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Sample records for factor bdnf expression

  1. Regional differences in the expression of brain-derived neurotrophic factor (BDNF) pro-peptide, proBDNF and preproBDNF in the brain confer stress resilience.

    Science.gov (United States)

    Yang, Bangkun; Yang, Chun; Ren, Qian; Zhang, Ji-Chun; Chen, Qian-Xue; Shirayama, Yukihiko; Hashimoto, Kenji

    2016-12-01

    Using learned helplessness (LH) model of depression, we measured protein expression of brain-derived neurotrophic factor (BDNF) pro-peptide, BDNF precursors (proBDNF and preproBDNF) in the brain regions of LH (susceptible) and non-LH rats (resilience). Expression of preproBDNF, proBDNF and BDNF pro-peptide in the medial prefrontal cortex of LH rats, but not non-LH rats, was significantly higher than control rats, although expression of these proteins in the nucleus accumbens of LH rats was significantly lower than control rats. This study suggests that regional differences in conversion of BDNF precursors into BDNF and BDNF pro-peptide by proteolytic cleavage may contribute to stress resilience.

  2. Brain-derived neurotrophic factor (BDNF) expression in normal and regenerating olfactory epithelium of Xenopus laevis.

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    Frontera, Jimena Laura; Cervino, Ailen Soledad; Jungblut, Lucas David; Paz, Dante Agustín

    2015-03-01

    Olfactory epithelium has the capability to continuously regenerate olfactory receptor neurons throughout life. Adult neurogenesis results from proliferation and differentiation of neural stem cells, and consequently, olfactory neuroepithelium offers an excellent opportunity to study neural regeneration and the factors involved in the maintenance and regeneration of all their cell types. We analyzed the expression of BDNF in the olfactory system under normal physiological conditions as well as during a massive regeneration induced by chemical destruction of the olfactory epithelium in Xenopus laevis larvae. We described the expression and presence of BDNF in the olfactory epithelium and bulb. In normal physiological conditions, sustentacular (glial) cells and a few scattered basal (stem) cells express BDNF in the olfactory epithelium as well as the granular cells in the olfactory bulb. Moreover, during massive regeneration, we demonstrated a drastic increase in basal cells expressing BDNF as well as an increase in BDNF in the olfactory bulb and nerve. Together these results suggest an important role of BDNF in the maintenance and regeneration of the olfactory system.

  3. Reduced brain-derived neurotrophic factor (BDNF) mRNA expression and presence of BDNF-immunoreactive granules in the spinocerebellar ataxia type 6 (SCA6) cerebellum.

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    Takahashi, Makoto; Ishikawa, Kinya; Sato, Nozomu; Obayashi, Masato; Niimi, Yusuke; Ishiguro, Taro; Yamada, Mitsunori; Toyoshima, Yasuko; Takahashi, Hitoshi; Kato, Takeo; Takao, Masaki; Murayama, Shigeo; Mori, Osamu; Eishi, Yoshinobu; Mizusawa, Hidehiro

    2012-12-01

    Spinocerebellar ataxia type 6 (SCA6) is an autosomal-dominant neurodegenerative disorder caused by a small expansion of tri-nucleotide (CAG) repeat encoding polyglutamine (polyQ) in the gene for α(1A) voltage-dependent calcium channel (Ca(v) 2.1). Thus, this disease is one of the nine neurodegenerative disorders called polyQ diseases. The Purkinje cell predominant neuronal loss is the characteristic neuropathology of SCA6, and a 75-kDa carboxy-terminal fragment (CTF) of Ca(v) 2.1 containing polyQ, which remains soluble in normal brains, becomes insoluble in the cytoplasm of SCA6 Purkinje cells. Because the suppression of the brain-derived neurotrophic factor (BDNF) expression is a potentially momentous phenomenon in many other polyQ diseases, we implemented BDNF expression analysis in SCA6 human cerebellum using quantitative RT-PCR for the BDNF mRNA, and by immunohistochemistry for the BDNF protein. We observed significantly reduced BDNF mRNA levels in SCA6 cerebellum (n = 3) compared to controls (n = 6) (Mann-Whitney U-test, P = 0.0201). On immunohistochemistry, BDNF protein was only weakly stained in control cerebellum. On the other hand, we found numerous BDNF-immunoreactive granules in dendrites of SCA6 Purkinje cells. We did not observe similar BDNF-immunoreactive granules in other polyQ diseases, such as Huntington's disease or SCA2. As we often observed that the 1C2-positive Ca(v) 2.1 aggregates existed more proximally than the BDNF-positive granules in the dendrites, we speculated that the BDNF protein trafficking in dendrites may be disturbed by Ca(v) 2.1 aggregates in SCA6 Purkinje cells. We conclude that the SCA6 pathogenic mechanism associates with the BDNF mRNA expression reduction and abnormal localization of BDNF protein.

