It has been reported both in clinic and rodent models that beyond spinal cord injury directly induced symptoms, such as paralysis, neuropathic pain, bladder/bowel dysfunction, and loss of sexual function, there are a ...It has been reported both in clinic and rodent models that beyond spinal cord injury directly induced symptoms, such as paralysis, neuropathic pain, bladder/bowel dysfunction, and loss of sexual function, there are a variety of secondary complications, including memory loss, cognitive decline, depression, and Alzheimer's disease. The largescale longitudinal population-based studies indicate that post-trauma depression is highly prevalent in spinal cord injury patients. Yet, few basic studies have been conducted to address the potential molecular mechanisms. One of possible factors underlying the depression is the reduction of adult hippocampal neurogenesis which may come from less physical activity, social isolation, chronic pain, and elevated neuroinflammation after spinal cord injury. However, there is no clear consensus yet. In this review, we will first summarize the alteration of hippocampal neurogenesis post-spinal cord injury. Then, we will discuss possible mechanisms underlie this important spinal cord injury consequence. Finally, we will outline the potential therapeutic options aimed at enhancing hippocampal neurogenesis to ameliorate depression.展开更多
Structural plasticity is critical for the functional diversity of neurons in the brain.Experimental autoimmune encephalomyelitis(EAE)is the most commonly used model for multiple sclerosis(MS),successfully mimicking it...Structural plasticity is critical for the functional diversity of neurons in the brain.Experimental autoimmune encephalomyelitis(EAE)is the most commonly used model for multiple sclerosis(MS),successfully mimicking its key pathological features(inflammation,demyelination,axonal loss,and gliosis)and clinical symptoms(motor and non-motordysfunctions).Recentstudieshave demonstrated the importance of synaptic plasticity in EAE pathogenesis.In the present study,we investigated the features of behavioral alteration and hippocampal structural plasticity in EAE-affected mice in the early phase(11 days post-immunization,DPI)and chronic phase(28DPI).EAE-affected mice exhibited hippocampus-related behavioral dysfunction in the open field test during both early and chronic phases.Dendritic complexity was largely affected in the cornu ammonis 1(CA1)and CA3 apical and dentate gyrus(DG)subregions of the hippocampus during the chronic phase,while this effect was only noted in the CA1 apical subregion in the early phase.Moreover,dendritic spine density was reduced in the hippocampal CA1 and CA3 apical/basal and DG subregions in the early phase of EAE,but only reduced in the DG subregion during the chronic phase.Furthermore,mRNA levels of proinflammatory cytokines(Il1β,Tnfα,and Ifnγ)and glial cell markers(Gfap and Cd68)were significantly increased,whereas the expression of activity-regulated cytoskeletonassociated protein(ARC)was reduced during the chronic phase.Similarly,exposure to the aforementioned cytokines in primary cultures of hippocampal neurons reduced dendritic complexity and ARC expression.Primary cultures of hippocampal neurons also showed significantly reduced extracellular signal-regulated kinase(ERK)phosphorylation upon treatment with proinflammatory cytokines.Collectively,these results suggest that autoimmune neuroinflammation alters structural plasticity in the hippocampus,possibly through the ERK-ARC pathway,indicating that this alteration may be associated with hippocampal dysfunctions in EAE.展开更多
BACKGROUND Akt plays diverse roles in humans.It is involved in the pathogenesis of type 2 diabetes mellitus(T2DM),which is caused by insulin resistance.Akt also plays a vital role in human platelet activation.Furtherm...BACKGROUND Akt plays diverse roles in humans.It is involved in the pathogenesis of type 2 diabetes mellitus(T2DM),which is caused by insulin resistance.Akt also plays a vital role in human platelet activation.Furthermore,the hippocampus is closely associated with memory and learning,and a decrease in hippocampal volume is reportedly associated with an insulin-resistant phenotype in T2DM patients without dementia.AIM To investigate the relationship between Akt phosphorylation in unstimulated platelets and the hippocampal volume in T2DM patients.METHODS Platelet-rich plasma(PRP)was prepared from the venous blood of patients with T2DM or age-matched controls.The pellet lysate of the centrifuged PRP was subjected to western blotting to analyse the phosphorylation of Akt,p38 mitogen-activated protein(MAP)kinase and glyceraldehyde 3-phosphate dehydrogenase(GAPDH).Phosphorylation levels were quantified by densitometric analysis.Hippocampal volume was analysed using a voxel-based specific regional analysis system for Alzheimer’s disease on magnetic resonance imaging,which proposes the Z-score as a parameter that reflects hippocampal volume.RESULTS The levels of phosphorylated Akt corrected with phosphorylated p38 MAP kinase were inversely correlated with the Z-scores in the T2DM subjects,whereas the levels of phosphorylated Akt corrected with GAPDH were not.However,this relationship was not observed in the control patients.CONCLUSION These results suggest that an inverse relationship may exist between platelet Akt activation and hippocampal atrophy in T2DM patients.Our findings provide insight into the molecular mechanisms underlying T2DM hippocampal atrophy.展开更多
Neurodegeneration affects a large number of cell types including neurons,astrocytes or oligodendrocytes,and neural stem cells.Neural stem cells can generate new neuronal populations through proliferation,migration,and...Neurodegeneration affects a large number of cell types including neurons,astrocytes or oligodendrocytes,and neural stem cells.Neural stem cells can generate new neuronal populations through proliferation,migration,and differentiation.This neurogenic potential may be a relevant factor to fight neurodegeneration and aging.In the last years,we can find growing evidence suggesting that melatonin may be a potential modulator of adult hippocampal neurogenesis.The lack of therapeutic strategies targeting neurogenesis led researchers to explore new molecules.Numerous preclinical studies with melatonin observed how melatonin can modulate and enhance molecular and signaling pathways involved in neurogenesis.We made a special focus on the connection between these modulation mechanisms and their implication in neurodegeneration,to summarize the current knowledge and highlight the therapeutic potential of melatonin.展开更多
OBJECTIVE To investigate whether electroacupuncture(EA)ameliorates abnormal trigeminal neuralgia(TN)orofacial pain and anxiety-like behavior by altering synaptic plasticity in the hippocampus CA1.METHODS A mouse infra...OBJECTIVE To investigate whether electroacupuncture(EA)ameliorates abnormal trigeminal neuralgia(TN)orofacial pain and anxiety-like behavior by altering synaptic plasticity in the hippocampus CA1.METHODS A mouse infraorbital nerve transection model(pTION)of neuropathic pain was established,and EA or sham EA was used to treat ipsilateral acu⁃puncture points(GV20-Baihui and ST7-Xia⁃guan).Golgi-Cox staining and transmission elec⁃tron microscopy(TEM)were administrated to observe the changes of synaptic plasticity in the hippocampus CA1.RESULTS Stable and persistent orofacial allodynia and anxiety-like behav⁃iors induced by pT-ION were related to changes in hippocampal synaptic plasticity.Golgi stain⁃ings showed a decrease in the density of dendritic spines,especially mushroom-type dendritic spines,in hippocampal CA1 neurons of pT-ION mice.TEM results showed that the density of synapses,membrane thickness of the postsynaptic density,and length of the synaptic active zone were decreased,whereas the width of the synaptic cleft was increased in pTION mice.EA attenu⁃ated pT-ION-induced orofacial allodynia and anx⁃iety-like behaviors and effectively reversed the abnormal changes in dendritic spines and syn⁃apse of the hippocampal CA1 region.CONCLU⁃SION EA modulates synaptic plasticity of hippo⁃campal CA1 neurons,and reduces abnormal oro⁃facial pain and anxiety-like behavior,providing evidence for a TN treatment strategy.展开更多
