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Objective To explore the anti-depression mechanism of Kai-Xin-San(KXS)via regulation of neurogenesis in hippocampus of depression-like mice.Methods The extracts of KXS were prepared and the anti-depression effects of KXS were evaluated by behavioral tests on chronic unpredictable mild stress(CUMS)induced depression-like mice.Evaluating depression-like behavior in CUMS mice through sucrose preference test,forced swimming test,tail suspension test,and other methods.Neurogenesis in hippocampus were determined by immunofluorescence assay.In addition,effects of KXS on regulating nestin expression and Wnt/b-catenin signaling pathway were explored by western blotting analysis.Amounts of cortisol,corticotropin-releasing factor(CRF),adrenocorticotropic hormone(ACTH),brain-derived neurotrophic factor(BDNF)and nerve growth factor(NGF)were determined by ELISA tests.Mouse primary neural stem cells(NSC)was used to evaluate the effect of KXS on promoting its proliferation by immunofluorescence assay.In addition,effects of KXS on regulating nestin and Wnt/β-catenin signaling pathway were also explored by Western blotting analysis.Results KXS significantly ameliorated the depression-like behaviors in presence of increased sucrose preference rate and decreased immobile time of tail suspension and forced swimming.KXS significantly promoted the neurogenesis in the hippocampus and expressions of nestin,reduced the expressions of cortisol,CRF,ACTH,increased the expressions of BDNF,NGF,and regulated Wnt/β-catenin signaling pathway.KXS also promoted the proliferation of NSCs and expressions of nestin,enhanced the translocation of b-catenin into nucleus,and regulated the expressions of proteins of Wnt/β-catenin signaling pathway.Conclusion KXS promoted neurogenesis in hippocampus and regulated Wnt/β-catenin pathway,which might contribute to its antidepressant effect.
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BACKGROUND:Exercise improves Alzheimer's disease,dementia,and age-related cognitive abilities.A potential mediator between exercise and these health benefits may be adult hippocampal neurogenesis.Therefore,it is of great significance to explore whether and how exercise affects the adult hippocampal neurogenesis process in Alzheimer's disease mice. OBJECTIVE:To observe the effect of aerobic exercise on adult hippocampal neurogenesis of Alzheimer's disease mice,and to explore whether aerobic exercise can promote their adult hippocampal neurogenesis. METHODS:Three-month-old wild-type(C57BL/6Jnju)and APP/PS1 double transgenic Alzheimer's disease mice were randomly divided into four groups:wild control group,wild exercise group,Alzheimer's disease control group and Alzheimer's disease exercise group,with 20 mice in each group.The control group did not do exercise,and the exercise group did aerobic exercise for 5 months.After exercise intervention,real-time PCR,immunofluorescence and western blot assay were used to detect the expression levels of DCX,Ki67,βIII-tubulin and NeuN in the hippocampal tissue of mice in each group. RESULTS AND CONCLUSION:The expressions of DCX,βIII-tubulin and NeuN in the hippocampal dentate gyrus in the Alzheimer's disease control group were significantly lower than those in the wild control group(P<0.05).The expressions of DCX,Ki67,βIII-tubulin and NeuN were significantly higher in the hippocampal dentate gyrus in the Alzheimer's disease exercise group than those in the Alzheimer's disease control group(P<0.05).It is indicated that long-term aerobic exercise intervention can strengthen the proliferation,migration and differentiation of neurons during adult hippocampal neurogenesis and significantly increase the number of neuronal precursor cells and new neurons in Alzheimer's disease mice.
