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
Distribution of peptidergic neurons in the hypothalamic paraventricular nucleus(PVN)of the rat was investigated by means of immunohistochemical technique,and thearea,perimeter,maximum diameter,minimum diameter and gre...Distribution of peptidergic neurons in the hypothalamic paraventricular nucleus(PVN)of the rat was investigated by means of immunohistochemical technique,and thearea,perimeter,maximum diameter,minimum diameter and grey scale of peptidergicneuronal cell bodies were measured with an image analyser.All of these peptidergicneurons,oxytocin(OXY)-,vasopressin(VP)-,substance P(SP)-,corticotropin releasingfactor(CRF)-,thyrotropin releasing hormone(TRH)-,neurotensin(NT)-,cholecystokinin(CCK)-,somatostatin(SOM)-,galanin(GAL)-,leucine-enkephalin(L-ENK)-,vasoactive intestine polypeptide(VIP)-,and ACTH-like neurons,were ob-served in the PVN.The data of image analysis showed that the area of peptidergicneuronal cell bodies in the magnocellular subnucleus part of the PVN was similar,but wasdifferent in the parvocellular subnucleus part of the PVN.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
Background:Visceral pain induced by pancreatic cancer seriously affects patients’quality of life,and there is no effective treatment,because the mechanism of its neural circuit is unknown.Therefore,the aim of this st...Background:Visceral pain induced by pancreatic cancer seriously affects patients’quality of life,and there is no effective treatment,because the mechanism of its neural circuit is unknown.Therefore,the aim of this study is to explore the main neural circuit mechanism regulating visceral pain induced by pancreatic cancer in mice.Methods:The mouse model of pancreatic cancer visceral pain was established on C57BL/6N mice by pancreatic injection of mPAKPC-luc cells.Abdominal mechanical hyperalgesia and hunch score were performed to assess visceral pain;the pseudorabies virus(PRV)was used to identify the brain regions innervating the pancreas;the c-fos co-labeling method was used to ascertain the types of activated neurons;in vitro electrophysiological patch-clamp technique was used to record the electrophysiological activity of specific neurons;the calcium imaging technique was used to determine the calcium activity of specific neurons;specific neuron destruction and chemogenetics methods were used to explore whether specific neurons were involved in visceral pain induced by pancreatic cancer.Results:The PRV injected into the pancreas was detected in the paraventricular nucleus of the hypothalamus(PVN).Immunofluorescence staining showed that the majority of c-fos were co-labeled with glutamatergic neurons in the PVN.In vitro electrophysiological results showed that the firing frequency of glutamatergic neurons in the PVN was increased.The calcium imaging results showed that the calcium activity of glutamatergic neurons in the PVN was enhanced.Both specific destruction of glutamatergic neurons and chemogenetics inhibition of glutamatergic neurons in the PVN alleviated visceral pain induced by pancreatic cancer.Conclusions:Glutamatergic neurons in the PVN participate in the regulation of visceral pain induced by pancreatic cancer in mice,providing new insights for the discovery of effective targets for the treatment of pancreatic cancer visceral pain.展开更多
The paraventricular nucleus of the hypothalamus(PVH)acts as a cohesive functional unit that regulates neuroendocrine and autonomic function,complex behavior,and negative emotions after stress.However,how the PVH integ...The paraventricular nucleus of the hypothalamus(PVH)acts as a cohesive functional unit that regulates neuroendocrine and autonomic function,complex behavior,and negative emotions after stress.However,how the PVH integrates arousal with these biological functions has only recently been explored.Clinical reports,combined with neurotoxic lesioning,immunochemistry,neuronal activity recordings,and the polysomnographic analyses of genetically modified animals,have revealed that the PVH is important for the control of wakefulness.Here,we review emerging anatomical and neural mechanisms for sleep–wake regulation in the PVH to support its essential role in the promotion and maintenance of wakefulness.展开更多
Cenpj is a centrosomal protein located at the centrosomes and the base of cilia,it plays essential roles in regulating neurogenesis and cerebral cortex development.Although centrosomal and cilium dysfunction are one o...Cenpj is a centrosomal protein located at the centrosomes and the base of cilia,it plays essential roles in regulating neurogenesis and cerebral cortex development.Although centrosomal and cilium dysfunction are one of the causes of obesity,insulin resistance,and type 2 diabetes,the role that Cenpj plays in the regulation of body weight remains unclear.Here,we deleted Cenpj by crossing Cenpjflox/flox mice with Nkx2.1-Cre mice.Loss of the centrosomal protein Cenpj in Nkx2.1-expressing cells causes morbid obesity in mice at approximately 4 months of age with expended brain ventricles but no change of brain size.We found that hypothalamic cells exhibited reduced proliferation and increased apoptosis upon Cenpj depletion at the embryonic stages,resulting in a dramatic decrease in the number of Proopiomelanocortin(POMC)neurons and electrophysiological dysfunction of NPY neurons in the arcuate nucleus(ARC)in adults.Furthermore,depletion of Cenpj also reduced the neuronal projection from the ARC to the paraventricular nucleus(PVN),with decreased melanocortin-4 receptors(MC4R)expression in PVN neurons.The study defines the roles that Cenpj plays in regulating hypothalamus development and body weight,providing a foundation for further understanding of the pathological mechanisms of related diseases.展开更多