Background:Hippocampal damage caused by status epilepticus(SE)can bring about cognitive decline and emotional disorders,which are common clinical comorbidities in patients with epilepsy.It is therefore imperative to d...Background:Hippocampal damage caused by status epilepticus(SE)can bring about cognitive decline and emotional disorders,which are common clinical comorbidities in patients with epilepsy.It is therefore imperative to develop a novel therapeutic strat-egy for protecting hippocampal damage after SE.Mitochondrial dysfunction is one of contributing factors in epilepsy.Given the therapeutic benefits of mitochondrial replenishment by exogenous mitochondria,we hypothesized that transplantation of mitochondria would be capable of ameliorating hippocampal damage following SE.Methods:Pilocarpine was used to induced SE in mice.SE-generated cognitive de-cline and emotional disorders were determined using novel object recognition,the tail suspension test,and the open field test.SE-induced hippocampal pathology was assessed by quantifying loss of neurons and activation of microglia and astrocytes.The metabolites underlying mitochondrial transplantation were determined using metabonomics.Results:The results showed that peripheral administration of isolated mitochon-dria could improve cognitive deficits and depressive and anxiety-like behaviors.Exogenous mitochondria blunted the production of reactive oxygen species,pro-liferation of microglia and astrocytes,and loss of neurons in the hippocampus.The metabonomic profiles showed that mitochondrial transplantation altered multiple metabolic pathways such as sphingolipid signaling pathway and carbon metabolism.Among potential affected metabolites,mitochondrial transplantation decreased levels of sphingolipid(d18:1/18:0)and methylmalonic acid,and elevated levels of D-fructose-1,6-bisphosphate.Conclusion:To the best of our knowledge,these findings provide the first direct ex-perimental evidence that artificial mitochondrial transplantation is capable of amelio-rating hippocampal damage following SE.These new findings support mitochondrial transplantation as a promising therapeutic strategy for epilepsy-associated psychiat-ric and cognitive disorders.展开更多
Adult neurogenesis is the creation of new neurons which integrate into the existing neural circuit of the adult brain.Recent evidence suggests that adult hippocampal neurogenesis(AHN)persists throughout life in mammal...Adult neurogenesis is the creation of new neurons which integrate into the existing neural circuit of the adult brain.Recent evidence suggests that adult hippocampal neurogenesis(AHN)persists throughout life in mammals,including humans.These newborn neurons have been implicated to have a crucial role in brain functions such as learning and memory.Importantly,studies have also found that hippocampal neurogenesis is impaired in neurodegenerative and neuropsychiatric diseases.Alzheimer’s disease(AD)is one of the most common forms of dementia affecting millions of people.Cognitive dysfunction is a common symptom of AD patients and progressive memory loss has been attributed to the degeneration of the hippocampus.Therefore,there has been growing interest in identifying how hippocampal neurogenesis is affected in AD.However,the link between cognitive decline and changes in hippocampal neurogenesis in AD is poorly understood.In this review,we summarized the recent literature on AHN and its impairments in AD.展开更多
Objective To detect the effects of microwave on calcium levels in primary hippocampal neurons and primary cardiomyocytes by the real-time microwave exposure combined with laser scanning confocal microscopy. Methods Th...Objective To detect the effects of microwave on calcium levels in primary hippocampal neurons and primary cardiomyocytes by the real-time microwave exposure combined with laser scanning confocal microscopy. Methods The primary hippocampal neurons and primary cardiomyocytes were cultured and labeled with probes, including Fluo-4 AM, Mag-Fluo-AM, and Rhod-2, to reflect the levels of whole calcium [Ca^(2+)], endoplasmic reticulum calcium [Ca^(2+)]ER, and mitochondrial calcium [Ca^(2+)]MIT, respectively. Then, the cells were exposed to a pulsed microwave of 2.856 GHz with specific absorption rate(SAR) values of 0, 4, and 40 W/kg for 6 min to observe the changes in calcium levels. Results The results showed that the 4 and 40 W/kg microwave radiation caused a significant decrease in the levels of [Ca^(2+)], [Ca^(2+)]ER, and [Ca^(2+)]MIT in primary hippocampal neurons. In the primary cardiomyocytes, only the 40 W/kg microwave radiation caused the decrease in the levels of [Ca^(2+)], [Ca^(2+)]ER, and [Ca^(2+)]MIT. Primary hippocampal neurons were more sensitive to microwave exposure than primary cardiomyocytes. The mitochondria were more sensitive to microwave exposure than the endoplasmic reticulum. Conclusion The calcium efflux was occurred during microwave exposure in primary hippocampal neurons and primary cardiomyocytes. Additionally, neurons and mitochondria were sensitive cells and organelle respectively.展开更多
Ilexonin A is a compound isolated from the root of Ilex pubescens,a traditional Chinese medicine.Ilexonin A has been shown to play a neuroprotective role by regulating the activation of astrocytes and microglia in the...Ilexonin A is a compound isolated from the root of Ilex pubescens,a traditional Chinese medicine.Ilexonin A has been shown to play a neuroprotective role by regulating the activation of astrocytes and microglia in the peri-infarct area after ischemia.However,the effects of ilexonin A on astrocytes and microglia in the infarct-free region of the hippocampal CA1 region remain unclear.Focal cerebral ischemia models were established by 2-hour occlusion of the middle cerebral artery in rats.Ilexonin A(20,40 or 80 mg/kg)was administered immediately after ischemia/reperfusion.The astrocyte marker glial fibrillary acidic protein,microglia marker Iba-1,neural stem cell marker nestin and inflammation markers were detected by immunohistochemistry and western blot assay.Expression levels of tumor necrosis factor-αand interleukin 1βwere determined by enzyme linked immunosorbent assay in the hippocampal CA1 tissue.Astrocytes were activated immediately in progressively increasing numbers from 1,3,to 7 days post-ischemia/reperfusion.The number of activated astrocytes further increased in the hippocampal CA1 region after treatment with ilexonin A.Microglial cells remained quiescent after ischemia/reperfusion,but became activated after treatment with ilexonin A.Ilexonin A enhanced nestin expression and reduced the expression of tumor necrosis factor-αand interleukin 1βin the hippocampus post-ischemia/reperfusion.The results of the present study suggest that ilexonin A has a neuroprotective effect in the hippocampus after ischemia/reperfusion,probably through regulating astrocytes and microglia activation,promoting neuronal stem cell proliferation and reducing the levels of pro-inflammatory factors.This study was approved by the Animal Ethics Committee of the Fujian Medical University Union Hospital,China.展开更多
N-methyl-D-aspartate receptor hypofunction is the basis of pathophysiology in schizophrenia. Blocking the N-methyl-D-aspartate receptor impairs learning and memory abilities and induces pathological changes in the bra...N-methyl-D-aspartate receptor hypofunction is the basis of pathophysiology in schizophrenia. Blocking the N-methyl-D-aspartate receptor impairs learning and memory abilities and induces pathological changes in the brain. Previous studies have paid little attention to the role of the N-methyl-D-aspartate receptor subunit 1 (NR1) in neurogenesis in the hippocampus of schizophrenia. A mouse model of schizophrenia was established by intraperitoneal injection of 0.6 mg/kg MK-801, once a day, for 14 days. In N-methyl-D-aspartate-treated mice, N-methyl-D-aspartate was administered by intracerebroventricular injection in schizophrenia mice on day 15. The number of NR1-, Ki67- or BrdU-immunoreactive cells in the dentate gyrus was measured by immunofluorescence staining. Our data showed the number of NR1-immunoreactive cells increased along with the decreasing numbers of BrdU- and Ki67-immunoreactive cells in the schizophrenia groups compared with the control group. N-methyl-D-aspartate could reverse the above changes. These results indicated that NR1 can regulate neurogenesis in the hippocampal dentate gyrus of schizophrenia mice, supporting NR1 as a promising therapeutic target in the treatment of schizophrenia. This study was approved by the Experimental Animal Ethics Committee of the Ningxia Medical University, China (approval No. 2014-014) on March 6, 2014.展开更多