  4. Over-expression of brain-derived neurotrophic factor in mesenchymal stem cells transfected with recombinant lentivirus BDNF gene.

    Science.gov (United States)

    Zhang, X; Zhu, J; Zhang, K; Liu, T; Zhang, Z

    2016-12-30

    This study was aimed at investigating the expression of brain-derived neurotrophic factor (BDNF) in mesenchymal stem cells (MSCs) modified with recombinant lentivirus bearing BDNF gene. Lentivirus vectors bearing BDNF gene were constructed. MSCs were isolated from rats and cultured. The lentiviral vectors containing BDNF gene were transfected into the MSCs, and BDNF gene and protein expressions were monitored with enhanced green fluorescent protein (EGFP). RT-PCR and Western blot were used to measure gene and protein expressions, respectibvely in MSCs, MSCs-EGFP and MSCs-EGFP-BDNF groups. Green fluorescence assay confirmed successful transfection of BDNF gene recombinant lentivirus into MSCs. RT-PCR and Western blot revealed that BDNF gene and protein expressions in the MSCs-EGFP-BDNF group were significantly higher than that in MSCs group and MSCs-EGFP group. There were no statistically significant differences in gene expression between MSCs and MSCs-EGFP groups. MSCs can over-express BDNF when transfected with recombinant lentivirus bearing BDNF gene.

  5. THE GENE EXPRESSION OF BDNF IN NORMAL RABBIT RETINA

    Institute of Scientific and Technical Information of China (English)

    王建明; 胡海涛; 马东亮; 孙乃学; 赵世平; 冯海晓

    2004-01-01

    Objective To investigate the distribution of brain-derived neurotrophic factor(BDNF) protein in the rabbit retina. Methods Immune response material in the retina was observed using BDNF antibody by the method of immunohistochemistry. Results BDNF gene expression was mainly found in the RGCs, also in innernuclei cells and outernuclei cells in rabbit retina. Conclusion RGC is not only the target cell of BDNF, but also express the BDNF protein. BDNF from multi-sources participates in the regulation of RGCs.

  6. Expression of brain-derived neurotrophic factor (BDNF) is regulated by the Wnt signaling pathway

    OpenAIRE

    Yi, Hyun; Hu, Jianfei; Qian, Jiang; Hackam, Abigail S.

    2012-01-01

    BDNF is a well-characterized neurotrophin that mediates a wide variety of activities in the central nervous system (CNS), including neuronal differentiation, neuroprotection and synaptic plasticity. The canonical Wnt signaling pathway is a critical regulator of embryonic development and homeostasis in adult tissues. Our group and others recently demonstrated that Wnt signaling induces BDNF expression in neurons and glia. However, the precise relationship between BDNF and Wnt signaling pathway...

  7. Amitriptyline induces brain-derived neurotrophic factor (BDNF) mRNA expression through ERK-dependent modulation of multiple BDNF mRNA variants in primary cultured rat cortical astrocytes and microglia.

