Solitário/metabolismo , Núcleo Solitário/fisiologia , Núcleo Solitário/efeitos dos fármacos , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/metabolismo , Hipóxia/metabolismo , Triazóis/farmacologia , Azepinas/farmacologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/fisiologiaRESUMO
Glucagon-like peptide-1 (GLP-1) and its analogs are widely used for diabetes treatment. The paraventricular nucleus (PVN) is crucial for regulating cardiovascular activity. This study aims to determine the roles of GLP-1 and its receptors (GLP-1R) in the PVN in regulating sympathetic outflow and blood pressure. Experiments were carried out in male normotensive rats and spontaneously hypertensive rats (SHR). Renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded. GLP-1 and GLP-1R expressions were present in the PVN. PVN microinjection of GLP-1R agonist recombinant human GLP-1 (rhGLP-1) or EX-4 increased RSNA and MAP, which were prevented by GLP-1R antagonist exendin 9-39 (EX9-39) or GLP-1R antagonist 1, superoxide scavenger tempol, antioxidant N-acetylcysteine, NADPH oxidase (NOX) inhibitor apocynin, adenylyl cyclase (AC) inhibitor SQ22536 or protein kinase A (PKA) inhibitor H89. PVN microinjection of rhGLP-1 increased superoxide production, NADPH oxidase activity, cAMP level, AC, and PKA activity, which were prevented by SQ22536 or H89. GLP-1 and GLP-1R were upregulated in the PVN of SHR. PVN microinjection of GLP-1 agonist increased RSNA and MAP in both WKY and SHR, but GLP-1 antagonists caused greater effects in reducing RSNA and MAP in SHR than in WKY. The increased superoxide production and NADPH oxidase activity in the PVN of SHR were augmented by GLP-1R agonists but attenuated by GLP-1R antagonists. These results indicate that activation of GLP-1R in the PVN increased sympathetic outflow and blood pressure via cAMP-PKA-mediated NADPH oxidase activation and subsequent superoxide production. GLP-1 and GLP-1R upregulation in the PVN partially contributes to sympathetic overactivity and hypertension.
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Peptídeo 1 Semelhante ao Glucagon , Receptor do Peptídeo Semelhante ao Glucagon 1 , Hipertensão , Núcleo Hipotalâmico Paraventricular , Ratos Endogâmicos SHR , Sistema Nervoso Simpático , Animais , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/metabolismo , Masculino , Hipertensão/fisiopatologia , Hipertensão/metabolismo , Ratos , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/antagonistas & inibidores , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Ratos Endogâmicos WKY , Ratos Sprague-DawleyRESUMO
Chronic stress induces depression and insulin resistance, between which there is a bidirectional relationship. However, the mechanisms underlying this comorbidity remain unclear. White adipose tissue (WAT), innervated by sympathetic nerves, serves as a central node in the interorgan crosstalk through adipokines. Abnormal secretion of adipokines is involved in mood disorders and metabolic morbidities. We describe here a brain-sympathetic nerve-adipose circuit originating in the hypothalamic paraventricular nucleus (PVN) with a role in depression and insulin resistance induced by chronic stress. PVN neurons are labelled after inoculation of pseudorabies virus (PRV) into WAT and are activated under restraint stress. Chemogenetic manipulations suggest a role for the PVN in depression and insulin resistance. Chronic stress increases the sympathetic innervation of WAT and downregulates several antidepressant and insulin-sensitizing adipokines, including leptin, adiponectin, Angptl4 and Sfrp5. Chronic activation of the PVN has similar effects. ß-adrenergic receptors translate sympathetic tone into an adipose response, inducing downregulation of those adipokines and depressive-like behaviours and insulin resistance. We finally show that AP-1 has a role in the regulation of adipokine expression under chronic stress.
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Resistência à Insulina , Núcleo Hipotalâmico Paraventricular , Ratos , Animais , Núcleo Hipotalâmico Paraventricular/metabolismo , Ratos Sprague-Dawley , Depressão , Obesidade/metabolismo , Adipocinas/metabolismo , Adipocinas/farmacologiaRESUMO
The paraventricular nucleus of the thalamus (PVT) is involved in drug addiction-related behaviors, and morphine is a widely used opioid for the relief of severe pain. Morphine acts via opioid receptors, but the function of opioid receptors in the PVT has not been fully elucidated. Here, we used in vitro electrophysiology to study neuronal activity and synaptic transmission in the PVT of male and female mice. Activation of opioid receptors suppresses the firing and inhibitory synaptic transmission of PVT neurons in brain slices. On the other hand, the involvement of opioid modulation is reduced after chronic morphine exposure, probably because of desensitization and internalization of opioid receptors in the PVT. Overall, the opioid system is essential for the modulation of PVT activities.SIGNIFICANCE STATEMENT Opioid receptors modulate the activities and synaptic transmission in the PVT by suppressing the firing rate and inhibitory synaptic inputs. These modulations were largely diminished after chronic morphine exposure.