Hippocampal neurons undergo various forms of cell death after status epilepticus.Necrostatin-1 specifically inhibits necroptosis mediated by receptor interacting protein kinase 1 (RIP1) and RIP3 receptors.However,ther...Hippocampal neurons undergo various forms of cell death after status epilepticus.Necrostatin-1 specifically inhibits necroptosis mediated by receptor interacting protein kinase 1 (RIP1) and RIP3 receptors.However,there are no reports of necroptosis in mouse models of status epilepticus.Therefore,in this study,we investigated the effects of necrostatin-1 on hippocampal neurons in mice with status epilepticus,and,furthermore,we tested different amounts of the compound to identify the optimal concentration for inhibiting necroptosis and apoptosis.A mouse model of status epilepticus was produced by intraperitoneal injection of kainic acid,12 mg/kg.Different concentrations of necrostatin- 1 (10,20,40,and 80 μM) were administered into the lateral ventricle 15 minutes before kainic acid injection.Hippocampal damage was assessed by hematoxylin-eosin staining 24 hours after the model was successfully produced.Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining,western blot assay and immunohistochemistry were used to evaluate the expression of apoptosis-related and necroptosis-related proteins.Necrostatin-1 alleviated damage to hippocampal tissue in the mouse model of epilepsy.The 40 μM concentration of necrostatin-1 significantly decreased the number of apoptotic cells in the hippocampal CA1 region.Furthermore,necrostatin-1 significantly downregulated necroptosis-related proteins (MLKL,RIP1,and RIP3) and apoptosis-related proteins (cleaved-Caspase-3,Bax),and it upregulated the expression of anti-apoptotic protein Bcl-2.Taken together,our findings show that necrostatin-1 effectively inhibits necroptosis and apoptosis in mice with status epilepticus,with the 40 μM concentration of the compound having an optimal effect.The experiments were approved by the Animal Ethics Committee of Fujian Medical University,China (approval No.2016-032) on November 9,2016.展开更多
Icariin(ICA) has a significant capacity to protect against depression and hippocampal injury,but it cannot effectively cross the bloodbrain barrier and accumulate in the brain.Therefore,the mechanism by which ICA prot...Icariin(ICA) has a significant capacity to protect against depression and hippocampal injury,but it cannot effectively cross the bloodbrain barrier and accumulate in the brain.Therefore,the mechanism by which ICA protects against hippocampal injury in depression remains unclear.In this study,we performed proteomics analysis of cerebrospinal fluid to investigate the mechanism by which ICA prevents dysfunctional hippocampal neurogenesis in depression.A rat model of depression was established through exposure to chronic unpredictable mild stress for 6 weeks,after which 120 mg/kg ICA was administered subcutaneously every day.The results showed that ICA alleviated depressive symptoms,learning and memory dysfunction,dysfunctional neurogenesis,and neuronal loss in the dentate gyrus of rats with depression.Neural stem cells from rat embryonic hippocampi were cultured in media containing 20% cerebrospinal fluid from each group of rats and then treated with 100 μM corticosterone.The addition of cerebrospinal fluid from rats treated with ICA largely prevented the corticosterone-mediated inhibition of neuronal proliferation and differentiation.Fifty-two differentially expressed proteins regulated by chronic unpredictable mild stress and ICA were identified through proteomics analysis of cerebrospinal fluid.These proteins were mainly involved in the ribosome,PI3 K-Akt signaling,and interleukin-17 signaling pathways.Parallel reaction monitoring mass spectrometry showed that Rps4 x,Rps12,Rps14,Rps19,Hsp90 b1,and Hsp90 aa1 were up-regulated by chronic unpredictable mild stress and down-regulated by ICA.In contrast,Htr A1 was down-regulated by chronic unpredictable mild stress and up-regulated by ICA.These findings suggest that ICA can prevent depression and dysfunctional hippocampal neurogenesis through regulating the expression of certain proteins found in the cerebrospinal fluid.The study was approved by the Experimental Animal Ethics Committee of Guangzhou University of Chinese Medicine of China in March 2017.展开更多
Glucagon-like peptide-1 receptor has anti-apoptotic,anti-inflammatory,and neuroprotective effects.It is now recognized that the occurrence and development of chronic pain are strongly associated with anti-inflammatory...Glucagon-like peptide-1 receptor has anti-apoptotic,anti-inflammatory,and neuroprotective effects.It is now recognized that the occurrence and development of chronic pain are strongly associated with anti-inflammatory responses;however,it is not clear whether glucagon-like peptide-1 receptor regulates chronic pain via anti-inflammatory mechanisms.We explored the effects of glucagon-like peptide-1 receptor on nociception,cognition,and neuroinflammation in chronic pain.A rat model of chronic pain was established using left L5 spinal nerve ligation.The glucagon-like peptide-1 receptor agonist exendin-4 was intrathecally injected into rats from 10 to 21 days after spinal nerve ligation.Electrophysiological examinations showed that,after treatment with exendin-4,paw withdrawal frequency of the left limb was significantly reduced,and pain was relieved.In addition,in the Morris water maze test,escape latency increased and the time to reach the platform decreased following exendin-4 treatment.Immunohistochemical staining and western blot assays revealed an increase in the numbers of activated microglia and astrocytes in the dentate gyrus of rat hippocampus,as well as an increase in the expression of tumor necrosis factor alpha,interleukin 1 beta,and interleukin 6.All of these effects could be reversed by exendin-4 treatment.These findings suggest that exendin-4 can alleviate pain-induced neuroinflammatory responses and promote the recovery of cognitive function via the glucagon-like peptide-1 receptor pathway.All experimental procedures and protocols were approved by the Experimental Animal Ethics Committee of Renmin Hospital of Wuhan University of China(approval No.WDRM 20171214)on September 22,2017.展开更多
Traumatic brain injury(TBI)is a major cause of mortality and morbidity in the pediatric population.With advances in medical care,the mortality rate of pediatric TBI has declined.However,more children and adolescents a...Traumatic brain injury(TBI)is a major cause of mortality and morbidity in the pediatric population.With advances in medical care,the mortality rate of pediatric TBI has declined.However,more children and adolescents are living with TBI-related cognitive and emotional impairments,which negatively affects the quality of their life.Adult hippocampal neurogenesis plays an important role in cognition and mood regulation.Alterations in adult hippocampal neurogenesis are associated with a variety of neurological and neurodegenerative diseases,including TBI.Promoting endogenous hippocampal neurogenesis after TBI merits significant attention.However,TBI affects the function of neural stem/progenitor cells in the dentate gyrus of hippocampus,which results in aberrant migration and impaired dendrite development of adult-born neurons.Therefore,a better understanding of adult hippocampal neurogenesis after TBI can facilitate a more successful neuro-restoration of damage in immature brains.Secondary injuries,such as neuroinflammation and oxidative stress,exert a significant impact on hippocampal neurogenesis.Currently,a variety of therapeutic approaches have been proposed for ameliorating secondary TBI injuries.In this review,we discuss the uniqueness of pediatric TBI,adult hippocampal neurogenesis after pediatric TBI,and current efforts that promote neuroprotection to the developing brains,which can be leveraged to facilitate neuroregeneration.展开更多
To observe the effects of different acupuncture manipulations on blood pressure and target organ damage in spontaneously hypertensive rats(SHRs), this study used the reinforcing twirling method(1.5–2-mm depth; rotati...To observe the effects of different acupuncture manipulations on blood pressure and target organ damage in spontaneously hypertensive rats(SHRs), this study used the reinforcing twirling method(1.5–2-mm depth; rotating needle clockwise for 360° and then counter clockwise for 360°, with the thumb moving heavily forward and gently backward, 60 times per minute for 1 minute, and retaining needle for 9 minutes), the reducing twirling method(1.5–2-mm depth; rotating needle counter clockwise for 360° and then clockwise for 360°, with the thumb moving heavily backward and gently forward, 60 times per minute for 1 minute, and retaining needle for 9 minutes), and the needle retaining method(1.5–2-mm depth and retaining the needle for 10 minutes). Bilateral Taichong(LR3) was treated by acupuncture using different manipulations and manual stimulation. Reinforcing twirling, reducing twirling, and needle retaining resulted in a decreased number of apoptotic cells, reduced Bax m RNA and protein expression, and an increased Bcl-2/Bax ratio in the hippocampus compared with the SHR group. Among these groups, the Bcl-2/Bax protein ratio was highest in the reducing twirling group, and the Bcl-2/Bax m RNA ratio was highest in the needle retaining group. These results suggest that reinforcing twirling, reducing twirling, and needle retaining methods all improve blood pressure and prevent target organ damage by increasing the hippocampal Bcl-2/Bax ratio and inhibiting cell apoptosis in the hippocampus in SHR.展开更多