    Science.gov (United States)

    Hisaoka-Nakashima, Kazue; Kajitani, Naoto; Kaneko, Masahiro; Shigetou, Takahiro; Kasai, Miho; Matsumoto, Chie; Yokoe, Toshiki; Azuma, Honami; Takebayashi, Minoru; Morioka, Norimitsu; Nakata, Yoshihiro

    2016-03-01

    A significant role of brain-derived neurotrophic factor (BDNF) has been previously implicated in the therapeutic effect of antidepressants. To ascertain the contribution of specific cell types in the brain that produce BDNF following antidepressant treatment, the effects of the tricyclic antidepressant amitriptyline on rat primary neuronal, astrocytic and microglial cortical cultures were examined. Amitriptyline increased the expression of BDNF mRNA in astrocytic and microglial cultures but not neuronal cultures. Antidepressants with distinct mechanisms of action, such as clomipramine, duloxetine and fluvoxamine, also increased BDNF mRNA expression in astrocytic and microglial cultures. There are multiple BDNF mRNA variants (exon I, IIA, IV and VI) expressed in astrocytes and microglia and the variant induced by antidepressants has yet to be elaborated. Treatment with antidepressants increased the expression of exon I, IV and VI in astrocyte and microglia. Clomipramine alone significantly upregulated expression of exon IIA. The amitriptyline-induced expression of both total and individual BDNF mRNA variants (exon I, IV and VI) were blocked by MEK inhibitor U0126, indicating MEK/ERK signaling is required in the expression of BDNF. These findings indicate that non-neural cells are a significant target of antidepressants and further support the contention that glial production of BDNF is crucial role in the therapeutic effect of antidepressants. The current data suggest that targeting of glial function could lead to the development of antidepressants with a truly novel mechanism of action.

  8. Serotonin transporter function, but not expression, is dependent on brain-derived neurotrophic factor (BDNF): in vivo studies in BDNF-deficient mice.

    Science.gov (United States)

    Daws, L C; Munn, J L; Valdez, M F; Frosto-Burke, T; Hensler, J G

    2007-05-01

    In the present study, we used high-speed chronoamperometry to examine serotonin (5-HT) transporter (5-HTT) function in vivo in 2-, 5-, and 10-month-old brain-derived neurotrophic factor (BDNF)+/- mice. The rate of clearance of exogenously applied 5-HT was measured in CA3 region of hippocampus. In 2-month-old mice, the rate of 5-HT clearance did not differ between BDNF+/+ and BDNF+/- mice. In BDNF+/+ mice, 5-HT clearance rate (Tc) increased markedly with age. In contrast, Tc remained relatively static in BDNF+/- mice across 2-, 5-, and 10-month age groups. At 5 months of age, female BDNF+/+ mice had a lower maximal velocity (Vmax) for 5-HT clearance than male BDNF+/+ mice. There was a similar trend in 5-month-old BDNF+/- mice, but this did not reach statistical significance. There was an age-dependent increase in KT value for 5-HT clearance (i.e., decreased in vivo affinity of 5-HTT), but no significant effect of genotype or gender. 5-HTT density, as measured by [3H]cyanoimipramine binding, was not different between BDNF+/+ and BDNF+/- mice, although there was a significant increase in 5-HTT binding with age. The selective 5-HT reuptake inhibitor fluvoxamine (50 and 100 pmol) significantly decreased 5-HT clearance in BDNF+/+ mice, but not in BDNF+/- mice. Our data suggest that the profoundly reduced ability of 5- and 10-month-old BDNF+/- mice to clear 5-HT is not because of a decrease in the total number of 5-HTTs, but may be due to functional deficits in the 5-HTT, e.g., in the machinery/signaling required for insertion of 5-HTTs into the plasma membrane and/or activation of the 5-HTT once it is positioned to take up 5-HT from extracellular fluid.

  9. The exposure to nicotine affects expression of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in neonate rats.

    Science.gov (United States)

    Xiaoyu, Wang

    2015-02-01

    In the current study effect of nicotine on expression of neurotrophins, brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) has been studied in hippocampus and frontal cortex during development of brain in rats. Neurotrophins are factors that help in development of brain among which BDNF and NGF are very important, expressed at different stages during the developmental process. Different sedatives are reported to alter the expression of these factors. In this study, three groups of neonate rats (1-5, 5-10 and 10-15 days age) were used each having 20 rats. Ten were subjected to a dose of 66 μg of nicotine while other ten received the same amount of saline at the same time interval. Then expression of the BDNF and NGF was observed in hippocampus and frontal cortex tissue using immunoassay. Western blotting was used to observe the presence of BDNF in hippocampus as well as frontal cortex. In all groups there was a significant decrease in concentration of neurotrophic factors where nicotine was applied as compared to control. The highest expression of BDNF and NGF in hippocampus and frontal cortex was observed in 10-15 days group (G3) and in 5-10 group (G2) as compared to the control, P BDNF and it effects the development of brain in neonates that can further impair brain functions.