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Analgésicos Opioides , Receptores Opioides , Masculino , Feminino , Camundongos , Animais , Analgésicos Opioides/farmacologia , Núcleo Hipotalâmico Paraventricular/fisiologia , Tálamo , Transmissão Sináptica , Morfina/farmacologiaRESUMO
Abdominal visceral pain is a predominant symptom in patients with chronic pancreatitis (CP); however, the underlying mechanism of pain in CP remains elusive. We hypothesized that astrocytes in the hypothalamic paraventricular nucleus (PVH) contribute to CP pain pathogenesis. A mouse model of CP was established by repeated intraperitoneal administration of caerulein to induce abdominal visceral pain. Abdominal mechanical stimulation, open field and elevated plus maze tests were performed to assess visceral pain and anxiety-like behavior. Fiber photometry, brain slice Ca2+ imaging, electrophysiology, and immunohistochemistry were used to investigate the underlying mechanisms. Mice with CP displayed long-term abdominal mechanical allodynia and comorbid anxiety, which was accompanied by astrocyte glial fibrillary acidic protein reactivity, elevated Ca2+ signaling, and astroglial glutamate transporter-1 (GLT-1) deficits in the PVH. Specifically, reducing astrocyte Ca2+ signaling in the PVH via chemogenetics significantly rescued GLT-1 deficits and alleviated mechanical allodynia and anxiety in mice with CP. Furthermore, we found that GLT-1 deficits directly contributed to the hyperexcitability of VGLUT2PVH neurons in mice with CP, and that pharmacological activation of GLT-1 alleviated the hyperexcitability of VGLUT2PVH neurons, abdominal visceral pain, and anxiety in these mice. Taken together, our data suggest that dysfunctional astrocyte glutamate uptake in the PVH contributes to visceral pain and anxiety in mice with CP, highlighting GLT-1 as a potential therapeutic target for chronic pain in patients experiencing CP.
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Chemerin is an adipokine that contributes to metabolism regulation. Nucleus tractus solitarius (NTS) is the first relay station in the brain for accepting various visceral afferent activities for regulating cardiovascular activity. However, the roles of chemerin in the NTS in regulating sympathetic activity and blood pressure are almost unknown. This study aimed to determine the role and potential mechanism of chemerin in the NTS in modulating sympathetic outflow and blood pressure. Bilateral NTS microinjections were performed in anaesthetized adult male Sprague-Dawley rats. Renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and heart rate (HR) were continuously recorded. Chemerin and its receptor chemokine-like receptor 1 (CMKLR1) were highly expressed in caudal NTS (cNTS). Microinjection of chemerin-9 to the cNTS increased RSNA, MAP and HR, which were prevented by CMKLR1 antagonist α-NETA, superoxide scavenger tempol or N-acetyl cysteine, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors diphenyleneiodonium or apocynin. Chemerin-9 increased superoxide production and NADPH oxidase activity in the cNTS. The increased superoxide production induced by chemerin-9 was inhibited by α-NETA. The effects of cNTS microinjection of chemerin-9 on the RSNA, MAP and HR were attenuated by the pretreatment with paraventricular nucleus (PVN) microinjection of NMDA receptor antagonist MK-801 rather than AMPA/kainate receptor antagonist CNQX. These results indicate that chemerin-9 in the NTS increases sympathetic outflow, blood pressure and HR via CMKLR1-mediated NADPH oxidase activation and subsequent superoxide production in anaesthetized normotensive rats. Glutamatergic inputs in the PVN are needed for the chemerin-9-induced responses.