The hypothalamic paraventricular nucleus(PVN) is a crucial region involved in maintaining homeostasis through the regulation of cardiovascular, neuroendocrine, and other functions. The PVN provides a dominant source o...The hypothalamic paraventricular nucleus(PVN) is a crucial region involved in maintaining homeostasis through the regulation of cardiovascular, neuroendocrine, and other functions. The PVN provides a dominant source of excitatory drive to the sympathetic outflow through innervation of the brainstem and spinal cord in hypertension. We discuss current findings on the role of the PVN in the regulation of sympathetic output in both normotensive and hypertensive conditions. The PVN seems to play a major role in generating the elevated sympathetic vasomotor activity that is characteristic of multiple forms of hypertension, including primary hypertension in humans. Recent studies in the spontaneously hypertensive rat model have revealed an imbalance of inhibitory and excitatory synaptic inputs to PVN presympathetic neurons as indicated by impaired inhibitory and enhanced excitatory synaptic inputs in hypertension.This imbalance of inhibitory and excitatory synaptic inputs in the PVN forms the basis for elevated sympathetic outflow in hypertension. In this review, we discuss the disruption of balance between glutamatergic and GABAergic inputs and the associated cellular and molecular alterations as mechanisms underlying the hyperactivity of PVN pre-sympathetic neurons in hypertension.展开更多
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.
文摘Distribution of peptidergic neurons in the hypothalamic paraventricular nucleus(PVN)of the rat was investigated by means of immunohistochemical technique,and thearea,perimeter,maximum diameter,minimum diameter and grey scale of peptidergicneuronal cell bodies were measured with an image analyser.All of these peptidergicneurons,oxytocin(OXY)-,vasopressin(VP)-,substance P(SP)-,corticotropin releasingfactor(CRF)-,thyrotropin releasing hormone(TRH)-,neurotensin(NT)-,cholecystokinin(CCK)-,somatostatin(SOM)-,galanin(GAL)-,leucine-enkephalin(L-ENK)-,vasoactive intestine polypeptide(VIP)-,and ACTH-like neurons,were ob-served in the PVN.The data of image analysis showed that the area of peptidergicneuronal cell bodies in the magnocellular subnucleus part of the PVN was similar,but wasdifferent in the parvocellular subnucleus part of the PVN.
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.
基金supported by Shanghai Municipal Science and Technology Major Project(Grant No.23Y11908100 to M.X.)Cross-disciplinary Research Fund of Shanghai Ninth People’s Hospital,Shanghai JiaoTong University School of Medicine(Grant No.JYJC202312 to M.X.)Postdoctoral Research Start-up Fund of Shanghai Ninth People’s Hospital,Shanghai JiaoTong University School of Medicine(to N.N.J.).
文摘Background:Visceral pain induced by pancreatic cancer seriously affects patients’quality of life,and there is no effective treatment,because the mechanism of its neural circuit is unknown.Therefore,the aim of this study is to explore the main neural circuit mechanism regulating visceral pain induced by pancreatic cancer in mice.Methods:The mouse model of pancreatic cancer visceral pain was established on C57BL/6N mice by pancreatic injection of mPAKPC-luc cells.Abdominal mechanical hyperalgesia and hunch score were performed to assess visceral pain;the pseudorabies virus(PRV)was used to identify the brain regions innervating the pancreas;the c-fos co-labeling method was used to ascertain the types of activated neurons;in vitro electrophysiological patch-clamp technique was used to record the electrophysiological activity of specific neurons;the calcium imaging technique was used to determine the calcium activity of specific neurons;specific neuron destruction and chemogenetics methods were used to explore whether specific neurons were involved in visceral pain induced by pancreatic cancer.Results:The PRV injected into the pancreas was detected in the paraventricular nucleus of the hypothalamus(PVN).Immunofluorescence staining showed that the majority of c-fos were co-labeled with glutamatergic neurons in the PVN.In vitro electrophysiological results showed that the firing frequency of glutamatergic neurons in the PVN was increased.The calcium imaging results showed that the calcium activity of glutamatergic neurons in the PVN was enhanced.Both specific destruction of glutamatergic neurons and chemogenetics inhibition of glutamatergic neurons in the PVN alleviated visceral pain induced by pancreatic cancer.Conclusions:Glutamatergic neurons in the PVN participate in the regulation of visceral pain induced by pancreatic cancer in mice,providing new insights for the discovery of effective targets for the treatment of pancreatic cancer visceral pain.