  10. Regulation of brain-derived neurotrophic factor (BDNF) expression and release from hippocampal neurons is mediated by non-NMDA type glutamate receptors.

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    Wetmore, C; Olson, L; Bean, A J

    1994-03-01

    We have examined the influence of glutamate on cortical brain-derived neurotrophic factor (BDNF) expression using in situ hybridization and immunohistochemistry. Kainic acid (KA) produced an upregulation of hippocampal and neocortical BDNF mRNA as well as BDNF protein that was blocked by a non-NMDA antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX), but was not affected by the NMDA antagonist 2-amino-7-phosphonoheptanoic acid (AP7). Basal levels of BDNF mRNA were not affected by NMDA, DNQX, or AP7 treatment. BDNF protein was also increased after kainate exposure with a spatial and temporal course distinct from that seen for the expression of BDNF mRNA. A dramatic shift in BDNF immunoreactivity (-IR) was observed from intracellular compartments to the neuropil surrounding CA3 pyramidal cells 2-3 hr after KA exposure. This shift in localization of BDNF-IR suggests a constitutive release of BDNF at the level of the cell body and dendrites. Moreover, we have localized mRNAs for full-length and truncated trkB, to a co-incident population of neurons and glia. These data suggest the neurons that produce BDNF also express components necessary for a biological response to the same neurotrophic factor. The present study also demonstrates increased BDNF-IR in the mossy fiber terminal zone of hippocampus after exposure to KA, as well as an increase in trkB mRNA, and provides evidence of local release of this neurotrophin into the surrounding neuropil where it would be available for local utilization. The synthesis and putative release of BDNF from somatic and/or dendritic sites within the hippocampus provide evidence of a potential autocrine or paracrine role for BDNF, and establish a local source of trophic support for the maintenance of synaptic plasticity and anatomic reorganization in the mature nervous system.

  11. Expressions of brain-derived neurotrophic factor (BDNF) in cerebrospinal fluid and plasma of children with meningitis and encephalitis/encephalopathy.

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    Morichi, Shinichiro; Kashiwagi, Yasuyo; Takekuma, Koji; Hoshika, Akinori; Kawashima, Hisashi

    2013-01-01

    Many reports in the field of childhood brain disorders have documented that brain-derived neurotrophic factor (BDNF) affects central nervous system (CNS) functions. In this clinical study, BDNF levels were evaluated in association with pediatric CNS infections. BDNF levels in the serum and cerebrospinal fluid (CSF) of 42 patients admitted during 5-year period, due to CNS infections, were measured by enzyme-linked immunosorbent assays (ELISAs). Control samples were collected from 108 patients with non-CNS infections (urinary tract infection, acute upper respiratory infection, acute gastroenteritis, etc.). Mean values of BDNF levels, at various ages, were determined and compared. BDNF levels were below the sensitivity of the ELISA in most CSF samples from the control group, but were significantly elevated in the patients with bacterial meningitis. The serum BDNF levels were elevated in all subgroups of patients with CNS infections, and the elevation was particularly notable in those with bacterial meningitis. BDNF expression in the CSF was correlated with CSF interleukin (IL)-6 levels as well as with blood platelet counts and neurological prognoses in those with bacterial meningitis. No correlation was found between BDNF levels and serum leukocyte numbers or C-reactive protein (CRP) levels. BDNF levels were found to be elevated in the serum and CSF of pediatric patients with CNS infections, particularly those with bacterial meningitis. Monitoring the changes in serum and CSF levels of BDNF may facilitate the diagnosis of acute meningitis and acute encephalopathy and allow the differential diagnosis of specific CNS infections.

  12. Apoptosis signal-regulating kinase 1 is involved in brain-derived neurotrophic factor (BDNF)-enhanced cell motility and matrix metalloproteinase 1 expression in human chondrosarcoma cells.