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Accumulating evidence suggests that electroacupuncture (EA) has obvious therapeutic effects and unique advantages in alleviating myocardial ischemia-reperfusion injury (MIRI), while the underlying neuromolecular mechanisms of EA intervention for MIRI have not been fully elucidated. The aim of the study is to investigate the role of the neural pathway of hypothalamic paraventricular nucleus (PVN) neurons projecting to the rostral ventrolateral medulla (RVLM) in the alleviation of MIRI rats by EA preconditioning. MIRI models were established by ligating the left anterior descending coronary artery for 30 min followed by reperfusion for 2 h. Electrocardiogram recording, chemogenetics, enzyme-linked immunosorbent assay, multichannel physiology recording and haematoxylin-eosin and immunofluorescence staining methods were conducted to demonstrate that the firing frequencies of neurons in the PVN and the expression of c-Fos decreased by EA pretreatment. Meanwhile, EA preconditioning significantly reduced the levels of creatine kinase isoenzymes (CK-MB), cardiac troponin I (cTnI) and lactic dehydrogenase (LDH). Virus tracing showed a projection connection between PVN and RVLM. The inhibition of the PVN-RVLM neural pathway could replicate the protective effect of EA pretreatment on MIRI rats. However, the activation of the pathway weakened the effect of EA preconditioning. EA pretreatment alleviated MIRI by regulating PVN neurons projecting to RVLM. This work provides novel evidence of EA pretreatment for alleviating MIRI.
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Unacylated ghrelin (UAG), the unacylated form of ghrelin, accounts for 80%-90% of its circulation. Accumulated studies have pointed out that UAG may be used to treat metabolic disorders. This study aimed to investigate the effect of intestinal perfusion of UAG on metabolically associated fatty liver disease (MAFLD) induced by a high-fat diet and its possible mechanisms. Neuronal retrograde tracking combined with immunofluorescence, central administration of a glucagon-like peptide-1 receptor (GLP-1R) antagonist, and hepatic vagotomy was performed to reveal its possible mechanism involving a central glucagon-like peptide-1 (GLP-1) pathway. The results showed that intestinal perfusion of UAG significantly reduced serum lipids, aminotransferases, and food intake in MAFLD rats. Steatosis and lipid accumulation in the liver were significantly alleviated, and lipid metabolism-related enzymes in the liver were regulated. UAG upregulated the expression of GLP-1 receptor (GLP-1R) in the paraventricular nucleus (PVN) and GLP-1 in the nucleus tractus solitarii (NTS), as well as activated GLP-1 neurons in the NTS. Furthermore, GLP-1 fibers projected from NTS to PVN were activated by the intestinal perfusion of UAG. However, hepatic vagotomy and GLP-1R antagonists delivered into PVN before intestinal perfusion of UAG partially attenuated its alleviation of MAFLD. In conclusion, intestinal perfusion of UAG showed a therapeutic effect on MAFLD, which might be related to its activation of the GLP-1 neuronal pathway from NTS to PVN. The present results provide a new strategy for the treatment of MAFLD.NEW & NOTEWORTHY Intestinal perfusion of UAG, the unacylated form of ghrelin, has shown promising potential for treating MAFLD. This study unveils a potential mechanism involving the central GLP-1 pathway, with UAG upregulating GLP-1R expression and activating GLP-1 neurons in specific brain regions. These findings propose a novel therapeutic strategy for MAFLD treatment through UAG and its modulation of the GLP-1 neuronal pathway.
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Grelina , Peptídeo 1 Semelhante ao Glucagon , Receptor do Peptídeo Semelhante ao Glucagon 1 , Animais , Grelina/metabolismo , Grelina/farmacologia , Masculino , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Fígado/metabolismo , Fígado/efeitos dos fármacos , Dieta Hiperlipídica , Metabolismo dos Lipídeos/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Perfusão/métodos , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , VagotomiaRESUMO
Kisspeptin is an important hormone involved in the stimulation of the hypothalamo-pituitary gonadal (HPG) axis. The HPG axis can be suppressed in certain conditions such as stress, which gives rise to the activation of the hypothalamo-pituitary-adrenal (HPA) axis. However, the physiological role of kisspeptin in the interaction of HPG and HPA axis is not fully understood yet. This study was conducted to investigate the possible effects of central kisspeptin injection on HPG axis as well as HPA axis activity. Adult male Wistar rats were randomly divided into seven groups as followed: sham (control), kisspeptin (50 pmol), P234 (1 nmol), kisspeptin + p234, kisspeptin + antalarmin (0.1 µg), kisspeptin + astressin 2B (1 µg), and kisspeptin + atosiban (300 ng/rat) (n = 10 each group). At the end of the experiments, the hypothalamus, pituitary, and serum samples of the rats were collected. There was no significant difference in corticotropic-releasing hormone immunoreactivity in the paraventricular nucleus of the hypothalamus, serum adrenocorticotropic hormone, and corticosterone levels among all groups. Moreover, no significant difference was detected in pituitary oxytocin level. Serum follicle-stimulating hormone and luteinizing hormone levels of the kisspeptin, kisspeptin + antalarmin, and kisspeptin + astressin 2B groups were significantly higher than the control group. Serum testosterone levels were significantly higher in the kisspeptin kisspeptin + antalarmin, kisspeptin + astressin 2B, and kisspeptin + atosiban groups compared to the control group. Our findings suggest that central kisspeptin injection causes activation in the HPG axis, but not the HPA axis in male rats.
