Effects of aerobic exercise on adult hippocampal neurogenesis in Alzheimer's disease mice / 中国组织工程研究

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.

A preliminary study of fecal microbiota transplantation alleviating inhibition of radiation-induced hippocampal neurogenesis in mice / 中华放射肿瘤学杂志

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.

Recent advance in role of hippocampal abnormalities in chronic pain / 中华神经医学杂志

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.

Preliminary study on cerebrospinal fluid proteomics of Erxian Decoction against neurogenesis impairment in late-onset depression / 中国中药杂志

This study aims to elucidate the underlying mechanism of Erxian Decoction(EXD) against neurogenesis impairment in late-onset depression(LOD) rats based on cerebrospinal fluid(CSF) proteomics. A total of 66 20-21-month-old male Wistar rats were randomized into naturally aged(AGED) group, LOD group, and EXD group. All rats received chronic unpredictable mild stress(CUMS) for 6 weeks for LOD modeling except for the AGED group. During the modeling, EXD group was given EXD(ig, twice a day at 4 g·kg~(-1)) and other groups received equivalent amount of normal saline(ig). After modeling, a series of behavioral tests, such as sucrose preference test(SPT), open-field test(OFT), forced swimming test(FST), and Morris water maze test(MWMT) were performed. Immunofluorescence method was used to detect the number of Ki-67/Nesti-positive cells and BrdU/DCX-positive cells in the hippocampal DG area of each group. High-concentration corticosterone(CORT) was combined with D-galactose(D-gal) to simulate the changes of LOD-related stress and aging and the proliferation and differentiation of primary neural stem cells of hippocampus in each group were observed. Data independent acquisition(DIA)-mass spectrometry(MS) was used to analyze the differential proteins in CSF among groups and bioinformatics analysis was performed to explore the biological functions of the proteins. Behavioral tests showed that sucrose consumption in SPT, total traveling distance in OFT, and times of crossing the platform in MWMT were all reduced(P<0.01) and the immobility time in FST was prolonged(P<0.01) in the LOD group compared with those in the AGED group, suggesting that LOD rats had developed depression symptoms such as anhedonia, decreased locomotor activity ability, and cognitive dysfunction. Behavioral abnormalities were alleviated(P<0.01, P<0.05) in the EXD group as compared with those in the LOD group. Immunofluorescence results demonstrated that Ki-67/Nesti-positive cells and BrdU/DCX-positive cells in the hippocampal DG area were fewer(P<0.05) in LOD group than in the AGED group, and the positive cells in the EXD group were more(P<0.05) than those in the LOD group. In vitro experiment showed that the proliferation and differentiation of primary hippocampal neural stem cells under the CORT+D-gal treatment were reduced(P<0.01). The proliferation rate of neural stem cells decreased(P<0.05) in CORT+D-gal+LOD-CSF group but increased(P<0.01) in CORT+D-gal+EXD-CSF group compared with that in the CORT+D-gal group. A total of 2 620 proteins were identified from rat CSF, with 135 differential proteins between the LOD group and AGED group and 176 between EXD group and LOD group. GDF11, NrCAM, NTRK2, and GhR were related to neurogenesis and 39 differential proteins were regulated by both LOD and EXD. EXD demonstrated obvious anti-LOD effect, as it improved the locomotor activity ability and cognitive function of LOD rats and protected the proliferation and differentiation of hippocampal neural stem cells. EXD exerts anti-LOD effect by regulating the proteins related to neurogenesis in CSF, such as GDF11, NrCAM, NTRK2, and GhR and maintaining hippocampal neurogenesis.

Active fraction combination from Liuwei Dihuang decoction improves adult hippocampal neurogenesis and neurogenic microenvironmentin cranially irradiated mice / 中国药理学与毒理学杂志

