Increased matrix stiffness of nucleus pulposus(NP)tissue is a main feature of intervertebral disc degeneration(IVDD)and affects various functions of nucleus pulposus cells(NPCs).Glycolysis is the main energy source fo...Increased matrix stiffness of nucleus pulposus(NP)tissue is a main feature of intervertebral disc degeneration(IVDD)and affects various functions of nucleus pulposus cells(NPCs).Glycolysis is the main energy source for NPC survival,but the effects and underlying mechanisms of increased extracellular matrix(ECM)stiffness on NPC glycolysis remain unknown.In this study,hydrogels with different stiffness were established to mimic the mechanical environment of NPCs.Notably,increased matrix stiffness in degenerated NP tissues from IVDD patients was accompanied with impaired glycolysis,and NPCs cultured on rigid substrates exhibited a reduction in glycolysis.展开更多
Aging is a pivotal risk factor for intervertebral disc degeneration(IVDD)and chronic low back pain(LBP).The restoration of aging nucleus pulposus cells(NPCs)to a youthful epigenetic state is crucial for IVDD treatment...Aging is a pivotal risk factor for intervertebral disc degeneration(IVDD)and chronic low back pain(LBP).The restoration of aging nucleus pulposus cells(NPCs)to a youthful epigenetic state is crucial for IVDD treatment,but remains a formidable challenge.Here,we proposed a strategy to partially reprogram and reinstate youthful epigenetics of senescent NPCs by delivering a plasmid carrier that expressed pluripotency-associated genes(Oct4,Klf4 and Sox2)in Cavin2-modified exosomes(OKS@M-Exo)for treatment of IVDD and alleviating LBP.The functional OKS@M-Exo efficaciously alleviated senescence markers(p16^(INK4a),p21^(CIP1)and p53),reduced DNA damage and H4K20me3 expression,as well as restored proliferation ability and metabolic balance in senescent NPCs,as validated through in vitro experiments.In a rat model of IVDD,OKS@M-Exo maintained intervertebral disc height,nucleus pulposus hydration and tissue structure,effectively ameliorated IVDD via decreasing the senescence markers.Additionally,OKS@MExo reduced nociceptive behavior and downregulated nociception markers,indicating its efficiency in alleviating LBP.The transcriptome sequencing analysis also demonstrated that OKS@M-Exo could decrease the expression of age-related pathways and restore cell proliferation.Collectively,reprogramming by the OKS@M-Exo to restore youthful epigenetics of senescent NPCs may hold promise as a therapeutic platform to treat IVDD.展开更多
Objective:To anatomically and phenotypically characterize the insular cortex(IC)-nucleus tractus soli-tari(NTS)neural pathway.Methods:Adult male Sprague-Dawley rats were divided into three experimental cohorts for neu...Objective:To anatomically and phenotypically characterize the insular cortex(IC)-nucleus tractus soli-tari(NTS)neural pathway.Methods:Adult male Sprague-Dawley rats were divided into three experimental cohorts for neural circuit tracing.Anterograde labeling was achieved by injecting anterograde self-complementary adeno-associated viruses(scAAVs)into the IC.Retrograde tracing involved NTS injections of either retrograde scAAVs or FluoroGold(FG),combined with immunofluorescence histochemical staining to identify IC-originating projection neurons.For postsynaptic neurochemical phenotype characterization,IC was injected with AAV2/1-CaMKII-Cre,while a mixture of AAV2/9-Syn-DIO-mCherry and AAV2/9-VGAT1-EGFP was injected into the NTS.The rats were allowed to survive for one week following scAAVs or FG injection or four weeks after recombinase-dependent systems injection.Then the rats were sacrificed,and serial brain sections were prepared for immunofluorescence histochemical staining(brain section containing FG)and subsequent fluorescence/confocal microscopic analysis.Results:(1)Anterograde viral tracing re-vealed dense axonal terminals from the IC projecting to the medial subnucleus of the NTS,while retrograde tracing re-vealed that IC neurons projecting to the NTS were predominantly localized within the dysgranular layer;(2)IC-NTS projection neurons were exclusive glutamatergic(100%,n=3);(3)NTS neurons receiving IC inputs were mainly lo-calized in the medial subnucleus,and were predominantly GABAergic(79.8±3.2%,n=3).Conclusion:The pres-ent results indicate that a descending pathway from excitatory neurons of the IC terminates onto inhibitory neurons of the NTS,which might represent a potential neuromodulatory target for visceral pain disorders.展开更多