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Sistema Hipotálamo-Hipofisário , Kisspeptinas , Sistema Hipófise-Suprarrenal , Ratos Wistar , Animais , Masculino , Kisspeptinas/administração & dosagem , Kisspeptinas/farmacologia , Kisspeptinas/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Ratos , Fragmentos de Peptídeos/administração & dosagem , Hormônio Luteinizante/sangue , Hormônio Luteinizante/metabolismo , Corticosterona/sangue , Vasotocina/farmacologia , Vasotocina/administração & dosagem , Testosterona/sangue , Injeções Intraventriculares , Gônadas/metabolismo , Gônadas/efeitos dos fármacos , Hipófise/metabolismo , Hipófise/efeitos dos fármacos , Hormônio Liberador de Gonadotropina/metabolismo , Hormônio Adrenocorticotrópico/sangue , Hormônio Liberador da Corticotropina , OligopeptídeosRESUMO
Social hierarchies are a prevalent feature of all animal groups, and an individual's rank within the group can significantly affect their overall health, typically at the greatest expense of the lowest-ranked individuals, or omegas. These subjects have been shown to exhibit various stress-related phenotypes, such as increased hypothalamic-pituitary axis activity and increased amygdalar corticotropin-releasing factor levels compared to higher-ranked subjects. However, these findings have been primarily characterized in males and in models requiring exhibition of severe aggression. The goals of the current study, therefore, were to characterize the formation and maintenance of social hierarchies using the tube test and palatable liquid competition in same-sex groups of male and female C57BL/6 J mice. We also aimed to examine the effects of tube test-determined social rank on plasma and hypothalamic oxytocin and vasopressin levels, peptides with established roles in social behaviors and the stress response. Lastly, we assessed the effects of environmental enrichment and length of testing on the measures outlined above. Overall, we demonstrated that males and females develop social hierarchies and that these hierarchies can be determined using the tube test. While we were unable to establish a consistent connection between peptide levels and social rank, we observed transient changes in these peptides reflecting complex interactions between social rank, sex, environment, and length of testing. We also found that many male and female omegas began to exhibit passive coping behavior after repeated tube test losses, demonstrating the potential of this assay to serve as a model of chronic, mild psychosocial stress.
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Hierarquia Social , Comportamento Social , Humanos , Animais , Camundongos , Masculino , Feminino , Camundongos Endogâmicos C57BL , Agressão/fisiologia , HipotálamoRESUMO
Hypertension is among the most harmful factors of cardiovascular and cerebrovascular diseases and poses an urgent problem for the development of human society. In addition to previous studies on its pathogenesis focusing on the peripheral sympathetic nervous system, investigating the central causes of high blood pressure involving the neuroendocrine and neuroinflammatory mechanisms of the hypothalamic paraventricular nucleus (PVN) is paramount. This nucleus is considered to regulate the output of neurohormones and sympathetic nerve activity. In this article, we focussed on the neuroendocrine mechanism, primarily exploring the specific contributions and interactions of various neurons and neuroendocrine hormones, including GABAergic and glutamatergic neurons, nitric oxide, arginine vasopressin, oxytocin, and the renin-angiotensin system. Additionally, the neuroinflammatory mechanism in the PVN was discussed, encompassing microglia, reactive oxygen species, inflammatory factors, and pathways, as well as immune connections between the brain and extracerebral organs. Notably, the two central mechanisms involved in the PVN not only exist independently but also communicate with each other, jointly maintaining the hypertensive state of the body. Furthermore, we introduce well-known molecules and signal transduction pathways within the PVN that can play a regulatory role in the two mechanisms to provide a basis and inspire ideas for further research.