    Science.gov (United States)

    Lin, Chih-Yang; Chang, Sunny Li-Yun; Fong, Yi-Chin; Hsu, Chin-Jung; Tang, Chih-Hsin

    2013-07-25

    Chondrosarcoma is the primary malignancy of bone that is characterized by a potent capacity to invade locally and cause distant metastasis, and is therefore associated with poor prognoses. Chondrosarcoma further shows a predilection for metastasis to the lungs. The brain-derived neurotrophic factor (BDNF) is a small molecule in the neurotrophin family of growth factors that is associated with the disease status and outcome of cancers. However, the effect of BDNF on cell motility in human chondrosarcoma cells is mostly unknown. Here, we found that human chondrosarcoma cell lines had significantly higher cell motility and BDNF expression compared to normal chondrocytes. We also found that BDNF increased cell motility and expression of matrix metalloproteinase-1 (MMP-1) in human chondrosarcoma cells. BDNF-mediated cell motility and MMP-1 up-regulation were attenuated by Trk inhibitor (K252a), ASK1 inhibitor (thioredoxin), JNK inhibitor (SP600125), and p38 inhibitor (SB203580). Furthermore, BDNF also promoted Sp1 activation. Our results indicate that BDNF enhances the migration and invasion activity of chondrosarcoma cells by increasing MMP-1 expression through a signal transduction pathway that involves the TrkB receptor, ASK1, JNK/p38, and Sp1. BDNF thus represents a promising new target for treating chondrosarcoma metastasis.

  13. Brain-derived neurotrophic factor (BDNF) and its precursor (proBDNF) in genetically defined fear-induced aggression.

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    Ilchibaeva, Tatiana V; Kondaurova, Elena M; Tsybko, Anton S; Kozhemyakina, Rimma V; Popova, Nina K; Naumenko, Vladimir S

    2015-09-01

    The brain-derived neurotrophic factor (BDNF), its precursor (proBDNF) and BDNF mRNA levels were studied in the brain of wild rats selectively bred for more than 70 generations for either high level or for the lack of affective aggressiveness towards man. Significant increase of BDNF mRNA level in the frontal cortex and increase of BDNF level in the hippocampus of aggressive rats was revealed. In the midbrain and hippocampus of aggressive rats proBDNF level was increased, whereas BDNF/proBDNF ratio was reduced suggesting the prevalence and increased influence of proBDNF in highly aggressive rats. In the frontal cortex, proBDNF level in aggressive rats was decreased. Thus, considerable structure-specific differences in BDNF and proBDNF levels as well as in BDNF gene expression between highly aggressive and nonaggressive rats were shown. The data suggested the implication of BDNF and its precursor proBDNF in the mechanism of aggressiveness and in the creation of either aggressive or nonaggressive phenotype.

  14. Temporal expression of brain-derived neurotrophic factor (BDNF) mRNA in the rat hippocampus after treatment with selective and mixed monoaminergic antidepressants.

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    Larsen, Marianne H; Hay-Schmidt, Anders; Rønn, Lars C B; Mikkelsen, Jens D

    2008-01-14

    Strong evidence suggests that antidepressants work by induction of neuroplastic changes mediated through regulation of brain-derived neurotrophic factor (BDNF). This study was undertaken to investigate the time-course of the effect of three antidepressants; fluoxetine, imipramine and venlafaxine, which differentially affect monoamine reuptake, on BDNF mRNA expression in the hippocampus. The consequences of increased BDNF in the hippocampus are still indefinite. Here, we also determined the effects on the expression of two other genes (synaptophysin and growth-associated protein-43 (GAP-43)) known to be involved in synapse formation and axonal growth and likely regulated by BDNF. The effects were determined in rats after sub-chronic (7 days) and chronic (14 and 21 days) treatment using semi-quantitative in situ hybridisation. BDNF mRNA levels in the dentate gyrus (DG) were increased after treatment with venlafaxine (7, 14 and 21 days) and imipramine (14 and 21 days), but not after treatment with fluoxetine, indicating that stimulation of BDNF mRNA expression is dependent on the pharmacological profile and on the time-course of drug treatment. A transient increase in synaptophysin mRNA was observed after treatment with venlafaxine and fluoxetine whereas imipramine had no effect. In the CA3 region a reduction of GAP-43 mRNA was observed after treatment with imipramine (21 days) and fluoxetine (7 and 14 days). These results suggest that venlafaxine and imipramine, but not fluoxetine, induce neuroplastic effects in the hippocampus through stimulation of BDNF mRNA expression, and that the effect on BDNF is not directly translated into regulation of synaptophysin and GAP-43 mRNA.