OBJECTIVE Cranial radiotherapy is clinically used in the treatment of brain tumors;however, the conse?quent cognitive and emotional dysfunctions seriously impair the life quality of patients. LW-AFC, an active fraction combi?nation extracted from classical traditional Chinese medicine prescription Liuwei Dihuang decoction, can improve cogni?tive and emotional dysfunctions in many animal models;however, the protective effect of LW-AFC on cranial irradiation-induced cognitive and emotional dysfunctions has not been reported. Recent studies indicate that impairment of adult hippocampal neurogenesis (AHN) and alterations of the neurogenic microenvironment in the hippocampus constitute crit?ical factors in cognitive and emotional dysfunctions following cranial irradiation. Here, our research further investigated the potential protective effects and mechanisms of LW-AFC on cranial irradiation-induced cognitive and emotional dys?functions in mice. METHODS LW-AFC (1.6 g·kg-1) was intragastrically administered to mice for 14 d before cranial irra?diation (7 Gyγ-ray). AHN was examined by quantifying the number of proliferative neural stem cells and immature neu?rons in the dorsal and ventral hippocampus. The contextual fear conditioning test, open field test, and tail suspension test were used to assess cognitive and emotional functions in mice. To detect the change of the neurogenic microenvi?ronment, colorimetry and multiplex bead analysis were performed to measure the level of oxidative stress, neurotrophic and growth factors, and inflammation in the hippocampus. RESULTS LW-AFC exerted beneficial effects on the contex?tual fear memory, anxiety behavior, and depression behavior in irradiated mice. Moreover, LW-AFC increased the num?ber of proliferative neural stem cells and immature neurons in the dorsal hippocampus, displaying a regional specificity of neurogenic response. For the neurogenic microenvironment, LW-AFC significantly increased the contents of superox?ide dismutase, glutathione peroxidase, glutathione, and catalase and decreased the content of malondialdehyde in the hippocampus of irradiated mice, accompanied by the increase in brain-derived neurotrophic factor, insulin-like growth factor-1, and interleukin-4 content. Together, LW-AFC improved cognitive and emotional dysfunctions, promoted AHN preferentially in the dorsal hippocampus, and ameliorated disturbance in the neurogenic microenvironment in irradiated mice. CONCLUSION LW-AFC ameliorates cranial irradiation-induced cognitive and emotional dysfunctions, and the underlying mechanisms are mediated by promoting AHN in the dorsal hippocampus and improving the neurogenic micro?environment. LW-AFC might be a promising therapeutic agent to treat cognitive and emotional dysfunctions in patients receiving cranial radiotherapy.

Neuroprotective effect of Liu Wei Di Huang Tang on adult hippocampal neurogenesis in mice / 中国药理学与毒理学杂志

OBJECTIVE To explore the effect and mechanisms of LW-AFC,a new formula derived from Liu Wei Di Huang Tang,on irradiation-induced reduction of mice adult hippocampal neurogenesis. METHODS C57BL/6J mice were randomly divided into seven groups (n=10): control group, LW-AFC group (1.6 g·kg-1), Liu Wei Di Huang Tang (LW) group (10 g·kg-1), brain derived neurotrophic factor (BDNF) group, irradiation group, irradiation+LW group, and irradiation+LW-AFC group. Reduction of mice adult hippocampal neurogenesis was induced by cranial irradiation.LW-AFC was administered by oral gavage for 30 d after cranial irradiation treatment. Immunofluorescence and Nissl′s staining were performed for histological morphology assessment. Bromodeoxyuridine (BrdU) staining was used in the detection of proliferation cells. The peripheral blood and hippocampal homogenate were collected to measure the content of tumor necrosis factor-α (TNF-α), interferon-gamma (INF-γ), interleukin-1β (IL-1β),IL-4 and IL-10.The hippocampal homogenate was used for Western blot to detect the BDNF-TrkB signal pathway, including extracellular regulated protein kinases1/2 (ERK1/2) and BDNF target protein. Morris water maze and new object recognition test were performed to examine the cognitive function of mice.The mice forced swimming and tail suspension test were used to assess alteration in depressive behavior. Long term potentiation was used to examine the synaptic plasticity change of mice. RESULTS Adult hippocampal neurogenesis was significantly reduced after irradiation of 20 Gray dose (10 Gray per day, total 2 d). LW-AFC treatment increased the BrdU number of irradiated mice (P<0.05). In Morris water maze test, LW-AFC group showed decreased escape latency in the learning period (P<0.05), while increased the number of crossing the platform in the memory period. LW-AFC can also reduce the immobility time of mice in the tail suspension test (P<0.01). CONCLU-SION LW-AFC modulates adult neurogenesis to ameliorate cognitive impairment and reduce depres-sive behavior in radiation injury mice.

Nutritional factors affecting adult neurogenesis and cognitive function / 基础医学与临床

Adult neurogenesis,a complex process by which stem cells in the hippocampal brain region proliferate and differentiate into new neurons and other resident brain cells,is known to be affected by many intrinsic and ex-trinsic factors,including diet. Neurogenesis plays a critical role in neural plasticity,brain homeostasis and mainte-nance in the central nervous system and is a crucial factor in preserving the cognitive function and repair of dam-aged brain cells affected by aging and brain disorders. Intrinsic factors such as aging,neuroinflammation,oxidative stress and brain injury, as well as lifestyle factors such as high-fat and high-sugar diets and alcohol consumption and opioid addiction,negatively affect adult neurogenesis.Conversely,many dietary components such as curcumin, resveratrol,blueberry polyphenols,polyunsaturated fatty acids (PUFAs), as well as caloric restriction, physical exercise and learning,have been shown to induce neurogenesis in adult brains. Although many of the underlying mechanisms by which nutrients and dietary factors affect adult neurogenesis have yet to be determined, nutritional approaches provide promising prospects to stimulate adult neurogenesis and combat neurodegenerative diseases and cognitive decline. In this review,we summarize the evidence supporting the role of nutritional factors in modifying adult neurogenesis and their potential to preserve cognitive function during aging.