基金partly supported by the National Major Project of China Science and Technology Innovation 2030 for Brain Science and BrainInspired Technology(Grant No.2021ZD0203400 to Z.-L.H.)the National Natural Science Foundation of China(Grant Nos.82020108014 and 32070984 to Z.-L.H.)+3 种基金the Shanghai Science and Technology Innovation Action Plan Laboratory Animal Research Project(Grant No.201409001800 to Z.-L.H.)Program for Shanghai Outstanding Academic Leaders(to Z.-L.H.)the Shanghai Municipal Science and Technology Major ProjectZJLab(Grant No.2018SHZDZX01 to Z-.L.H.)。
文摘The paraventricular nucleus of the hypothalamus(PVH)acts as a cohesive functional unit that regulates neuroendocrine and autonomic function,complex behavior,and negative emotions after stress.However,how the PVH integrates arousal with these biological functions has only recently been explored.Clinical reports,combined with neurotoxic lesioning,immunochemistry,neuronal activity recordings,and the polysomnographic analyses of genetically modified animals,have revealed that the PVH is important for the control of wakefulness.Here,we review emerging anatomical and neural mechanisms for sleep–wake regulation in the PVH to support its essential role in the promotion and maintenance of wakefulness.
基金the National Basic Research Program of China(2017YFA0102601,2019YFA0110101,2017YFA0103303)the National Natural Science Foundation of China(31671072,91732301,31771140,81891001)+1 种基金Strategic Priority Research Program of the Chinese Academy of Sciences,the Grants of Beijing Brain Initiative of Beijing Municipal Science and Technology Commission(Z181100001518004)Open Research Fund of the State Key Laboratory of Cognitive Neuroscience and Learning.
文摘Cenpj is a centrosomal protein located at the centrosomes and the base of cilia,it plays essential roles in regulating neurogenesis and cerebral cortex development.Although centrosomal and cilium dysfunction are one of the causes of obesity,insulin resistance,and type 2 diabetes,the role that Cenpj plays in the regulation of body weight remains unclear.Here,we deleted Cenpj by crossing Cenpjflox/flox mice with Nkx2.1-Cre mice.Loss of the centrosomal protein Cenpj in Nkx2.1-expressing cells causes morbid obesity in mice at approximately 4 months of age with expended brain ventricles but no change of brain size.We found that hypothalamic cells exhibited reduced proliferation and increased apoptosis upon Cenpj depletion at the embryonic stages,resulting in a dramatic decrease in the number of Proopiomelanocortin(POMC)neurons and electrophysiological dysfunction of NPY neurons in the arcuate nucleus(ARC)in adults.Furthermore,depletion of Cenpj also reduced the neuronal projection from the ARC to the paraventricular nucleus(PVN),with decreased melanocortin-4 receptors(MC4R)expression in PVN neurons.The study defines the roles that Cenpj plays in regulating hypothalamus development and body weight,providing a foundation for further understanding of the pathological mechanisms of related diseases.
基金supported by National Institutes of Health Grants HL131161,HL139523,and HL142133
文摘The hypothalamic paraventricular nucleus(PVN) is a crucial region involved in maintaining homeostasis through the regulation of cardiovascular, neuroendocrine, and other functions. The PVN provides a dominant source of excitatory drive to the sympathetic outflow through innervation of the brainstem and spinal cord in hypertension. We discuss current findings on the role of the PVN in the regulation of sympathetic output in both normotensive and hypertensive conditions. The PVN seems to play a major role in generating the elevated sympathetic vasomotor activity that is characteristic of multiple forms of hypertension, including primary hypertension in humans. Recent studies in the spontaneously hypertensive rat model have revealed an imbalance of inhibitory and excitatory synaptic inputs to PVN presympathetic neurons as indicated by impaired inhibitory and enhanced excitatory synaptic inputs in hypertension.This imbalance of inhibitory and excitatory synaptic inputs in the PVN forms the basis for elevated sympathetic outflow in hypertension. In this review, we discuss the disruption of balance between glutamatergic and GABAergic inputs and the associated cellular and molecular alterations as mechanisms underlying the hyperactivity of PVN pre-sympathetic neurons in hypertension.