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ObjectiveThis study aims to investigate the effectiveness and potential mechanism of Erxian Decoction （二仙汤） for late-onset depression （LOD）. MethodsForty Wistar male rats of 7-8 weeks were divided into 20 each of normal group and youth depression group. Sixty Wistar male rats of 20 months were divided into 20 each of elder group， LOD group and Erxian Decoction group. The rats in youth depression group were modelled with chronic unpredictable mild stress （CUMS） for 6 weeks to build a depression model， and the elder rats in LOD group and Erxian Decoction group were modelled with CUMS for 6 weeks to build a LOD model， with no interventions in the normal group and the elder group. Gastric administration was carried out at the same time of modelling， rats in Erxian Decoction group were given 8 g/（kg·d） of Erxian Decoction by gavage， and rats in the normal group， youth depression group， elder group， and LOD group were given 4 ml/（kg·d） of pure water by gavage， for 6 weeks in each group. Sugar water preference experiment and forced swimming experiment were used to evaluate the depression-like behaviour of rats， absent field experiment was used to evaluate the spontaneous activity ability of rats， and T-maze experiment was used to evaluate the cognitive function of rats； Western blot assay was used to detect neuronal nuclei （NeuN）， nestin， doublecortin （DCX） in hippocampal tissue， and zonula occludens-l （ZO-1）， folate receptor α （FRα）， reduced folate carrier （RFC）， and protoncoupledfolate transporter （PCFT） protein expression in choroid plexus； immunofluorescence was used to detect the number of double-positive cells for Ki-67/nestin， the number of double-positive cells for 5-bromodeoxyuracil nucleoside （BrdU）/DCX in hippocampal dentate gyrus， and the protein expression of ZO-1， FRα， RFC， and PCFT in choroid plexus tissues； ELISA technique was used to detect plasma， cerebrospinal fluid， 5-methyltetrahydrofolate （5-MTHF） in hippocampal tissues； Pearson correlation analysis was used to correlate the 5-MTHF content in cerebrospinal fluid and hippocampal tissues and the expression of nestin， DCX， and NeuN proteins in hippocampal tissues of rats in youth depression group and LOD group. ResultsCompared with normal group， rats in youth depression group and LOD group showed reduced sugar water preference， reduced total distance travelled in the absent field， reduced number of times through the grid， prolonged forced swimming immobilisation， reduced hippocampal NeuN， nestin and DCX protein expression， reduced number of Ki-67/nestin double-positive cells in hippocampal dentate gyrus， reduced number of BrdU/DCX double-positive cells in hippocampal dentate gyrus， and reduced expression of ZO-1 and FRα proteins and fluorescence intensity （P＜0.05 or P＜0.01）； the correct rate of T-maze on days 3 and 4 in the rats of youth depression group and on days 2 to 4 in the rats of LOD group significantly decreased， and the content of 5-MTHF in the cerebrospinal fluid and hippocampal tissues of the rats of LOD group significantly decreased as well （P＜0.05 or P＜0.01）. Compared with youth depression group， rats in LOD group showed a decrease in total distance travelled in absenteeism， number of times through the grid， a significant decrease in the correct rate of the T-maze on day 1-4， a decrease in NeuN， nestin， DCX protein expression of hippocampal tissue and the number of Ki-67/nestin double-positive cells， BrdU/DCX double-positive cells of hippocampal dentate gyrus （P＜0.05 or P＜0.01）. Compared with LOD group， rats in Erxian Decoction group had elevated sugar-water preference and total distance travelled in absenteeism and number of times through the grid， shorter forced swimming immobility time， significantly higher correct rate of the T-maze on day 3-4， elevated expression of NeuN， nestin， and DCX proteins in hippocampal tissues， increased number of Ki-67/nestin double-positive cells and BrdU/DCX double-positive cells in hippocampal dentate gyrus， and increased 5-MTHF content in cerebrospinal fluid and hippocampal， and ZO-1， FRα， RFC， PCFT protein expression and fluorescence intensity increased in choroid plexus （P＜0.05 or P＜0.01）. Correlation analysis showed that there was a positive correlation between 5-MTHF content in cerebrospinal fluid （r = 0.466）， hippocampal tissue （r = 0.522） and nestin expression in hippocampal tissue （P＜0.05）. ConclusionErxian Decoction could improve depressive-like behaviour and cognitive impairment in LOD model rats， and its mechanism may promote hippocampal neurogenesis by alleviating structural damage to the choroid plexus of the brain tissue， and improving impaired choroid plexus folate transport.