Adolescent depression is increasingly recognized as a serious mental health disorder with distinct clinical and molecular features.Using single-nucleus RNA sequencing,we identified cell-specific transcriptomic changes...Adolescent depression is increasingly recognized as a serious mental health disorder with distinct clinical and molecular features.Using single-nucleus RNA sequencing,we identified cell-specific transcriptomic changes in the nucleus accumbens(NAc),particularly in astrocytes,of adolescent macaques exhibiting depressive-like behaviors.The level of diacylglycerol kinase beta was significantly reduced in neurons and glial cells of depressed macaques,while FKBP5 levels increased in glial cells.Disruption of GABAergic synapses and disruption of D-glutamine and D-glutamate metabolism were linked to depressive phenotypes in medium spiny neurons(MSNs)and subtypes of astrocytes.Communication pathways between astrocytes and D1/D2-MSNs were also disrupted,involving factors like bone morphogenetic protein-6 and Erb-B2 receptor tyrosine kinase-4.Bulk transcriptomic and proteomic analyses corroborated these findings,and FKBP5 upregulation was confirmed by qRT-PCR,western blotting,and immunofluorescence in the NAc of rats and macaques with chronic unpredictable mild stress.Our results highlight the specific roles of different cell types in adolescent depression in the NAc,offering potential targets for new antidepressant therapies.展开更多
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 suprachiasmatic nucleus in the hypothalamus is the master circadian clock in mammals,coordinating physiological processes with the 24-hour day–night cycle.Comprising various cell types,the suprachiasmatic nucleus...The suprachiasmatic nucleus in the hypothalamus is the master circadian clock in mammals,coordinating physiological processes with the 24-hour day–night cycle.Comprising various cell types,the suprachiasmatic nucleus(SCN)integrates environmental signals to maintain complex and robust circadian rhythms.Understanding the complexity and synchrony within SCN neurons is essential for effective circadian clock function.Synchrony involves coordinated neuronal firing for robust rhythms,while complexity reflects diverse activity patterns and interactions,indicating adaptability.Interestingly,the SCN retains circadian rhythms in vitro,demonstrating intrinsic rhythmicity.This study introduces the multiscale structural complexity method to analyze changes in SCN neuronal activity and complexity at macro and micro levels,based on Bagrov et al.’s approach.By examining structural complexity and local complexities across scales,we aim to understand how tetrodotoxin,a neurotoxin that inhibits action potentials,affects SCN neurons.Our method captures critical scales in neuronal interactions that traditional methods may overlook.Validation with the Goodwin model confirms the reliability of our observations.By integrating experimental data with theoretical models,this study provides new insights into the effects of tetrodotoxin(TTX)on neuronal complexities,contributing to the understanding of circadian rhythms.展开更多
Erratum to:Current Medical Science 44(5):987–1000,2024 https://doi.org/10.1007/s11596-024-2908-9 In the originally published article,there was an error in the funding information.Instead of“Shenzhen Science and Tech...Erratum to:Current Medical Science 44(5):987–1000,2024 https://doi.org/10.1007/s11596-024-2908-9 In the originally published article,there was an error in the funding information.Instead of“Shenzhen Science and Technology Program(No.2021-22154)”,it should be corrected to“Shenzhen Science and Technology Program(No.JCYJ20210324111609024)”.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.展开更多