Glial glutamate transporter-1(GLT-1)is the predominant subtype of glutamate transporters and is responsible for the clearance of extracellular glutamate and for limiting the concentration of extracellular glutamate.Ou...Glial glutamate transporter-1(GLT-1)is the predominant subtype of glutamate transporters and is responsible for the clearance of extracellular glutamate and for limiting the concentration of extracellular glutamate.Our previous studies have shown that the up-regulation of GLT-1 expression plays an important role展开更多
Several lines of evidence have established that proliferation and differentiation of neural stem cells into neurons within the sub-granular zone of the dentate gyrus,a process named adult hippocampal neurogenesis,cont...Several lines of evidence have established that proliferation and differentiation of neural stem cells into neurons within the sub-granular zone of the dentate gyrus,a process named adult hippocampal neurogenesis,contribute to maintaining healthy cognitive functions throughout life.The rate of adult hippocampal neurogenesis decreases with aging and a premature impairment of adult hippocampal neurogenesis has been observed both in animal models of Alzheimer’s disease and human post-mortem tissues.The causal relationship between adult hippocampal neurogenesis and the development of Alzheimer’s disease pathology has,however,not been established.This is partly due to the limitation of recapitulating the development of Alzheimer’s disease pathology in rodent models and the lack of translatable biomarkers to identify tractable targets in humans.While it is tempting to postulate that adult hippocampal neurogenesis could be leveraged to improve cognitive deficits in Alzheimer’s disease,consensual results have yet to be reached to fully explore this hypothesis.In this review,we discuss how the recent progress in identifying molecular pathways in adult hippocampal neurogenesis provides a good framework to initiate strategies for drug-based intervention in neurodegenerative diseases,especially in Alzheimer’s disease.We outline how discrepancies in pre-clinical disease models and experimental methodology have resulted in contradictory findings and propose a shift towards using more translatable approaches to model neurogenesis in Alzheimer’s disease.In particular,we review how exploring novel experimental paradigms including the use of human induced pluripotent stem cells and more complex cell culture systems,as well as standardizing protocols used to investigate evidence of neurogenesis in human tissues,could deliver deeper mechanistic insights that would kick-start innovative drug discovery efforts to promote healthy aging and cellular rejuvenation.展开更多
Adult hippocampal neurogenesis is a finely tuned process regulated by extrinsic factors. Neuroinflammation is a hallmark of several pathological conditions underlying dysregulation of neurogenesis. In animal models, l...Adult hippocampal neurogenesis is a finely tuned process regulated by extrinsic factors. Neuroinflammation is a hallmark of several pathological conditions underlying dysregulation of neurogenesis. In animal models, lipopolysaccharide(LPS)-induced neuroinflammation leads to a neurogenic decrease mainly associated to the early inflammatory response. However, it is not well understood how the neuroinflammatory response progresses over time and if neurogenesis continues to be diminished during the late neuroinflammatory response. Moreover, it is unknown if repeated intermittent administration of LPS along time induces a greater reduction in neurogenesis. We administered one single intraperitoneal injection of LPS or saline or four repeated injections(one per week) of LPS or saline to young-adult mice. A cohort of new cells was labeled with three 5-bromo-2-deoxyuridine injections(one per day) 4 days after the last LPS injection. We evaluated systemic and neuroinflammation-associated parameters and compared the effects of the late neuroinflammatory response on neurogenesis induced by each protocol. Our results show that 1) a single LPS injection leads to a late pro-inflammatory response characterized by microglial activation, moderate astrocytic reaction and increased interleukin-6 levels. This response correlates in time with decreased neurogenesis and 2) a repeated intermittent injection of LPS does not elicit a late pro-inflammatory response although activated microglia persists. The latter profile is not accompanied by a continued longterm hippocampal neurogenic decrease. Hereby, we provide evidence that the neuroinflammatory response is a dynamic process that progresses in a milieu-dependent manner and does not necessarily lead to a neurogenic decrease, highlighting the complex interaction between the immune system and neurogenesis.展开更多
Bisperoxo(1,10-phenanthroline) oxovanadate(BpV) can reportedly block the cell cycle. The present study examined whether BpV alters gene expression by affecting DNA methyltransferases(DNMTs), which would impact the cel...Bisperoxo(1,10-phenanthroline) oxovanadate(BpV) can reportedly block the cell cycle. The present study examined whether BpV alters gene expression by affecting DNA methyltransferases(DNMTs), which would impact the cell cycle. Immortalized mouse hippocampal neuronal precursor cells(HT_(22)) were treated with 0.3 or 3 μM BpV. Proliferation, morphology, and viability of HT_(22) cells were detected with an IncuCyte real-time video imaging system or inverted microscope and 3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethonyphenol)-2-(4-sulfophenyl)-2H-tetrazolium, respectively. mRNA and protein expression of DNMTs and p21 in HT_(22) cells was detected by real-time polymerase chain reaction and immunoblotting, respectively. In addition, DNMT activity was measured with an enzyme-linked immunosorbent assay. Effects of BpV on the cell cycle were analyzed using flow cytometry. Results demonstrated that treatment with 0.3 μM BpV did not affect cell proliferation, morphology, or viability; however, treatment with 3 μM BpV decreased cell viability, increased expression of both DNMT3B mRNA and protein, and inhibited the proliferation of HT_(22) cells; and 3 μM BpV also blocked the cell cycle and increased expression of the regulatory factor p21 by increasing DNMT expression in mouse hippocampal neurons.展开更多
Rhesus monkey neural stem cells are capable of differentiating into neurons and glial cells.Therefore,neural stem cell transplantation can be used to promote functional recovery of the nervous system.Rhesus monkey neu...Rhesus monkey neural stem cells are capable of differentiating into neurons and glial cells.Therefore,neural stem cell transplantation can be used to promote functional recovery of the nervous system.Rhesus monkey neural stem cells(1×105 cells/μL) were injected into bilateral hippocampi of rats with hippocampal lesions.Confocal laser scanning microscopy demonstrated that green fluorescent protein-labeled transplanted cells survived and grew well.Transplanted cells were detected at the lesion site,but also in the nerve fiber-rich region of the cerebral cortex and corpus callosum.Some transplanted cells differentiated into neurons and glial cells clustering along the ventricular wall,and integrated into the recipient brain.Behavioral tests revealed that spatial learning and memory ability improved,indicating that rhesus monkey neural stem cells noticeably improve spatial learning and memory abilities in rats with hippocampal lesions.展开更多
基金supported by the Showalter Research Trust Fund (to XG)Indiana Spinal Cord&Brain Injury Research Fund (ISCBIRF) from the Indiana State Departm ent of Health (to XG)。
文摘It has been reported both in clinic and rodent models that beyond spinal cord injury directly induced symptoms, such as paralysis, neuropathic pain, bladder/bowel dysfunction, and loss of sexual function, there are a variety of secondary complications, including memory loss, cognitive decline, depression, and Alzheimer's disease. The largescale longitudinal population-based studies indicate that post-trauma depression is highly prevalent in spinal cord injury patients. Yet, few basic studies have been conducted to address the potential molecular mechanisms. One of possible factors underlying the depression is the reduction of adult hippocampal neurogenesis which may come from less physical activity, social isolation, chronic pain, and elevated neuroinflammation after spinal cord injury. However, there is no clear consensus yet. In this review, we will first summarize the alteration of hippocampal neurogenesis post-spinal cord injury. Then, we will discuss possible mechanisms underlie this important spinal cord injury consequence. Finally, we will outline the potential therapeutic options aimed at enhancing hippocampal neurogenesis to ameliorate depression.