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ObjectiveTo decipher the mechanism of Wenxiao powder in alleviating corticosterone-induced depression-like behaviors in mice. MethodMale ICR mice were randomized into normal， model， paroxetine （20 mg·kg-1）， and low- and high-dose （3.27， 6.54 g·kg-1， respectively） Wenxiao powder groups. The mice in normal and model groups received equal volume of saline. Other groups except the normal group were injected with corticosterone subcutaneously 0.5 h after gavage to induce depression. Mice were tested for depression-like behaviors after drug administration. Enzyme-linked immunosorbent assay （ELISA） was performed to measure the corticosterone content in the serum. Nissl staining was performed to observe the damage of hippocampal neurons. Immunofluorescence staining was employed to observe the expression of double cortin （DCX） in the dentate gyrus （DG） of the hippocampus. Western blot was employed to determine the expression of proteins in the brain-derived neurotrophic factor （BDNF）/tyrosine kinase receptor B （TrkB）/extracellular signal-regulated kinase （ERK）/cAMP-response element-binding protein （CREB） pathway in the hippocampus. ResultCompared with the normal group， the model group showed decreased sucrose preference rate， increased immobility time in the tail suspension test （P<0.01）， and reduced residence time in the central area of the open field and the total movement distance （P<0.05， P<0.01）. In addition， the modeling elevated the corticosterone level in the serum （P<0.01）， decreased the volume and intensified the nuclear staining of hippocampal neurons in the DG area， reduced the expression of DCX in the DG area， and down-regulated the protein levels of BDNF， phosphorylated （p）-TrkB， p-ERK， and p-CREB in the hippocampus （P<0.05， P<0.01）. Compared with the model group， low-dose Wenxiao powder improved the mouse behavivors in the sucrose preference， open field， and tail suspension tests （P<0.05， P<0.01）， and high-dose Wenxiao powder improved the behaviors in the sucrose preference and open field tests （P<0.05， P<0.01）. In addition， Wenxiao powder lowered the serum corticosterone level （P<0.01） and recovered the structure and morphology of neurons with obvious nuclei and presence of Nissl bodies in the DG area of the hippocampus. Moreover， Wenxiao powder at both doses promoted the expression of DCX in the DG area， and high-dose Wenxiao powder up-regulated the protein levels of BDNF， p-TrkB， p-ERK， and p-CREB in the hippocampus （P<0.05， P<0.01）. ConclusionWenxiao powder can alleviate corticosterone-induced depression-like behaviors and promote neurogenesis in mice possibly by activating the BDNF/TrkB/ERK/CREB signaling pathway.
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Interactions between brain-resident and peripheral infiltrated immune cells are thought to contribute to neuroplasticity after cerebral ischemia. However, conventional bulk sequencing makes it challenging to depict this complex immune network. Using single-cell RNA sequencing, we mapped compositional and transcriptional features of peri-infarct immune cells. Microglia were the predominant cell type in the peri-infarct region, displaying a more diverse activation pattern than the typical pro- and anti-inflammatory state, with axon tract-associated microglia (ATMs) being associated with neuronal regeneration. Trajectory inference suggested that infiltrated monocyte-derived macrophages (MDMs) exhibited a gradual fate trajectory transition to activated MDMs. Inter-cellular crosstalk between MDMs and microglia orchestrated anti-inflammatory and repair-promoting microglia phenotypes and promoted post-stroke neurogenesis, with SOX2 and related Akt/CREB signaling as the underlying mechanisms. This description of the brain's immune landscape and its relationship with neurogenesis provides new insight into promoting neural repair by regulating neuroinflammatory responses.