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Hipertensão , Núcleo Hipotalâmico Paraventricular , Humanos , Núcleo Hipotalâmico Paraventricular/metabolismo , Pressão Sanguínea/fisiologia , Hipertensão/metabolismo , Sistema Nervoso Simpático/metabolismo , Neurônios/fisiologiaRESUMO
Sympathetic activation is a hallmark of heart failure and the underlying mechanism remains elusive. Butyrate is generated by gut microbiota and influences numerous physiological and pathological processes in the host. The present study aims to investigate whether the intestinal metabolite butyrate reduces sympathetic activation in rats with heart failure (HF) and the underlying mechanisms involved. Sprague-Dawley rats (220â250â g) are anaesthetized with isoflurane, and the left anterior descending artery is ligated to model HF. Then, the rats are treated with or without butyrate sodium (NaB, a donor of butyrate, 10â g/L in water) for 8 weeks. Blood pressure and renal sympathetic nerve activity (RSNA) are recorded to assess sympathetic outflow. Cardiac function is improved (mean ejection fraction, 22.6%±4.8% vs 38.3%±5.3%; P<0.05), and sympathetic activation is decreased (RSNA, 36.3%±7.9% vs 23.9%±7.6%; P<0.05) in HF rats treated with NaB compared with untreated HF rats. The plasma and cerebrospinal fluid levels of norepinephrine are decreased in HF rats treated with NaB. The infusion of N-methyl-D-aspartic acid (NMDA) into the paraventricular nucleus (PVN) of the hypothalamus of HF model rats increases sympathetic nervous activity by upregulating the NMDA receptor. Microglia polarized to the M2 phenotype and inflammation are markedly attenuated in the PVN of HF model rats after NaB administration. In addition, HF model rats treated with NaB exhibit enhanced intestinal barrier function and increased levels of GPR109A, zona occludens-1 and occludin, but decreased levels of lipopolysaccharide-binding protein and zonulin. In conclusion, butyrate attenuates sympathetic activation and improves cardiac function in rats with HF. The improvements in intestinal barrier function, reductions in microglia-mediated inflammation and decreases in NMDA receptor 1 expression in the PVN are all due to the protective effects of NaB.
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BACKGROUND: Fibroblast growth factor 21 (FGF21) has a protective effect against cardiovascular disease. However, the role of FGF21 in hypertension remains elusive. METHODS: Ten-week-old male C57BL/6 mice were randomly divided into normal-salt (NS) group, NS+FGF21 group, deoxycorticosterone acetate-salt (DOCA) group and DOCA+FGF21 group. The mice in NS group underwent uninephrectomy without receiving DOCA and 1% NaCl and the mice in DOCA group were subjected to uninephrectomy and DOCA-salt (DOCA and 1% NaCl) treatment for 6 weeks. At the same time, the mice were infused with vehicle (artificial cerebrospinal fluid, aCSF) or FGF21 (1 mg/kg) into the bilateral paraventricular nucleus (PVN) of mice. RESULTS: Here, we showed that FGF21 treatment lowered DOCA salt-induced inflammation and oxidative stress in the PVN, which reduced sympathetic nerve activity and hypertension. Mechanistically, FGF21 treatment decreased the expression of HNF4α and inhibited the binding activity of HNF4α to the promoter region of ACE2 in the PVN of DOCA salt-treated mice, which further up-regulated ACE2/Ang (1-7) signals in the PVN. In addition, ACE2 deficiency abolished the protective effect of FGF21 in DOCA salt-treated mice, suggesting that FGF21-mediated antihypertensive effect was dependent on ACE2. CONCLUSIONS: The results demonstrate that FGF21 protects against salt-sensitive hypertension via regulating HNF4α/ACE2/Ang (1-7) axis in the PVN of DOCA salt-treated mice via multi-organ crosstalk between liver, brain and blood vessels.