基金supported by the National Research Foundation (NRF)of Korea Grant funded by the Korean Government (NRF-2022R1A2C100402212RS-2023-00219517)。
文摘Structural plasticity is critical for the functional diversity of neurons in the brain.Experimental autoimmune encephalomyelitis(EAE)is the most commonly used model for multiple sclerosis(MS),successfully mimicking its key pathological features(inflammation,demyelination,axonal loss,and gliosis)and clinical symptoms(motor and non-motordysfunctions).Recentstudieshave demonstrated the importance of synaptic plasticity in EAE pathogenesis.In the present study,we investigated the features of behavioral alteration and hippocampal structural plasticity in EAE-affected mice in the early phase(11 days post-immunization,DPI)and chronic phase(28DPI).EAE-affected mice exhibited hippocampus-related behavioral dysfunction in the open field test during both early and chronic phases.Dendritic complexity was largely affected in the cornu ammonis 1(CA1)and CA3 apical and dentate gyrus(DG)subregions of the hippocampus during the chronic phase,while this effect was only noted in the CA1 apical subregion in the early phase.Moreover,dendritic spine density was reduced in the hippocampal CA1 and CA3 apical/basal and DG subregions in the early phase of EAE,but only reduced in the DG subregion during the chronic phase.Furthermore,mRNA levels of proinflammatory cytokines(Il1β,Tnfα,and Ifnγ)and glial cell markers(Gfap and Cd68)were significantly increased,whereas the expression of activity-regulated cytoskeletonassociated protein(ARC)was reduced during the chronic phase.Similarly,exposure to the aforementioned cytokines in primary cultures of hippocampal neurons reduced dendritic complexity and ARC expression.Primary cultures of hippocampal neurons also showed significantly reduced extracellular signal-regulated kinase(ERK)phosphorylation upon treatment with proinflammatory cytokines.Collectively,these results suggest that autoimmune neuroinflammation alters structural plasticity in the hippocampus,possibly through the ERK-ARC pathway,indicating that this alteration may be associated with hippocampal dysfunctions in EAE.
基金Research Funding for Longevity Science from The National Center for Geriatrics and Gerontology,Japan,No.19-21and No.22-19.
文摘BACKGROUND Akt plays diverse roles in humans.It is involved in the pathogenesis of type 2 diabetes mellitus(T2DM),which is caused by insulin resistance.Akt also plays a vital role in human platelet activation.Furthermore,the hippocampus is closely associated with memory and learning,and a decrease in hippocampal volume is reportedly associated with an insulin-resistant phenotype in T2DM patients without dementia.AIM To investigate the relationship between Akt phosphorylation in unstimulated platelets and the hippocampal volume in T2DM patients.METHODS Platelet-rich plasma(PRP)was prepared from the venous blood of patients with T2DM or age-matched controls.The pellet lysate of the centrifuged PRP was subjected to western blotting to analyse the phosphorylation of Akt,p38 mitogen-activated protein(MAP)kinase and glyceraldehyde 3-phosphate dehydrogenase(GAPDH).Phosphorylation levels were quantified by densitometric analysis.Hippocampal volume was analysed using a voxel-based specific regional analysis system for Alzheimer’s disease on magnetic resonance imaging,which proposes the Z-score as a parameter that reflects hippocampal volume.RESULTS The levels of phosphorylated Akt corrected with phosphorylated p38 MAP kinase were inversely correlated with the Z-scores in the T2DM subjects,whereas the levels of phosphorylated Akt corrected with GAPDH were not.However,this relationship was not observed in the control patients.CONCLUSION These results suggest that an inverse relationship may exist between platelet Akt activation and hippocampal atrophy in T2DM patients.Our findings provide insight into the molecular mechanisms underlying T2DM hippocampal atrophy.
文摘Neurodegeneration affects a large number of cell types including neurons,astrocytes or oligodendrocytes,and neural stem cells.Neural stem cells can generate new neuronal populations through proliferation,migration,and differentiation.This neurogenic potential may be a relevant factor to fight neurodegeneration and aging.In the last years,we can find growing evidence suggesting that melatonin may be a potential modulator of adult hippocampal neurogenesis.The lack of therapeutic strategies targeting neurogenesis led researchers to explore new molecules.Numerous preclinical studies with melatonin observed how melatonin can modulate and enhance molecular and signaling pathways involved in neurogenesis.We made a special focus on the connection between these modulation mechanisms and their implication in neurodegeneration,to summarize the current knowledge and highlight the therapeutic potential of melatonin.
基金the National Natural Science Foundation of China(82001190)Natural Sci⁃ence Foundation of Shandong Province(ZR2021LZY016)+1 种基金Natural Science Foundation of Shandong Province(ZR2020MH348)Science and Technology Foundation of Shandong Traditional Chinese Medicine(2020Q035)。
文摘OBJECTIVE To investigate whether electroacupuncture(EA)ameliorates abnormal trigeminal neuralgia(TN)orofacial pain and anxiety-like behavior by altering synaptic plasticity in the hippocampus CA1.METHODS A mouse infraorbital nerve transection model(pTION)of neuropathic pain was established,and EA or sham EA was used to treat ipsilateral acu⁃puncture points(GV20-Baihui and ST7-Xia⁃guan).Golgi-Cox staining and transmission elec⁃tron microscopy(TEM)were administrated to observe the changes of synaptic plasticity in the hippocampus CA1.RESULTS Stable and persistent orofacial allodynia and anxiety-like behav⁃iors induced by pT-ION were related to changes in hippocampal synaptic plasticity.Golgi stain⁃ings showed a decrease in the density of dendritic spines,especially mushroom-type dendritic spines,in hippocampal CA1 neurons of pT-ION mice.TEM results showed that the density of synapses,membrane thickness of the postsynaptic density,and length of the synaptic active zone were decreased,whereas the width of the synaptic cleft was increased in pTION mice.EA attenu⁃ated pT-ION-induced orofacial allodynia and anx⁃iety-like behaviors and effectively reversed the abnormal changes in dendritic spines and syn⁃apse of the hippocampal CA1 region.CONCLU⁃SION EA modulates synaptic plasticity of hippo⁃campal CA1 neurons,and reduces abnormal oro⁃facial pain and anxiety-like behavior,providing evidence for a TN treatment strategy.
基金the National Natural Science Foundation of China(Grant No.82173803,81872847).