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Humanos , Accidente Cerebrovascular Isquémico , Encéfalo/metabolismo , Macrófagos , Isquemia Encefálica/metabolismo , Microglía/metabolismo , Perfilación de la Expresión Génica , Antiinflamatorios , Plasticidad Neuronal/fisiología , Infarto/metabolismoRESUMEN
The seat of human intelligence is the human cerebral cortex, which is responsible for our exceptional cognitive abilities. Identifying principles that lead to the development of the large-sized human cerebral cortex will shed light on what makes the human brain and species so special. The remarkable increase in the number of human cortical pyramidal neurons and the size of the human cerebral cortex is mainly because human cortical radial glial cells, primary neural stem cells in the cortex, generate cortical pyramidal neurons for more than 130 days, whereas the same process takes only about 7 days in mice. The molecular mechanisms underlying this difference are largely unknown. Here, we found that bone morphogenic protein 7 (BMP7) is expressed by increasing the number of cortical radial glial cells during mammalian evolution (mouse, ferret, monkey, and human). BMP7 expression in cortical radial glial cells promotes neurogenesis, inhibits gliogenesis, and thereby increases the length of the neurogenic period, whereas Sonic Hedgehog (SHH) signaling promotes cortical gliogenesis. We demonstrate that BMP7 signaling and SHH signaling mutually inhibit each other through regulation of GLI3 repressor formation. We propose that BMP7 drives the evolutionary expansion of the mammalian cortex by increasing the length of the neurogenic period.
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Animales , Ratones , Humanos , Células Ependimogliales/metabolismo , Proteínas Hedgehog/metabolismo , Hurones/metabolismo , Corteza Cerebral , Neurogénesis , Mamíferos/metabolismo , Neuroglía/metabolismo , Proteína Morfogenética Ósea 7/metabolismoRESUMEN
Objective To investigate the effect of 5-Aza-CdR on Notch1 pathway and neural regeneration and to explore the effects of 5-Aza-CdR on learning memory ability in mice by exploring active avoidance behavior.Methods Sixty 6～8-week-old SPF-grade ICR male mice were divided into two groups.5-Aza-CdR was administered to one group of mice via lateral ventricular injection,while the control group was injected with bovine serum albumin.Notch1 and HES1 mRNA and protein expression levels were detected by Real-time PCR and Western blot 24 hours after injection;5-bromo-2'-deoxyuridine-positive cells were observed by laser confocal microscopy,and Notch1 expression in hippocampal dentate gyrus was viewed with laser confocal microscopy.Notch1 methylation changes were detected by ethylation-specific PCR,and learning and memory behaviors of mice were assessed by passive avoidance tests and shuttle avoidance assays.Results Injection of 5-Aza-CdR increased hippocampal Notch1 pathway activity,promoted neuronal regeneration in the DG region,decreased methylation levels in the Notch1 promoter region,and enhanced the ability of mice to perform active avoidance behavior.Conclusions The effect of 5-Aza-CdR on active avoidance behavior may be related to the influence of hippocampal neural regeneration through the Notch 1 pathway.