The isospin asymmetry and quadrupole deformation value of drip-line nuclei are investigated using the Weizsäcker-Skyrme nuclear mass formula.We observe that for heavy nuclei at the neutron drip line,the Coulomb e...The isospin asymmetry and quadrupole deformation value of drip-line nuclei are investigated using the Weizsäcker-Skyrme nuclear mass formula.We observe that for heavy nuclei at the neutron drip line,the Coulomb energy heightened by an aug-mented charge could not be mitigated completely by symmetry energy because of isospin asymmetry saturation but is resisted complementally by strong nuclear deformation.The positions of saltation for the difference in proton numbers between two neighboring nuclei at the neutron drip line,and the isospin asymmetry of the neutron drip-line nucleus as a function of the neutron number distinctly correspond to the known magic numbers,which can serve as a reference to verify the undeter-mined neutron magic number.Through fitting of the binding energy difference between mirror nuclei(BEDbMN),a set of Coulomb energy coefficients with greater accuracy is obtained.A high-precision description of the BEDbMN is useful for accurately determining the experimentally unknown mass of the nucleus close to the proton drip line if the mass of its mirror nucleus is measured experimentally.展开更多
Our research reveals the critical role of the suprachiasmatic nucleus(SCN)vasoactive intestinal peptide(VIP)neurons in mediating light-induced transient forgetting.Acute exposure to bright light selectively impairs tr...Our research reveals the critical role of the suprachiasmatic nucleus(SCN)vasoactive intestinal peptide(VIP)neurons in mediating light-induced transient forgetting.Acute exposure to bright light selectively impairs trace fear memory by activating VIP neurons in the SCN,as demonstrated by increased c-Fos expression and Ca2+recording.This effect can be replicated and reversed through optogenetic and chemogenetic manipulations of SCN VIP neurons.Furthermore,we identify the SCN→PVT(paraventricular nucleus of the thalamus)VIP neuronal circuitry as essential in this process.These findings establish a novel role for SCN VIP neurons in modulating memory accessibility in response to environmental light cues,extending their known function beyond circadian regulation and revealing a mechanism for transient forgetting.展开更多
BACKGROUND Degenerative disc disease(DDD)is characterized by the loss of nucleus pulposus cells(NPCs).Inducing differentiation of bone marrow mesenchymal stem cells(MSCs)into NPCs has emerged as a novel therapeutic st...BACKGROUND Degenerative disc disease(DDD)is characterized by the loss of nucleus pulposus cells(NPCs).Inducing differentiation of bone marrow mesenchymal stem cells(MSCs)into NPCs has emerged as a novel therapeutic strategy for DDD.However,the efficiency of MSC differentiation and the underlying mechanisms remain to be fully elucidated.AIM To investigate the role and mechanism of miR-365 in promoting the differentiation of MSCs into NPCs for DDD treatment.METHODS In vitro,the effects of miR-365 on MSC proliferation,apoptosis,and differentiation were assessed by cell counting kit-8 assay,flow cytometry,and quantitative realtime polymerase chain reaction(qRT-PCR).In vivo,the expression levels of miR-365,HIF-1α,Sox9,Kdm6a,and HOXA9 in the spinal cord of rats with spinal cord injury were determined by qRT-PCR and Western blot.RESULTS In vitro,miR-365 significantly promoted MSC proliferation and inhibited MSC apoptosis.The expression levels of glycosaminoglycans,proteoglycan,and type 2 collagen were significantly increased with miR-365 ectopic expression.In vivo,the expression levels of miR-365,HIF-1α,Sox9,and Kdm6a were significantly increased,whereas HOXA9 was remarkably decreased.Mechanically,miR-365 inhibited HOXA9 expression by directly binding to its 3’untranslated region.HOXA9 could inhibit HIF-1αexpression by binding to the Hif-1αpromoter,thereby affecting the expression levels of Sox9 and Kdm6a.Moreover,HOXA9 knockdown significantly reversed the differentiation of MSCs into NPCs induced by miR-365.CONCLUSION miR-365 promotes HOXA9-mediated differentiation of MSCs into NPCs by interacting with HIF-1αand may serve as a potential target for DDD treatment.展开更多
Dear Editor,General anesthetics play a pivotal role in inducing a safe and reversible loss of consciousness in patients,the importance of which cannot be overstated[1].Among the intravenous anesthetics,propofol stands...Dear Editor,General anesthetics play a pivotal role in inducing a safe and reversible loss of consciousness in patients,the importance of which cannot be overstated[1].Among the intravenous anesthetics,propofol stands out for its rapid onset and swift systemic clearance,effectively eliminating the prolonged sedation associated with earlier agents[2].展开更多