文摘Background:Hippocampal damage caused by status epilepticus(SE)can bring about cognitive decline and emotional disorders,which are common clinical comorbidities in patients with epilepsy.It is therefore imperative to develop a novel therapeutic strat-egy for protecting hippocampal damage after SE.Mitochondrial dysfunction is one of contributing factors in epilepsy.Given the therapeutic benefits of mitochondrial replenishment by exogenous mitochondria,we hypothesized that transplantation of mitochondria would be capable of ameliorating hippocampal damage following SE.Methods:Pilocarpine was used to induced SE in mice.SE-generated cognitive de-cline and emotional disorders were determined using novel object recognition,the tail suspension test,and the open field test.SE-induced hippocampal pathology was assessed by quantifying loss of neurons and activation of microglia and astrocytes.The metabolites underlying mitochondrial transplantation were determined using metabonomics.Results:The results showed that peripheral administration of isolated mitochon-dria could improve cognitive deficits and depressive and anxiety-like behaviors.Exogenous mitochondria blunted the production of reactive oxygen species,pro-liferation of microglia and astrocytes,and loss of neurons in the hippocampus.The metabonomic profiles showed that mitochondrial transplantation altered multiple metabolic pathways such as sphingolipid signaling pathway and carbon metabolism.Among potential affected metabolites,mitochondrial transplantation decreased levels of sphingolipid(d18:1/18:0)and methylmalonic acid,and elevated levels of D-fructose-1,6-bisphosphate.Conclusion:To the best of our knowledge,these findings provide the first direct ex-perimental evidence that artificial mitochondrial transplantation is capable of amelio-rating hippocampal damage following SE.These new findings support mitochondrial transplantation as a promising therapeutic strategy for epilepsy-associated psychiat-ric and cognitive disorders.
基金supported by the Medical Scientist Training Program(T32 GM008444)Mechanistic Study of Declining Hippocampal Neurogenesis in the Aging Brain(R01AG066912 to S.G.)。
文摘Adult neurogenesis is the creation of new neurons which integrate into the existing neural circuit of the adult brain.Recent evidence suggests that adult hippocampal neurogenesis(AHN)persists throughout life in mammals,including humans.These newborn neurons have been implicated to have a crucial role in brain functions such as learning and memory.Importantly,studies have also found that hippocampal neurogenesis is impaired in neurodegenerative and neuropsychiatric diseases.Alzheimer’s disease(AD)is one of the most common forms of dementia affecting millions of people.Cognitive dysfunction is a common symptom of AD patients and progressive memory loss has been attributed to the degeneration of the hippocampus.Therefore,there has been growing interest in identifying how hippocampal neurogenesis is affected in AD.However,the link between cognitive decline and changes in hippocampal neurogenesis in AD is poorly understood.In this review,we summarized the recent literature on AHN and its impairments in AD.
基金funded by the National Natural Science Foundation of China General [Grant No.81172620,No.81402629,and No.61401497]Innovation Foundation of Academy of Military Medical Sciences [2017CXJJ17,2015CXJJ06]
文摘Objective To detect the effects of microwave on calcium levels in primary hippocampal neurons and primary cardiomyocytes by the real-time microwave exposure combined with laser scanning confocal microscopy. Methods The primary hippocampal neurons and primary cardiomyocytes were cultured and labeled with probes, including Fluo-4 AM, Mag-Fluo-AM, and Rhod-2, to reflect the levels of whole calcium [Ca^(2+)], endoplasmic reticulum calcium [Ca^(2+)]ER, and mitochondrial calcium [Ca^(2+)]MIT, respectively. Then, the cells were exposed to a pulsed microwave of 2.856 GHz with specific absorption rate(SAR) values of 0, 4, and 40 W/kg for 6 min to observe the changes in calcium levels. Results The results showed that the 4 and 40 W/kg microwave radiation caused a significant decrease in the levels of [Ca^(2+)], [Ca^(2+)]ER, and [Ca^(2+)]MIT in primary hippocampal neurons. In the primary cardiomyocytes, only the 40 W/kg microwave radiation caused the decrease in the levels of [Ca^(2+)], [Ca^(2+)]ER, and [Ca^(2+)]MIT. Primary hippocampal neurons were more sensitive to microwave exposure than primary cardiomyocytes. The mitochondria were more sensitive to microwave exposure than the endoplasmic reticulum. Conclusion The calcium efflux was occurred during microwave exposure in primary hippocampal neurons and primary cardiomyocytes. Additionally, neurons and mitochondria were sensitive cells and organelle respectively.
基金supported by the Natural Science Foundation of Fujian Province of China,No.2014J01327the Program for New Century Excellent Talents in Colleges and Universities of Fujian Province of China,No.NCETFJ-0704the Professorial Academic Development Foundation of Fujian Medical University of China,No.JS09014(all to GYZ)
文摘Ilexonin A is a compound isolated from the root of Ilex pubescens,a traditional Chinese medicine.Ilexonin A has been shown to play a neuroprotective role by regulating the activation of astrocytes and microglia in the peri-infarct area after ischemia.However,the effects of ilexonin A on astrocytes and microglia in the infarct-free region of the hippocampal CA1 region remain unclear.Focal cerebral ischemia models were established by 2-hour occlusion of the middle cerebral artery in rats.Ilexonin A(20,40 or 80 mg/kg)was administered immediately after ischemia/reperfusion.The astrocyte marker glial fibrillary acidic protein,microglia marker Iba-1,neural stem cell marker nestin and inflammation markers were detected by immunohistochemistry and western blot assay.Expression levels of tumor necrosis factor-αand interleukin 1βwere determined by enzyme linked immunosorbent assay in the hippocampal CA1 tissue.Astrocytes were activated immediately in progressively increasing numbers from 1,3,to 7 days post-ischemia/reperfusion.The number of activated astrocytes further increased in the hippocampal CA1 region after treatment with ilexonin A.Microglial cells remained quiescent after ischemia/reperfusion,but became activated after treatment with ilexonin A.Ilexonin A enhanced nestin expression and reduced the expression of tumor necrosis factor-αand interleukin 1βin the hippocampus post-ischemia/reperfusion.The results of the present study suggest that ilexonin A has a neuroprotective effect in the hippocampus after ischemia/reperfusion,probably through regulating astrocytes and microglia activation,promoting neuronal stem cell proliferation and reducing the levels of pro-inflammatory factors.This study was approved by the Animal Ethics Committee of the Fujian Medical University Union Hospital,China.
基金supported by the National Natural Science Foundation of China,No.81160169(to JL),81460214(to JL),31660270(to JD),31460255(to JD)the Natural Science Foundation of Ningxia Hui Autonomous Region of China,No.2018AAC02005(to JL)
文摘N-methyl-D-aspartate receptor hypofunction is the basis of pathophysiology in schizophrenia. Blocking the N-methyl-D-aspartate receptor impairs learning and memory abilities and induces pathological changes in the brain. Previous studies have paid little attention to the role of the N-methyl-D-aspartate receptor subunit 1 (NR1) in neurogenesis in the hippocampus of schizophrenia. A mouse model of schizophrenia was established by intraperitoneal injection of 0.6 mg/kg MK-801, once a day, for 14 days. In N-methyl-D-aspartate-treated mice, N-methyl-D-aspartate was administered by intracerebroventricular injection in schizophrenia mice on day 15. The number of NR1-, Ki67- or BrdU-immunoreactive cells in the dentate gyrus was measured by immunofluorescence staining. Our data showed the number of NR1-immunoreactive cells increased along with the decreasing numbers of BrdU- and Ki67-immunoreactive cells in the schizophrenia groups compared with the control group. N-methyl-D-aspartate could reverse the above changes. These results indicated that NR1 can regulate neurogenesis in the hippocampal dentate gyrus of schizophrenia mice, supporting NR1 as a promising therapeutic target in the treatment of schizophrenia. This study was approved by the Experimental Animal Ethics Committee of the Ningxia Medical University, China (approval No. 2014-014) on March 6, 2014.