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Objective To explore the effects and mechanism of Baishile Capsules regulating SHH/Gli1 signaling pathway on hippocampal neurogenesis of depression model rats.Methods Totally 32 SD rats were randomly divided into control group,model group,fluoxetine(5.4 mg/kg)group and Baishile Capsules(2.88 g/kg)group,with 8 rats in each group.A depression rat model was established using chronic unpredictable mild stress and single cage feeding method.The model was established and administered simultaneously for 21 consecutive days.Depression-like behavior in rats were evaluated by sucrose preference experiment and open field experiment,ELISA was used to detect brain derived neurotrophic factor(BDNF)contents in rat serum and hippocampal tissue,the number of BrdU,BrdU/DCX,BrdU/NeuN positive cells in dentate gyrus of the hippocampus was observed by immunofluorescence,immunofluorescence and Western blot were used to detect the fluorescence intensity and protein expression of SHH,Gli1,Smo,Ptch in hippocampal tissue.Results Compared with the control group,the degree of sucrose preference significantly decreased in the model group(P<0.01),the number of horizontal and vertical movements significantly decreased(P<0.01),the contents of BDNF in serum and hippocampal tissue significantly decreased(P<0.05),the number of BrdU,BrdU/DCX,BrdU/NeuN positive cells in dentate gyrus of the hippocampus significantly decreased(P<0.01),and the fluorescence intensity and protein expression of SHH,Gli1,Smo,Ptch in hippocampal tissue significantly decreased(P<0.01,P<0.05).Compared with the model group,the degree of sucrose preference and the number of horizontal and vertical movements in fluoxetine group and Baishile Capsule group increased significantly(P<0.05,P<0.01),the contents of BDNF in serum and hippocampal tissue significantly increased(P<0.05,P<0.01),and the number of BrdU,BrdU/DCX,BrdU/NeuN positive cells in dentate gyrus of the hippocampus significantly increased(P<0.01,P<0.05),the fluorescence intensity and protein expressions of SHH,Gli1,Smo,Ptch in hippocampal tissue significantly increased(P<0.01,P<0.05).Conclusion Baishile Capsule can promote the hippocampus neurogenesis in depression model rats by regulating SHH/Gli1 signaling pathway,and play an antidepressant role.
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Depression is a prevalent mental illness worldwide, its multifaceted pathogenesis is still in the exploratory stage. MicroRNA (miRNA), as a crucial epigenetic regulator, plays an important role in depression. miR-124 is one of the most abundant miRNAs in the central nervous system including neurons and microglia, and involved in various biological events like neuron development and differentiation, synaptic and axonal growth, neural plasticity, inflammation and autophagy. Recent studies have reported abnormal expression of miR-124 in both depression patients and animal models. Most of the studies showed that miR-124 is upregulated in the hippocampus or prefrontal cortex in stress-induced rodent depression animal models such as CUMS, CSDS, CORT, CRS and LH but some evidence for divergence. Upregulation of miR-124 expression may be involved in depression-like behavior via CREB/BDNF/TrkB pathway, GR pathway, SIRT1 pathway, apoptosis and autophagy pathways by directly targeting these genes including Creb, Bdnf, Sirt1, Nr3c1, Ezh2 and Stat3. The downregulation of miR-124 expression in neurons is mainly involved in the neurogenesis and neuroplasticity impairments in depression by targeting the Notch signaling pathway and DDIT4/TSC1/2/mTORC1 pathway. The downregulation of miR-124 expression also was found in the activated microglia in the stress-induced models, and resulted in neuroinflammation. In summary, the abnormal expression of miR-124 in the brain of depression-related models and its related mechanisms are complex and even contradictory, and still need further research. This review provides a summary of the research progress of miR-124 in depression.
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Abstract New hippocampal neurons are continuously generated in the adult human brain. Several studies have demonstrated that the proliferation of hippocampal cells is strongly influenced by a variety of stimuli, including pesticides exposure. These effects are particularly important because neurogenesis dysregulation could be associated with the decline of neuronal and cognitive functions and the possible development of neuropsychiatric disorders.
Resumo Novos neurônios hipocampais são gerados continuamente no cérebro humano adulto. Vários estudos têm demonstrado que a proliferação de células do hipocampo é influenciada por uma variedade de estímulos, incluindo a exposição a pesticidas. Estes efeitos são particularmente importantes porque a desregulação da neurogênese pode estar associada ao declínio das funções neuronais e cognitivas e ao possível desenvolvimento de doenças neuropsiquiátricas.