The ventral anterior (VA) nucleus of the thalamus is a major target of the basal ganglia and is closely associated with the pathogenesis of Parkinson’s disease (PD). Notably, the VA receives direct innervation from t...The ventral anterior (VA) nucleus of the thalamus is a major target of the basal ganglia and is closely associated with the pathogenesis of Parkinson’s disease (PD). Notably, the VA receives direct innervation from the hypothalamic histaminergic system. However, its role in PD remains unknown. Here, we assessed the contribution of histamine to VA neuronal activity and PD motor deficits. Functional magnetic resonance imaging showed reduced VA activity in PD patients. Optogenetic activation of VA neurons or histaminergic afferents significantly alleviated motor deficits in 6-OHDA-induced PD rats. Furthermore, histamine excited VA neurons via H1 and H2 receptors and their coupled hyperpolarization-activated cyclic nucleotide-gated channels, inward-rectifier K^(+) channels, or Ca^(2+)-activated K+ channels. These results demonstrate that histaminergic afferents actively compensate for Parkinsonian motor deficits by biasing VA activity. These findings suggest that targeting VA histamine receptors and downstream ion channels may be a potential therapeutic strategy for PD motor dysfunction.展开更多
Social behaviors are crucial for gregarious animals,including humans.In order to exhibit appropriate behaviors in a complex social context,such as mating,aggression,avoidance,and cooperation,individuals need to rememb...Social behaviors are crucial for gregarious animals,including humans.In order to exhibit appropriate behaviors in a complex social context,such as mating,aggression,avoidance,and cooperation,individuals need to remember their previous experiences with other members and accurately recognize them when they meet again.This ability is called“social memory”[1].Many psychiatric disorders in humans,such as autism spectrum disorder,attention deficit hyperactivity disorder,and schizophrenia,are characterized by social memory impairments.Patients with these disorders,along with corresponding animal models,often show defects associated with the thalamic reticular nucleus(TRN).The TRN,a thin layer of neurons surrounding the thalamus,mainly regulates and coordinates the transfer of information between the cortex and the thalamus,playing a role in higher brain functions such as consciousness,attention,and sensory processing.However,whether the TRN is involved in social memory remains unknown.展开更多
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
The functional role of glutamatergic(vGluT2)neurons in the pedunculopontine nucleus(PPN)in modulating motor activity remains controversial.Here,we demonstrated that the activity of vGluT2 neurons in the rostral PPN is...The functional role of glutamatergic(vGluT2)neurons in the pedunculopontine nucleus(PPN)in modulating motor activity remains controversial.Here,we demonstrated that the activity of vGluT2 neurons in the rostral PPN is correlated with locomotion and ipsilateral head-turning.Beyond these motor functions,we found that these rostral PPN-vGluT2 neurons remarkably respond to salient stimuli.Furthermore,we systematically traced the upstream and downstream projections of these neurons and identifed two downstream projections from these neurons to the caudal pontine reticular nucleus/anterior gigantocellular reticular nucleus(PnC/GiA)and the zona incerta(ZI).Our fndings indicate that the projections to the PnC/GiA inhibit movement,consistent with‘pause-and-play’behavior,whereas those to the ZI promote locomotion,and others respond to a new‘pause-switch-play’pattern.Collectively,these fndings elucidate the multifaceted infuence of the PPN on motor functions and provide a robust theoretical framework for understanding its physiological and potential therapeutic implications.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
基金supported by the National Nature Science Foundation of China(No.82002345 to J.D and 81902179 to L.S)the Gusu Talent Program(No.Qngg2022008 and GSWS2021027 to J.D)the Preliminary Research Project of the Second Affiliated Hospital of Soochow University(No.SDFEYBS1905 to J.D).