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Enzima de Conversão de Angiotensina 2 , Acetato de Desoxicorticosterona , Fatores de Crescimento de Fibroblastos , Fator 4 Nuclear de Hepatócito , Hipertensão , Camundongos Endogâmicos C57BL , Núcleo Hipotalâmico Paraventricular , Animais , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Fatores de Crescimento de Fibroblastos/metabolismo , Masculino , Camundongos , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Enzima de Conversão de Angiotensina 2/metabolismo , Fator 4 Nuclear de Hepatócito/metabolismo , Fator 4 Nuclear de Hepatócito/genética , Estresse Oxidativo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Cloreto de Sódio na DietaRESUMO
Hypothalamic regulation of feeding and energy expenditure is a fundamental and evolutionarily conserved neurophysiological process critical for survival. Dysregulation of these processes, due to environmental or genetic causes, can lead to a variety of pathological conditions ranging from obesity to anorexia. Melanocortins and endogenous cannabinoids (eCBs) have been implicated in the regulation of feeding and energy homeostasis; however, the interaction between these signaling systems is poorly understood. Here, we show that the eCB 2-arachidonoylglycerol (2-AG) regulates the activity of melanocortin 4 receptor (MC4R) cells in the paraventricular nucleus of the hypothalamus (PVNMC4R) via inhibition of afferent GABAergic drive. Furthermore, the tonicity of eCBs signaling is inversely proportional to energy state, and mice with impaired 2-AG synthesis within MC4R neurons weigh less, are hypophagic, exhibit increased energy expenditure, and are resistant to diet-induced obesity. These mice also exhibit MC4R agonist insensitivity, suggesting that the energy state-dependent, 2-AG-mediated suppression of GABA input modulates PVNMC4R neuron activity to effectively respond to the MC4R natural ligands to regulate energy homeostasis. Furthermore, post-developmental disruption of PVN 2-AG synthesis results in hypophagia and death. These findings illustrate a functional interaction at the cellular level between two fundamental regulators of energy homeostasis, the melanocortin and eCB signaling pathways in the hypothalamic feeding circuitry.
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Canabinoides/metabolismo , Metabolismo Energético/fisiologia , Homeostase/fisiologia , Receptor Tipo 4 de Melanocortina/fisiologia , Animais , Ácidos Araquidônicos/fisiologia , Peso Corporal , Endocanabinoides/fisiologia , Jejum , Comportamento Alimentar/fisiologia , Teste de Tolerância a Glucose , Glicerídeos/fisiologia , Resistência à Insulina , Camundongos , Obesidade/genética , Receptor Tipo 4 de Melanocortina/agonistas , Ácido gama-Aminobutírico/metabolismoRESUMO
Oxytocin, a significant pleiotropic neuropeptide, regulates psychological stress adaptation and social communication, as well as peripheral actions, such as uterine contraction and milk ejection. Recently, a Japanese Kampo medicine called Kamikihito (KKT) has been reported to stimulate oxytocin neurons to induce oxytocin secretion. Two-pore-domain potassium channels (K2P) regulate the resting potential of excitable cells, and their inhibition results in accelerated depolarization that elicits neuronal and endocrine cell activation. We assessed the effects of KKT and 14 of its components on a specific K2P, the potassium channel subfamily K member 2 (TREK-1), which is predominantly expressed in oxytocin neurons in the central nervous system (CNS). KKT inhibited the activity of TREK-1 induced via the channel activator ML335. Six of the 14 components of KKT inhibited TREK-1 activity. Additionally, we identified that 22 of the 41 compounds in the six components exhibited TREK-1 inhibitory effects. In summary, several compounds included in KKT partially activated oxytocin neurons by inhibiting TREK-1. The pharmacological effects of KKT, including antistress effects, may be partially mediated through the oxytocin pathway.
Assuntos
Neurônios , Ocitocina , Canais de Potássio de Domínios Poros em Tandem , Animais , Humanos , Camundongos , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/química , Medicina Kampo , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Ocitocina/farmacologia , Ocitocina/metabolismo , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Canais de Potássio de Domínios Poros em Tandem/antagonistas & inibidoresRESUMO
BACKGROUND: Despite hypothalamus has long being considered to be involved in the pathophysiology of cluster headache, the inconsistencies of previous neuroimaging studies and a limited understanding of the hypothalamic areas involved, impede a comprehensive interpretation of its involvement in this condition. METHODS: We used an automated algorithm to extract hypothalamic subunit volumes from 105 cluster headache patients (57 chronic and 48 episodic) and 59 healthy individuals; after correcting the measures for the respective intracranial volumes, we performed the relevant comparisons employing logist regression models. Only for subunits that emerged as abnormal, we calculated their correlation with the years of illness and the number of headache attacks per day, and the effects of lithium treatment. As a post-hoc approach, using the 7 T resting-state fMRI dataset from the Human Connectome Project, we investigated whether the observed abnormal subunit, comprising the paraventricular nucleus and preoptic area, shows robust functional connectivity with the mesocorticolimbic system, which is known to be modulated by oxytocin neurons in the paraventricular nucleus and that is is abnormal in chronic cluster headache patients. RESULTS: Patients with chronic (but not episodic) cluster headache, compared to control participants, present an increased volume of the anterior-superior hypothalamic subunit ipsilateral to the pain, which, remarkably, also correlates significantly with the number of daily attacks. The post-hoc approach showed that this hypothalamic area presents robust functional connectivity with the mesocorticolimbic system under physiological conditions. No evidence of the effects of lithium treatment on this abnormal subunit was found. CONCLUSIONS: We identified the ipsilateral-to-the-pain antero-superior subunit, where the paraventricular nucleus and preoptic area are located, as the key hypothalamic region of the pathophysiology of chronic cluster headache. The significant correlation between the volume of this area and the number of daily attacks crucially reinforces this interpretation. The well-known roles of the paraventricular nucleus in coordinating autonomic and neuroendocrine flow in stress adaptation and modulation of trigeminovascular mechanisms offer important insights into the understanding of the pathophysiology of cluster headache.