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Abstract Astrocytes are the most abundant cell subtypes in the central nervous system. Previous studies believed that astrocytes are supporting cells in the brain, which only provide nutrients for neurons. However, recent studies have found that astrocytes have more crucial and complex functions in the brain, such as neurogenesis, phagocytosis, and ischemic tolerance. After an ischemic stroke, the activated astrocytes can exert neuroprotective or neurotoxic effects through a variety of pathways. In this review, we will discuss the neuroprotective mechanisms of astrocytes in cerebral ischemia, and mainly focus on reactive astrocytosis or glial scar, neurogenesis, phagocytosis, and cerebral ischemic tolerance, for providing new strategies for the clinical treatment of stroke.
Resumo Os astrócitos são os subtipos de células mais abundantes no sistema nervoso central. Estudos anteriores acreditavam que os astrócitos são células de suporte no cérebro, que apenas fornecem nutrientes para os neurônios. No entanto, estudos recentes descobriram que os astrócitos têm funções mais cruciais e complexas no cérebro, como neurogênese, fagocitose e tolerância isquêmica. Após um acidente vascular cerebral isquêmico, os astrócitos ativados podem exercer efeitos neuroprotetores ou neurotóxicos através de uma variedade de vias. Nesta revisão, discutiremos os mecanismos neuroprotetores dos astrócitos na isquemia cerebral, e focaremos principalmente na astrocitose reativa ou cicatriz glial, neurogênese, fagocitose e tolerância isquêmica cerebral, para fornecer novas estratégias para o tratamento clínico do acidente vascular cerebral.
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Objective:To evaluate the effects of whole brain irradiation (WBI) and fecal microbiota transplantation (FMT) on hippocampal neurogenesis and the composition of gut microbiota in mice.Methods:Forty specific pathogen free ICR male mice (8-week-old, weighed 30 g) were divided into four groups by simple random sample method: control group (group C), radiation group (group R), group C+FMT and group R+FMT, 10 in each group. Animal models were established by WBI at a dose of 10 Gy by 4 MeV electron beam. In group C+FMT and group R+FMT, mice were gavaged with normal fecal bacteria suspension on day 2 post-irradiation, while those in group C and group R were gavaged with phosphate buffered saline as alternative. Hippocampal tissues and feces in four groups were collected on day 15 post-irradiation. 16S rRNA sequencing was used to detect the species and abundance of fecal flora. BrdU +/NeuN + immunofluorescence staining was performed to observe the neurogenesis in hippocampus of mice. Results:WBI and FMT had no effect on survival rate and body weight of mice. WBI induced the inhibition of hippocampal neurogenesis and flora disorder. The quantity of Bacteroideae and Rumen bacteria was increased by 28.6% and 102.9%, whereas that of Lactobacillus was significantly decreased by 70.6% ( P<0.05). FMT regulated the abundance of bacteria. The abundance of Enterobacteriaceae was significantly declined by 65.1% ( P=0.028), while that of Lactobacillus was increased by 58.2% ( P=0.015). FMT also promoted hippocampal neurogenesis to some extent after WBI. Conclusions:This preliminary study demonstrates that FMT alleviates the inhibition of hippocampal neurogenesis and flora disorder induced by WBI in mice. Ionizing radiation directly acting on the whole brain of mice indirectly disturbs the composition of gut microbiota, which in turn affects the degree of hippocampal neurogenesis in the brain of mice. There is a bidirectional interaction between gut microbiota and brain.
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Dickkopf-1 (DKK1) is a secreted glycoprotein that acts as an inhibitor of the Wnt/β-catenin pathway and plays an important role in embryonic development, neurogenesis and synaptogenesis. After cerebral ischemia, DKK1 inhibits neurogenesis and angiogenesis by promoting neuronal apoptosis and blood-brain barrier damage, thus aggravating brain injury. In addition, serum DKK1 in patients with ischemic stroke was associated with different disease stages and outcomes. Therefore, the development of specific inhibitors targeting DKK1 is expected to be applied in the treatment of ischemic stroke.