文摘Increased matrix stiffness of nucleus pulposus(NP)tissue is a main feature of intervertebral disc degeneration(IVDD)and affects various functions of nucleus pulposus cells(NPCs).Glycolysis is the main energy source for NPC survival,but the effects and underlying mechanisms of increased extracellular matrix(ECM)stiffness on NPC glycolysis remain unknown.In this study,hydrogels with different stiffness were established to mimic the mechanical environment of NPCs.Notably,increased matrix stiffness in degenerated NP tissues from IVDD patients was accompanied with impaired glycolysis,and NPCs cultured on rigid substrates exhibited a reduction in glycolysis.
基金supported by the Ministry of Science and Technology of China(2020YFA0908900)National Natural Science Foundation of China(21935011 and 82072490)+1 种基金Shenzhen Science and Technology Innovation Commission(KQTD20200820113012029 and KJZD20230923114612025)Guangdong Provincial Key Laboratory of Advanced Biomaterials(2022B1212010003).
文摘Aging is a pivotal risk factor for intervertebral disc degeneration(IVDD)and chronic low back pain(LBP).The restoration of aging nucleus pulposus cells(NPCs)to a youthful epigenetic state is crucial for IVDD treatment,but remains a formidable challenge.Here,we proposed a strategy to partially reprogram and reinstate youthful epigenetics of senescent NPCs by delivering a plasmid carrier that expressed pluripotency-associated genes(Oct4,Klf4 and Sox2)in Cavin2-modified exosomes(OKS@M-Exo)for treatment of IVDD and alleviating LBP.The functional OKS@M-Exo efficaciously alleviated senescence markers(p16^(INK4a),p21^(CIP1)and p53),reduced DNA damage and H4K20me3 expression,as well as restored proliferation ability and metabolic balance in senescent NPCs,as validated through in vitro experiments.In a rat model of IVDD,OKS@M-Exo maintained intervertebral disc height,nucleus pulposus hydration and tissue structure,effectively ameliorated IVDD via decreasing the senescence markers.Additionally,OKS@MExo reduced nociceptive behavior and downregulated nociception markers,indicating its efficiency in alleviating LBP.The transcriptome sequencing analysis also demonstrated that OKS@M-Exo could decrease the expression of age-related pathways and restore cell proliferation.Collectively,reprogramming by the OKS@M-Exo to restore youthful epigenetics of senescent NPCs may hold promise as a therapeutic platform to treat IVDD.
文摘Objective:To anatomically and phenotypically characterize the insular cortex(IC)-nucleus tractus soli-tari(NTS)neural pathway.Methods:Adult male Sprague-Dawley rats were divided into three experimental cohorts for neural circuit tracing.Anterograde labeling was achieved by injecting anterograde self-complementary adeno-associated viruses(scAAVs)into the IC.Retrograde tracing involved NTS injections of either retrograde scAAVs or FluoroGold(FG),combined with immunofluorescence histochemical staining to identify IC-originating projection neurons.For postsynaptic neurochemical phenotype characterization,IC was injected with AAV2/1-CaMKII-Cre,while a mixture of AAV2/9-Syn-DIO-mCherry and AAV2/9-VGAT1-EGFP was injected into the NTS.The rats were allowed to survive for one week following scAAVs or FG injection or four weeks after recombinase-dependent systems injection.Then the rats were sacrificed,and serial brain sections were prepared for immunofluorescence histochemical staining(brain section containing FG)and subsequent fluorescence/confocal microscopic analysis.Results:(1)Anterograde viral tracing re-vealed dense axonal terminals from the IC projecting to the medial subnucleus of the NTS,while retrograde tracing re-vealed that IC neurons projecting to the NTS were predominantly localized within the dysgranular layer;(2)IC-NTS projection neurons were exclusive glutamatergic(100%,n=3);(3)NTS neurons receiving IC inputs were mainly lo-calized in the medial subnucleus,and were predominantly GABAergic(79.8±3.2%,n=3).Conclusion:The pres-ent results indicate that a descending pathway from excitatory neurons of the IC terminates onto inhibitory neurons of the NTS,which might represent a potential neuromodulatory target for visceral pain disorders.