基金supported by the Key Discipline Construction Project of the Union Hospital of Fujian Province,China,No.Δ211002#
文摘Hippocampal neurons undergo various forms of cell death after status epilepticus.Necrostatin-1 specifically inhibits necroptosis mediated by receptor interacting protein kinase 1 (RIP1) and RIP3 receptors.However,there are no reports of necroptosis in mouse models of status epilepticus.Therefore,in this study,we investigated the effects of necrostatin-1 on hippocampal neurons in mice with status epilepticus,and,furthermore,we tested different amounts of the compound to identify the optimal concentration for inhibiting necroptosis and apoptosis.A mouse model of status epilepticus was produced by intraperitoneal injection of kainic acid,12 mg/kg.Different concentrations of necrostatin- 1 (10,20,40,and 80 μM) were administered into the lateral ventricle 15 minutes before kainic acid injection.Hippocampal damage was assessed by hematoxylin-eosin staining 24 hours after the model was successfully produced.Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining,western blot assay and immunohistochemistry were used to evaluate the expression of apoptosis-related and necroptosis-related proteins.Necrostatin-1 alleviated damage to hippocampal tissue in the mouse model of epilepsy.The 40 μM concentration of necrostatin-1 significantly decreased the number of apoptotic cells in the hippocampal CA1 region.Furthermore,necrostatin-1 significantly downregulated necroptosis-related proteins (MLKL,RIP1,and RIP3) and apoptosis-related proteins (cleaved-Caspase-3,Bax),and it upregulated the expression of anti-apoptotic protein Bcl-2.Taken together,our findings show that necrostatin-1 effectively inhibits necroptosis and apoptosis in mice with status epilepticus,with the 40 μM concentration of the compound having an optimal effect.The experiments were approved by the Animal Ethics Committee of Fujian Medical University,China (approval No.2016-032) on November 9,2016.
基金supported by the National Natural Science Foundation of China,No.81774102 (to LLW)。
文摘Icariin(ICA) has a significant capacity to protect against depression and hippocampal injury,but it cannot effectively cross the bloodbrain barrier and accumulate in the brain.Therefore,the mechanism by which ICA protects against hippocampal injury in depression remains unclear.In this study,we performed proteomics analysis of cerebrospinal fluid to investigate the mechanism by which ICA prevents dysfunctional hippocampal neurogenesis in depression.A rat model of depression was established through exposure to chronic unpredictable mild stress for 6 weeks,after which 120 mg/kg ICA was administered subcutaneously every day.The results showed that ICA alleviated depressive symptoms,learning and memory dysfunction,dysfunctional neurogenesis,and neuronal loss in the dentate gyrus of rats with depression.Neural stem cells from rat embryonic hippocampi were cultured in media containing 20% cerebrospinal fluid from each group of rats and then treated with 100 μM corticosterone.The addition of cerebrospinal fluid from rats treated with ICA largely prevented the corticosterone-mediated inhibition of neuronal proliferation and differentiation.Fifty-two differentially expressed proteins regulated by chronic unpredictable mild stress and ICA were identified through proteomics analysis of cerebrospinal fluid.These proteins were mainly involved in the ribosome,PI3 K-Akt signaling,and interleukin-17 signaling pathways.Parallel reaction monitoring mass spectrometry showed that Rps4 x,Rps12,Rps14,Rps19,Hsp90 b1,and Hsp90 aa1 were up-regulated by chronic unpredictable mild stress and down-regulated by ICA.In contrast,Htr A1 was down-regulated by chronic unpredictable mild stress and up-regulated by ICA.These findings suggest that ICA can prevent depression and dysfunctional hippocampal neurogenesis through regulating the expression of certain proteins found in the cerebrospinal fluid.The study was approved by the Experimental Animal Ethics Committee of Guangzhou University of Chinese Medicine of China in March 2017.
基金supported by the Special Grant for Scientific and Technological Development Conducted by The Central Government of China in 2016:Quality Test and Operation with Anesthesia Center of Experimental Animal of Hubei Province,No.2060403(to BHZ)
文摘Glucagon-like peptide-1 receptor has anti-apoptotic,anti-inflammatory,and neuroprotective effects.It is now recognized that the occurrence and development of chronic pain are strongly associated with anti-inflammatory responses;however,it is not clear whether glucagon-like peptide-1 receptor regulates chronic pain via anti-inflammatory mechanisms.We explored the effects of glucagon-like peptide-1 receptor on nociception,cognition,and neuroinflammation in chronic pain.A rat model of chronic pain was established using left L5 spinal nerve ligation.The glucagon-like peptide-1 receptor agonist exendin-4 was intrathecally injected into rats from 10 to 21 days after spinal nerve ligation.Electrophysiological examinations showed that,after treatment with exendin-4,paw withdrawal frequency of the left limb was significantly reduced,and pain was relieved.In addition,in the Morris water maze test,escape latency increased and the time to reach the platform decreased following exendin-4 treatment.Immunohistochemical staining and western blot assays revealed an increase in the numbers of activated microglia and astrocytes in the dentate gyrus of rat hippocampus,as well as an increase in the expression of tumor necrosis factor alpha,interleukin 1 beta,and interleukin 6.All of these effects could be reversed by exendin-4 treatment.These findings suggest that exendin-4 can alleviate pain-induced neuroinflammatory responses and promote the recovery of cognitive function via the glucagon-like peptide-1 receptor pathway.All experimental procedures and protocols were approved by the Experimental Animal Ethics Committee of Renmin Hospital of Wuhan University of China(approval No.WDRM 20171214)on September 22,2017.
基金This work was supported by the Startup Grant for ZZ from the Department of Natural Sciences,University of Michigan-Dearborn and“CASL Faculty Summer Research Grant”for ZZ from Office of Research&Sponsored Programs,University of Michigan-Dearborn.
文摘Traumatic brain injury(TBI)is a major cause of mortality and morbidity in the pediatric population.With advances in medical care,the mortality rate of pediatric TBI has declined.However,more children and adolescents are living with TBI-related cognitive and emotional impairments,which negatively affects the quality of their life.Adult hippocampal neurogenesis plays an important role in cognition and mood regulation.Alterations in adult hippocampal neurogenesis are associated with a variety of neurological and neurodegenerative diseases,including TBI.Promoting endogenous hippocampal neurogenesis after TBI merits significant attention.However,TBI affects the function of neural stem/progenitor cells in the dentate gyrus of hippocampus,which results in aberrant migration and impaired dendrite development of adult-born neurons.Therefore,a better understanding of adult hippocampal neurogenesis after TBI can facilitate a more successful neuro-restoration of damage in immature brains.Secondary injuries,such as neuroinflammation and oxidative stress,exert a significant impact on hippocampal neurogenesis.Currently,a variety of therapeutic approaches have been proposed for ameliorating secondary TBI injuries.In this review,we discuss the uniqueness of pediatric TBI,adult hippocampal neurogenesis after pediatric TBI,and current efforts that promote neuroprotection to the developing brains,which can be leveraged to facilitate neuroregeneration.