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Endothelial progenitor cells (EPCs) are immature endothelial cells that can proliferate and differentiate into mature endothelial cells. After vascular injury, EPCs migrate from the bone marrow to the ischemic area, participating in damaged endothelial repair and neovascularization, providing a new potential therapeutic approach for vascular diseases including ischemic stroke. This article reviews the feasibility and limitations of EPCs as potential therapeutic targets for ischemic stroke.
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Cerebral infarction, with high incidence, high mortality, high disability and high recurrence rates, can impose a serious burden on families and society. After cerebral infarction occurrence, neurons, as the fundamental structures of the central nervous system, are unable to renew or multiply after death; hence, full recovery from neurological impairments following cerebral infarction is challenging. With stem cell and genetic recombination advancements, cellular replacement therapy after cerebral infarction progresses, which helps clinical transformation and application. In this paper, the basic researches of cellular replacement therapy after cerebral infarction are reviewed from 3 aspects: endogenous nerve regeneration, exogenous stem cell transplantation, and in situ somatic cell trans-differentiation into neurons, in order to provide references for cerebral infarction treatment
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Chronic pain can develop from acute pain, and it is not only difficult to cure, but also easy to develop secondary psychological problems and negative emotions such as anxiety and depression, and the hippocampal plays a vital role in chronic pain. The morphological and functional changes in the hippocampus mediate the development and maintenance of chronic pain. This review focuses on the role of hippocampal abnormalities in chronic pain in recent years, in order to provide new ideas for the treatments of chronic pain and related dysthymic disorder complications in the future.
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Aim To study the ability of tetramethylpyrazine (TMP) on promoting neurogenesis in neural stem cell microenvironment after oxygen-glucose deprivation (OGD) injury in vitro. Methods Neural stem cells (NSCs), astrocytes (ACs) and cerebral microvascular endothelial cells (BMECs) were respectively extracted and separated to establish a co-culture system. The OGD modeling conditions were optimized by NSCs activity, and the concentration of TMP was optimized by Nissl staining. Then CCK-8 and Nestin
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Objective To investigate the effect of cholesterol on the proliferation and differentiation of neural stem cells (NSCs) in ob/ob obese mice, and to explore the possible mechanism of central nervous systym dysfunction caused by obesity. Methods Selected 64-month-old ob/ob and wild type (WT) mice, and cell proliferation antigen (Ki67) and doublecortin (DCX) immunofluorescenct staining were used to detect ob/ob mice lateral ventricle subventricular zone (SVZ) neurogenesis level. Cultured SVZ NSCs isolated from 184-month-old ob/ob and WT mice, and BrdU incorporation experiment and β-III-tubulin (Tuj1) immunofluorescent staining were employed to detect the self-renewal and differentiation ability of NSCs. Matrix-assisted laser desorption/ionization time of flight mass spectrometry(MALDI- MS)was used to detect the lipid distribution in 4-month-old ob/ob and WT mice brain tissues, and measure the changes of cholesterol(ST) content and the expression genes related to cholesterol synthesis. Cultured 15 WT postnatal day 0(P0) mouse SVZ NSCs in vitro and electrotransfected with the small interfering RNA(siRNA) sequence of cholesterol synthesis rate-limiting enzyme 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (Hmgcr) verified the knockdown efficiency, to detecte the effect of Hmgcr gene knockdown on NSCs by BrdU incorporation experiment and Tuj1 immunofluorescent staining. Results Compared with the WT mice, the number of Ki67