基金supported by STI2030-Major Projects(2022ZD0212900)the Joint Project of Chongqing Municipal Science and Technology Bureau and Chongqing Health Commission(2023CCXM003)+4 种基金the National Key Research and Development Program of China(2017YFA0505700)the National Natural Science Foundation of China(82271565 and 82301714)the China Postdoctoral Science Foundation(2023TQ0398,GZB20230916,2023MD734124)the Natural Science Foundation of Chongqing,China(CSTB2023NSCQ-BHX0106)the Postdoctoral Innovation Talents Support Program of Chongqing,China(2208013341918508).
文摘Adolescent depression is increasingly recognized as a serious mental health disorder with distinct clinical and molecular features.Using single-nucleus RNA sequencing,we identified cell-specific transcriptomic changes in the nucleus accumbens(NAc),particularly in astrocytes,of adolescent macaques exhibiting depressive-like behaviors.The level of diacylglycerol kinase beta was significantly reduced in neurons and glial cells of depressed macaques,while FKBP5 levels increased in glial cells.Disruption of GABAergic synapses and disruption of D-glutamine and D-glutamate metabolism were linked to depressive phenotypes in medium spiny neurons(MSNs)and subtypes of astrocytes.Communication pathways between astrocytes and D1/D2-MSNs were also disrupted,involving factors like bone morphogenetic protein-6 and Erb-B2 receptor tyrosine kinase-4.Bulk transcriptomic and proteomic analyses corroborated these findings,and FKBP5 upregulation was confirmed by qRT-PCR,western blotting,and immunofluorescence in the NAc of rats and macaques with chronic unpredictable mild stress.Our results highlight the specific roles of different cell types in adolescent depression in the NAc,offering potential targets for new antidepressant therapies.
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.
基金Project supported by the National Natural Science Foundation of China(Grant Nos.12275179,11875042,and 12150410309)the Natural Science Foundation of Shanghai(Grant No.21ZR1443900).
文摘The suprachiasmatic nucleus in the hypothalamus is the master circadian clock in mammals,coordinating physiological processes with the 24-hour day–night cycle.Comprising various cell types,the suprachiasmatic nucleus(SCN)integrates environmental signals to maintain complex and robust circadian rhythms.Understanding the complexity and synchrony within SCN neurons is essential for effective circadian clock function.Synchrony involves coordinated neuronal firing for robust rhythms,while complexity reflects diverse activity patterns and interactions,indicating adaptability.Interestingly,the SCN retains circadian rhythms in vitro,demonstrating intrinsic rhythmicity.This study introduces the multiscale structural complexity method to analyze changes in SCN neuronal activity and complexity at macro and micro levels,based on Bagrov et al.’s approach.By examining structural complexity and local complexities across scales,we aim to understand how tetrodotoxin,a neurotoxin that inhibits action potentials,affects SCN neurons.Our method captures critical scales in neuronal interactions that traditional methods may overlook.Validation with the Goodwin model confirms the reliability of our observations.By integrating experimental data with theoretical models,this study provides new insights into the effects of tetrodotoxin(TTX)on neuronal complexities,contributing to the understanding of circadian rhythms.
文摘Erratum to:Current Medical Science 44(5):987–1000,2024 https://doi.org/10.1007/s11596-024-2908-9 In the originally published article,there was an error in the funding information.Instead of“Shenzhen Science and Technology Program(No.2021-22154)”,it should be corrected to“Shenzhen Science and Technology Program(No.JCYJ20210324111609024)”.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.
基金supported by the Ministry of Science and Technology of China(No.2022YFE0103400)Natural Science Foundation of Guangxi Province(No.2021GXNSFAA196052)National Natural Science Foundation of China(No.11965004).