Effects of Baishile Capsules on Neurogenesis Related Protein in Hippocampal DG and CA3 ;Area of Model Rats with Chronic Unpredicted Mile Stress Depression / 中国中医药信息杂志

Objective To investigate effects of Baishile Capsules on cAMP-CREB-BDNF signal pathway about hippocampal neurogenesis in model rats with chronic unpredicted stress depression. Methods SD rats were randomly divided into blank group, model group, fluoxetine hydrochloride group, and Baishile Capsules high, medium, and low dose groups. Chronic stress depression rat model was established by chronic and mild unpredictable stressors. All groups were given relevant medicine for 21 days. The open-field test, sugar consumption experiment, place navigation test, and space searching experiment were used to detect behavior changes of the rats. ELISA was used to detect content of corticosterone in plasma. The protein expressions of PKA, BDNF, and CREB were detected by immunohistochemical method. Results Compared with model group, Baishile Capsules high dose and medium dose groups could remarkably increase the number of vertical and horizontal activities and 1% sucrose partial eclipse. Platform latency and target quadrant searching time decreased significantly in Baishile Capsules high dose group (P<0.05), and content of corticosterone in plasma increased obviously (P<0.05) in Baishile Capsules all dose groups. Protein expressions of PKA, CREB, and BDNF in hippocampal DG and CA3 area increased significantly (P<0.05) in Baishile Capsules high dose group. Conclusion Baishile Capsules can promote hippocampal neurogenesis through the cAMP-CREB-BDNF signal pathway and realize anti-depression effect.

Effect of bexarotene on spatial cognition, impairment in memory and learning and hippocampal nerve regeneration of Aβ25-35 mice / 中华神经医学杂志

Objective To explore the effect of bexarotene (BEX) on spatial cognition,impairment in memory and learning and hippocampal nerve regeneration of Aβ25-35 mice.Methods Eighty healthy male ICR mice were randomly divided into control group,model group,low-dosage BEX treatment group and high-dosage BEX treatment group (n=20); AD mouse models in the later three groups were induced by intracerebroventricular injection of Aβ25-35; and mice in the low-dosage BEX treatment group and high-dosage BEX treatment group treated with BEX (50 and 100 mg/kg·d) by gavage 7 days after Aβ25-35 injection for consecutive 14 days.Morris water maze and Y-maze tests were used to test the spatial cognitive function and abilities of learning and memory,respectively,28 days after Aβ25-35 injection.Intraperitoneal injection of 5-bromodeoxyuridine (BrdU) three times daily for 28 days was performed,and then,immumohistochemical staining was employed to detect the BrdU expression in the hippocampus; dual cortex protein (DCX) staining and Hoechst staining were,respectively,used to evaluate the proliferation and migration,and apoptosis of neuronal precursor cells; toluidine blue staining was employed to evaluate the mature neurons in the hippocampus.The levels of hippocampal brain-derived neurotrophic factor (BDNF) and the expressions of hippocampal glial fibrillary acidic protein (GFAP) and growth associated protein-43 (GAP-43) were measured by ELISA and Western blotting,respectively.Results Morris water maze test showed that the latency of crossing the platform was gradually increased in the control group,high-dosage BEX treatment group,low-dosage BEX treatment group and model group on the 3nd,4th,5th and 6th day,and the duration of stay was gradually decreased on the 6th day; increased learning frequency and reduced memory frequency was noted in Y-maze test; number of BrdU-positive cells,length and density of DCX neurite,and number of granule cells in the hippocampus decreased gradually,while Hoechst-positive cells decreased gradually; hippocampal levels of GFAP,GAP-43 and BDNF decreased gradually; the differences in the above levels were statistically significant (P＜0.05).Conclusion BEX can improve the spatial cognition and the impairment in memory and learning and promote their hippocampal neurogenesis of Aβ25-35 mice.

Normal Adult Hippocampal Neurogenesis in SRG3-overexpressing Transgenic Mice

SRG3 (SWI3-related gene) is a core subunit of mouse SWI/SNF complex and is known to play a critical role in stabilizing the SWI/SNF complex by attenuating its proteasomal degradation. SWI/SNF chromatin remodeling complex is reported to act as an important endogenous regulator in the proliferation and differentiation of mammalian neural stem cells. Because limited expression of SRG3 occurs in the brain and thymus during mouse embryogenesis, it was hypothesized that the altered SRG3 expression level might affect the process of adult hippocampal neurogenesis. Due to the embryonic lethality of homozygous knockout mice, this study focuses on dissecting the effect of overexpressed SRG3 on adult hippocampal neurogenesis. The BrdU incorporation assay, immunostaing with neuronal markers for each differentiation stage, and imunoblotting analysis with intracellular molecules involved in survival in adult hippocampal neurogenesis found no alteration, suggesting that the overexpression of SRG3 protein in mature neurons had no effect on the entire process of adult hippocampal neurogenesis including proliferation, differentiation, and survival.