基金supported by the National Natural Science Foundation of China,No.81072861,81373727
文摘To observe the effects of different acupuncture manipulations on blood pressure and target organ damage in spontaneously hypertensive rats(SHRs), this study used the reinforcing twirling method(1.5–2-mm depth; rotating needle clockwise for 360° and then counter clockwise for 360°, with the thumb moving heavily forward and gently backward, 60 times per minute for 1 minute, and retaining needle for 9 minutes), the reducing twirling method(1.5–2-mm depth; rotating needle counter clockwise for 360° and then clockwise for 360°, with the thumb moving heavily backward and gently forward, 60 times per minute for 1 minute, and retaining needle for 9 minutes), and the needle retaining method(1.5–2-mm depth and retaining the needle for 10 minutes). Bilateral Taichong(LR3) was treated by acupuncture using different manipulations and manual stimulation. Reinforcing twirling, reducing twirling, and needle retaining resulted in a decreased number of apoptotic cells, reduced Bax m RNA and protein expression, and an increased Bcl-2/Bax ratio in the hippocampus compared with the SHR group. Among these groups, the Bcl-2/Bax protein ratio was highest in the reducing twirling group, and the Bcl-2/Bax m RNA ratio was highest in the needle retaining group. These results suggest that reinforcing twirling, reducing twirling, and needle retaining methods all improve blood pressure and prevent target organ damage by increasing the hippocampal Bcl-2/Bax ratio and inhibiting cell apoptosis in the hippocampus in SHR.
文摘Glial glutamate transporter-1(GLT-1)is the predominant subtype of glutamate transporters and is responsible for the clearance of extracellular glutamate and for limiting the concentration of extracellular glutamate.Our previous studies have shown that the up-regulation of GLT-1 expression plays an important role
文摘Several lines of evidence have established that proliferation and differentiation of neural stem cells into neurons within the sub-granular zone of the dentate gyrus,a process named adult hippocampal neurogenesis,contribute to maintaining healthy cognitive functions throughout life.The rate of adult hippocampal neurogenesis decreases with aging and a premature impairment of adult hippocampal neurogenesis has been observed both in animal models of Alzheimer’s disease and human post-mortem tissues.The causal relationship between adult hippocampal neurogenesis and the development of Alzheimer’s disease pathology has,however,not been established.This is partly due to the limitation of recapitulating the development of Alzheimer’s disease pathology in rodent models and the lack of translatable biomarkers to identify tractable targets in humans.While it is tempting to postulate that adult hippocampal neurogenesis could be leveraged to improve cognitive deficits in Alzheimer’s disease,consensual results have yet to be reached to fully explore this hypothesis.In this review,we discuss how the recent progress in identifying molecular pathways in adult hippocampal neurogenesis provides a good framework to initiate strategies for drug-based intervention in neurodegenerative diseases,especially in Alzheimer’s disease.We outline how discrepancies in pre-clinical disease models and experimental methodology have resulted in contradictory findings and propose a shift towards using more translatable approaches to model neurogenesis in Alzheimer’s disease.In particular,we review how exploring novel experimental paradigms including the use of human induced pluripotent stem cells and more complex cell culture systems,as well as standardizing protocols used to investigate evidence of neurogenesis in human tissues,could deliver deeper mechanistic insights that would kick-start innovative drug discovery efforts to promote healthy aging and cellular rejuvenation.
基金supported by grants from Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica(PAPIIT):203015,208518Consejo Nacional de Ciencia y Tecnología(CONACyT):282470(all to AZ)
文摘Adult hippocampal neurogenesis is a finely tuned process regulated by extrinsic factors. Neuroinflammation is a hallmark of several pathological conditions underlying dysregulation of neurogenesis. In animal models, lipopolysaccharide(LPS)-induced neuroinflammation leads to a neurogenic decrease mainly associated to the early inflammatory response. However, it is not well understood how the neuroinflammatory response progresses over time and if neurogenesis continues to be diminished during the late neuroinflammatory response. Moreover, it is unknown if repeated intermittent administration of LPS along time induces a greater reduction in neurogenesis. We administered one single intraperitoneal injection of LPS or saline or four repeated injections(one per week) of LPS or saline to young-adult mice. A cohort of new cells was labeled with three 5-bromo-2-deoxyuridine injections(one per day) 4 days after the last LPS injection. We evaluated systemic and neuroinflammation-associated parameters and compared the effects of the late neuroinflammatory response on neurogenesis induced by each protocol. Our results show that 1) a single LPS injection leads to a late pro-inflammatory response characterized by microglial activation, moderate astrocytic reaction and increased interleukin-6 levels. This response correlates in time with decreased neurogenesis and 2) a repeated intermittent injection of LPS does not elicit a late pro-inflammatory response although activated microglia persists. The latter profile is not accompanied by a continued longterm hippocampal neurogenic decrease. Hereby, we provide evidence that the neuroinflammatory response is a dynamic process that progresses in a milieu-dependent manner and does not necessarily lead to a neurogenic decrease, highlighting the complex interaction between the immune system and neurogenesis.
基金supported by the National Natural Science Foundation of China,No.81160244,81360316,81460283,81660307(all to GS)the Inner Mongolia Science Foundation of China,No.2018LH08078(to GS),2016MS(LH)0307(to SYJ)+4 种基金the Baotou Health Foundation,China,No.WSJJ2016008(to SYJ)the Inner Mongolia Educational Research Foundation of China,No.NJZY207(to GS),NJZY17243(to SCY),NJZY17250(to XLL),NJZY17251(to SYJ)the Baotou Medical College Foundation of China,No.BYJJ-DF201602,BYJJ-YF201615,BSJJ201617,BYJJ-QM201633,BYJJ-QM201656,BYJJ201502(to GS)the Science and Technology Planning Project of Baotou of China,No.CX2017-5(to GS)the National Key R&D Program of China,No.2017YFC1308405(to GS)
文摘Bisperoxo(1,10-phenanthroline) oxovanadate(BpV) can reportedly block the cell cycle. The present study examined whether BpV alters gene expression by affecting DNA methyltransferases(DNMTs), which would impact the cell cycle. Immortalized mouse hippocampal neuronal precursor cells(HT_(22)) were treated with 0.3 or 3 μM BpV. Proliferation, morphology, and viability of HT_(22) cells were detected with an IncuCyte real-time video imaging system or inverted microscope and 3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethonyphenol)-2-(4-sulfophenyl)-2H-tetrazolium, respectively. mRNA and protein expression of DNMTs and p21 in HT_(22) cells was detected by real-time polymerase chain reaction and immunoblotting, respectively. In addition, DNMT activity was measured with an enzyme-linked immunosorbent assay. Effects of BpV on the cell cycle were analyzed using flow cytometry. Results demonstrated that treatment with 0.3 μM BpV did not affect cell proliferation, morphology, or viability; however, treatment with 3 μM BpV decreased cell viability, increased expression of both DNMT3B mRNA and protein, and inhibited the proliferation of HT_(22) cells; and 3 μM BpV also blocked the cell cycle and increased expression of the regulatory factor p21 by increasing DNMT expression in mouse hippocampal neurons.
基金supported by the National Natural Science Foundation of China,No.31571109,81460261the Chinese-Finnish Joint Project Fund,No.813111172+2 种基金a grant from the Yunnan Key Program of Science and Technology of China,No.2014FC005the Key Science and Technology Research Project Fund of Hainan Province of China,No.ZDYF2016156the National Clinical Key Subject Construction Project Fund of China
文摘Rhesus monkey neural stem cells are capable of differentiating into neurons and glial cells.Therefore,neural stem cell transplantation can be used to promote functional recovery of the nervous system.Rhesus monkey neural stem cells(1×105 cells/μL) were injected into bilateral hippocampi of rats with hippocampal lesions.Confocal laser scanning microscopy demonstrated that green fluorescent protein-labeled transplanted cells survived and grew well.Transplanted cells were detected at the lesion site,but also in the nerve fiber-rich region of the cerebral cortex and corpus callosum.Some transplanted cells differentiated into neurons and glial cells clustering along the ventricular wall,and integrated into the recipient brain.Behavioral tests revealed that spatial learning and memory ability improved,indicating that rhesus monkey neural stem cells noticeably improve spatial learning and memory abilities in rats with hippocampal lesions.