文摘The isospin asymmetry and quadrupole deformation value of drip-line nuclei are investigated using the Weizsäcker-Skyrme nuclear mass formula.We observe that for heavy nuclei at the neutron drip line,the Coulomb energy heightened by an aug-mented charge could not be mitigated completely by symmetry energy because of isospin asymmetry saturation but is resisted complementally by strong nuclear deformation.The positions of saltation for the difference in proton numbers between two neighboring nuclei at the neutron drip line,and the isospin asymmetry of the neutron drip-line nucleus as a function of the neutron number distinctly correspond to the known magic numbers,which can serve as a reference to verify the undeter-mined neutron magic number.Through fitting of the binding energy difference between mirror nuclei(BEDbMN),a set of Coulomb energy coefficients with greater accuracy is obtained.A high-precision description of the BEDbMN is useful for accurately determining the experimentally unknown mass of the nucleus close to the proton drip line if the mass of its mirror nucleus is measured experimentally.
基金supported by grants from the National Natural Science Foundation of China(32021002 and 31900724)the STI2030-Major Projects(2022ZD0204900)the Tsinghua-Peking Joint Center for Life Sciences.
文摘Our research reveals the critical role of the suprachiasmatic nucleus(SCN)vasoactive intestinal peptide(VIP)neurons in mediating light-induced transient forgetting.Acute exposure to bright light selectively impairs trace fear memory by activating VIP neurons in the SCN,as demonstrated by increased c-Fos expression and Ca2+recording.This effect can be replicated and reversed through optogenetic and chemogenetic manipulations of SCN VIP neurons.Furthermore,we identify the SCN→PVT(paraventricular nucleus of the thalamus)VIP neuronal circuitry as essential in this process.These findings establish a novel role for SCN VIP neurons in modulating memory accessibility in response to environmental light cues,extending their known function beyond circadian regulation and revealing a mechanism for transient forgetting.
基金Supported by Academic Subject Boosting Plan in Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine,No.SY-XKZT-2019-3002Academic Project from the Health Commission of Hongkou District,Shanghai,No.2202-25Clinical Key Specialty Construction Unit from The Health Commission of Hongkou District,Shanghai,No.HKLCZD2024B03.
文摘BACKGROUND Degenerative disc disease(DDD)is characterized by the loss of nucleus pulposus cells(NPCs).Inducing differentiation of bone marrow mesenchymal stem cells(MSCs)into NPCs has emerged as a novel therapeutic strategy for DDD.However,the efficiency of MSC differentiation and the underlying mechanisms remain to be fully elucidated.AIM To investigate the role and mechanism of miR-365 in promoting the differentiation of MSCs into NPCs for DDD treatment.METHODS In vitro,the effects of miR-365 on MSC proliferation,apoptosis,and differentiation were assessed by cell counting kit-8 assay,flow cytometry,and quantitative realtime polymerase chain reaction(qRT-PCR).In vivo,the expression levels of miR-365,HIF-1α,Sox9,Kdm6a,and HOXA9 in the spinal cord of rats with spinal cord injury were determined by qRT-PCR and Western blot.RESULTS In vitro,miR-365 significantly promoted MSC proliferation and inhibited MSC apoptosis.The expression levels of glycosaminoglycans,proteoglycan,and type 2 collagen were significantly increased with miR-365 ectopic expression.In vivo,the expression levels of miR-365,HIF-1α,Sox9,and Kdm6a were significantly increased,whereas HOXA9 was remarkably decreased.Mechanically,miR-365 inhibited HOXA9 expression by directly binding to its 3’untranslated region.HOXA9 could inhibit HIF-1αexpression by binding to the Hif-1αpromoter,thereby affecting the expression levels of Sox9 and Kdm6a.Moreover,HOXA9 knockdown significantly reversed the differentiation of MSCs into NPCs induced by miR-365.CONCLUSION miR-365 promotes HOXA9-mediated differentiation of MSCs into NPCs by interacting with HIF-1αand may serve as a potential target for DDD treatment.
基金supported by grants from the National Natural Science Foundation of China(82101273)the Second Affiliated Hospital of the Army Medical University Incubation Program for Young Doctoral Talents(2023YQB007).
文摘Dear Editor,General anesthetics play a pivotal role in inducing a safe and reversible loss of consciousness in patients,the importance of which cannot be overstated[1].Among the intravenous anesthetics,propofol stands out for its rapid onset and swift systemic clearance,effectively eliminating the prolonged sedation associated with earlier agents[2].