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Objective To study the effect of dexmedetomidine (DEX), an α2- adrenoceptor agonist, on the pain-related anxiety-like and depression-like behaviour induced by complete Freund' s adjuvant (CFA) injection and its possible regulatory mechanism. Methods Thirty-six ICR female mice were randomly divided into normal saline (NS) group, CFA group and DEX + CFA group, n = 12 for each group. Chronic inflammatory pain model was established by subcutaneous injection of 10 μl CFA into the right hind limb of mice. DEX + CFA group mice were injected intraperitoneally with 0.025 mg/kg DEX 30 minutes before nociceptive behavior test, and once a day for 7 days. Von-frey fiber was used to evaluate the threshold of mechanical pain in mice, n = 12 for each group. The anxiety-like behavior of mice were detected by open field test, n = 12 for each group. Sucrose preference, tail suspension test and forced swimming test were used to detected the depression-like behavior of mice, n = 12 for each group. The expression of adrenergic receptor β2 (ADRB2), Brain-derived neurotrophic factor (BDNF), tyrosine kinase B receptor (TrkB), and glutamate receptors 1 (GluR1) and GluR2 were detected by Western blotting, n = 8 for each group. Immunohistochemical staining was used to detect the expression of recombinant doublecortin(DCX), which is a marker of newborn neurons in the hippocampus, n = 4 for each group. Results Compared with the NS group, the mechanical threshold of mice on the 1st, 3rd and 7th day after CFA injection decreased significantly (P 0.05). Compared with the NS group, the time spent in the inner ares (P<0.01), number of entering the central grid area (P<0.01) and distance travelled in the inner area (P<0.01) of CFA group mice reduced significantly, while the time (P<0.01), numbers (P < 0.05) and distance (P < 0.05) of DEX + CFA group mice entering the central grid area enhanced significantly. The result of depression-like behavior tests showed that the sucrose preference percentage (P < 0.05) reduced significantly in CFA group when compared with NS group, and the immobility time increased significantly in tail suspension test (P<0.01) and forced swimming test (P< 0.001) in CFA mice when compared with NS group, while DEX intervention could significantly increase the sucrose preference scores (P<0.05) and decreased the immobility time in tail suspension test (P<0.05) and forced swimming test (P<0.05). The result of Western blotting showed that compared with the NS group, the levels of ADRB2 (P<0.0010), BDNF (P < 0.001), TrkB (P < 0.01), GluR1 (P < 0.001) and GluR2 (P < 0.001) in the hippocampus of CFA group were significantly decreased, while DEX intervention could significantly increase the expression of ADRB2 (P<0.05), BDNF (P < 0.001), TrkB (P < 0.001), GluR1 (P < 0.001) and GluR2 (P < 0.001). Immunohistochemical result showed that compared with the NS group, the average absorbance (AA) of DCX decreased significantly in hippocampus of CFA group (P<0.05), but increased significantly in DEX+CFA group (P < 0.05). Conclusion Dexmedetomidine may promote hippocampal neurogenesis through upregulated the expression of BDNF-TrkB, thus improving CFA-induced anxiety-like and depression-like behaviors in mice.
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Alzheimer's disease (AD) is a multifactorial and heterogenic disorder. MiRNA is a class of non-coding RNAs with 19-22 nucleotides in length that can regulate the expression of target genes in the post-transcriptional level. It has been found that the miRNAome in AD patients is significantly altered in brain tissues, cerebrospinal fluid and blood circulation, as compared to healthy subjects. Experimental studies have suggested that expression changes in miRNA could drive AD onset and development via different mechanisms. Therefore, targeting miRNA expression to regulate the key genes involved in AD progression is anticipated to be a promising approach for AD prevention and treatment. Rodent AD models have demonstrated that targeting miRNAs could block biogenesis and toxicity of amyloid β, inhibit the production and hyper-phosphorylation of τ protein, prevent neuronal apoptosis and promote neurogenesis, maintain neural synaptic and calcium homeostasis, as well as mitigate neuroinflammation mediated by microglia. In addition, animal and human studies support the view that miRNAs are critical players contributing to the beneficial effects of cell therapy and lifestyle intervention to AD. This article reviews the most recent advances in the roles, mechanisms and applications of targeting miRNA in AD prevention and treatment based on rodent AD models and human intervention studies. The potential opportunities and challenges in clinical application of targeting miRNA for AD patients are also discussed.