Assuntos
Cefaleia Histamínica , Humanos , Cefaleia Histamínica/terapia , Dor , Cefaleia , Hipotálamo/diagnóstico por imagem , Compostos de LítioRESUMO
People of all ages could suffer from sleep disorders, which are increasingly recognized as common manifestations of neurologic disease. Acorus tatarinowii is a herb that has been used in traditional medicine to promote sleep. ß-asarone, as the main component of volatile oil obtained from Acorus tatarinowii, may be the main contributor to the sleeping-promoting efficacy of Acorus tatarinowii. In the study, adult male C57BL/6 mice were administered ß-asarone at 12.5 mg/kg, 25 mg/kg, and 50 mg/kg. Behavioral experiments showed that ß-asarone at 25 mg/kg could significantly improve sleep duration. It was also observed that the proportion of NREM (Non-Rapid Eye Movement) sleep increased considerably after administration of ß-asarone. In the PVN (paraventricular nucleus of hypothalamus) region of the hypothalamus, it was observed that the glutamate content decreased after ß-asarone treatment. At the same time, the expression of VGLUT2 (vesicular glutamate transporters 2) decreased while the expression of GAD65 (glutamic acid decarboxylase 65) and GABARAP (GABA Type A Receptor-Associated Protein) increased in the hypothalamus, suggesting that ß-asarone may suppress arousal by reducing glutamate and promoting transformation of glutamate to the inhibitory neurotransmitter GABA (γ-aminobutyric acid). This study is the first to focus on the association between ß-asarone and sleep, shedding perspectives for pharmacological applications of ß-asarone and providing a new direction for future research.
Assuntos
Ácido Glutâmico , Núcleo Hipotalâmico Paraventricular , Masculino , Camundongos , Animais , Camundongos Endogâmicos C57BL , Sono , Anisóis/farmacologia , Ácido gama-AminobutíricoRESUMO
BACKGROUND: Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) is involved in the stress response and may play a key role in mood disorders, but no information is available on PACAP for the human brain in relation to mood disorders. METHODS: PACAP-peptide levels were determined in a major stress-response site, the hypothalamic paraventricular nucleus (PVN), of people with major depressive disorder (MDD), bipolar disorder (BD) and of a unique cohort of Alzheimer's disease (AD) patients with and without depression, all with matched controls. The expression of PACAP-(Adcyap1mRNA) and PACAP-receptors was determined in the MDD and BD patients by qPCR in presumed target sites of PACAP in stress-related disorders, the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC). RESULTS: PACAP cell bodies and/or fibres were localised throughout the hypothalamus with differences between immunocytochemistry and in situ hybridisation. In the controls, PACAP-immunoreactivity-(ir) in the PVN was higher in women than in men. PVN-PACAP-ir was higher in male BD compared to the matched male controls. In all AD patients, the PVN-PACAP-ir was lower compared to the controls, but higher in AD depressed patients compared to those without depression. There was a significant positive correlation between the Cornell depression score and PVN-PACAP-ir in all AD patients combined. In the ACC and DLPFC, alterations in mRNA expression of PACAP and its receptors were associated with mood disorders in a differential way depending on the type of mood disorder, suicide, and psychotic features. CONCLUSION: The results support the possibility that PACAP plays a role in mood disorder pathophysiology.