基金supported by grants from the National Natural Science Foundation of China(32030044,32171012,82101332,32200948,and 323B1008)the Natural Science Foundation of Jiangsu Province,China(BK20240168+3 种基金BK20190008)the grant from the State Key Laboratory of Pharmaceutical Biotechnology(LNSN-202402)the Fundamental Research Funds for the Central Universities(020814380197,020814380208)Nanjing University Integrated Research Platform of the Ministry of Education-Top Talents Program(2024300475).
文摘The ventral anterior (VA) nucleus of the thalamus is a major target of the basal ganglia and is closely associated with the pathogenesis of Parkinson’s disease (PD). Notably, the VA receives direct innervation from the hypothalamic histaminergic system. However, its role in PD remains unknown. Here, we assessed the contribution of histamine to VA neuronal activity and PD motor deficits. Functional magnetic resonance imaging showed reduced VA activity in PD patients. Optogenetic activation of VA neurons or histaminergic afferents significantly alleviated motor deficits in 6-OHDA-induced PD rats. Furthermore, histamine excited VA neurons via H1 and H2 receptors and their coupled hyperpolarization-activated cyclic nucleotide-gated channels, inward-rectifier K^(+) channels, or Ca^(2+)-activated K+ channels. These results demonstrate that histaminergic afferents actively compensate for Parkinsonian motor deficits by biasing VA activity. These findings suggest that targeting VA histamine receptors and downstream ion channels may be a potential therapeutic strategy for PD motor dysfunction.
基金supported by grants from the National Natural Science Foundation of China(32125018 and 32071005)Zhejiang Provincial Natural Science Foundation of China(LD24H090002)+3 种基金Nanhu Brain-computer Interface Institute(010904008)Innovative Research Team of High-level Local Universities in Shanghai(SHSMUZDCX20211102)Fundamental Research Funds for the Central Universities(226-2024-00133)the MOE Frontiers Science Center for Brain Science&Brain-Machine Integration of Zhejiang University.
文摘Social behaviors are crucial for gregarious animals,including humans.In order to exhibit appropriate behaviors in a complex social context,such as mating,aggression,avoidance,and cooperation,individuals need to remember their previous experiences with other members and accurately recognize them when they meet again.This ability is called“social memory”[1].Many psychiatric disorders in humans,such as autism spectrum disorder,attention deficit hyperactivity disorder,and schizophrenia,are characterized by social memory impairments.Patients with these disorders,along with corresponding animal models,often show defects associated with the thalamic reticular nucleus(TRN).The TRN,a thin layer of neurons surrounding the thalamus,mainly regulates and coordinates the transfer of information between the cortex and the thalamus,playing a role in higher brain functions such as consciousness,attention,and sensory processing.However,whether the TRN is involved in social memory remains unknown.
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support from the Optical Imaging Facility and the Animal Facility of the Institute of Neuroscience,Center for Excellence in Brain Science&Intelligence Technology,Chinese Academy of Sciences,supported by the STI2030-Major Projects(2022ZD0205100).
文摘The functional role of glutamatergic(vGluT2)neurons in the pedunculopontine nucleus(PPN)in modulating motor activity remains controversial.Here,we demonstrated that the activity of vGluT2 neurons in the rostral PPN is correlated with locomotion and ipsilateral head-turning.Beyond these motor functions,we found that these rostral PPN-vGluT2 neurons remarkably respond to salient stimuli.Furthermore,we systematically traced the upstream and downstream projections of these neurons and identifed two downstream projections from these neurons to the caudal pontine reticular nucleus/anterior gigantocellular reticular nucleus(PnC/GiA)and the zona incerta(ZI).Our fndings indicate that the projections to the PnC/GiA inhibit movement,consistent with‘pause-and-play’behavior,whereas those to the ZI promote locomotion,and others respond to a new‘pause-switch-play’pattern.Collectively,these fndings elucidate the multifaceted infuence of the PPN on motor functions and provide a robust theoretical framework for understanding its physiological and potential therapeutic implications.
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）.