  15. Robust changes in expression of brain-derived neurotrophic factor (BDNF) mRNA and protein across the brain do not translate to detectable changes in BDNF levels in CSF or plasma.

    Science.gov (United States)

    Lanz, Thomas A; Bove, Susan E; Pilsmaker, Catherine D; Mariga, Abigail; Drummond, Elena M; Cadelina, Gregory W; Adamowicz, Wendy O; Swetter, Brentt J; Carmel, Sharon; Dumin, Jo Ann; Kleiman, Robin J

    2012-09-01

    Adult rats were treated acutely with peripheral kainic acid (KA), and changes in brain-derived neurotrophic factor (BDNF) mRNA and protein were tracked over time across multiple brain regions. Despite robust elevation in both mRNA and protein in multiple brain regions, plasma BDNF was unchanged and cerebrospinal fluid (CSF) BDNF levels remained undetectable. Primary neurons were then treated with KA. BDNF was similarly elevated within neurons, but was undetectable in neuronal media. Thus, while deficits in BDNF signaling have been implicated in a number of diseases, these data suggest that extracellular concentrations of BDNF may not be a facile biomarker for changes in neurons.

  16. DNA methylation and expression profiles of the brain-derived neurotrophic factor (BDNF) and dopamine transporter (DAT1) genes in patients with schizophrenia.

    Science.gov (United States)

    Kordi-Tamandani, Dor Mohammad; Sahranavard, Roya; Torkamanzehi, Adam

    2012-12-01

    Methylation and expression profile of CpG islands were examined in the promoters of the brain-derived neurotrophic factor (BDNF) and dopamine transporter (DAT1) genes. These are well known to be involved in the pathophysiology of psychiatric disorders such as schizophrenia. Genomic DNA was extracted from peripheral blood of 80 patients with schizophrenia and 71 healthy controls. Methylation pattern was studied by Methylation-Specific PCR. RNA expression analysis was done on extracted RNA from blood samples from patients suffering from schizophrenia (n = 17) and healthy controls (n = 17). Frequency of the BDNF gene methylation was highlighted as a statistically significant relationship between cases and controls regarding decreased risk of disease in comparison to unmethylated patterns (OR = 0.24; 95 % CI = 1.11-0.50; P = 0.00007). For the DAT1 gene, this relationship was insignificant in 61 cases (76.25 %) and 52 controls (73.23 %) (OR = 1.17; 95 % CI = 0.53-2.61). Estimates of relative gene expression revealed a statistically significant association of the BDNF gene between schizophrenic patients and healthy controls (Mean ± SD: 13.3920 ± 15.19 and 0.437 ± 0.328, P = 0.0001) respectively; however, it was not significant for the DAT1 gene. This first hand evidence, regarding BDNF and DAT1 gene methylation and their expression profile with risk of schizophrenia, indicated a significant function for the BDNF gene in the development of schizophrenia. However, further populations with large sample sizes need to be studied to verify the exact role of BDNF in mental disorders such as schizophrenia.

  17. Sleep deprivation effects on growth factor expression in neonatal rats: a potential role for BDNF in the mediation of delta power.

    Science.gov (United States)

    Hairston, Ilana S; Peyron, Christelle; Denning, Daniel P; Ruby, Norman F; Flores, Judith; Sapolsky, Robert M; Heller, H Craig; O'Hara, Bruce F

    2004-04-01

    The sleeping brain differs from the waking brain in its electrophysiological and molecular properties, including the expression of growth factors and immediate early genes (IEG). Sleep architecture and homeostatic regulation of sleep in neonates is distinct from that of adults. Hence, the present study addressed the question whether the unique homeostatic response to sleep deprivation in neonates is reflected in mRNA expression of the IEG cFos, brain-derived nerve growth factor (BDNF), and basic fibroblast growth factor (FGF2) in the cortex. As sleep deprivation is stressful to developing rats, we also investigated whether the increased levels of corticosterone would affect the expression of growth factors in the hippocampus, known to be sensitive to glucocorticoid levels. At postnatal days 16, 20, and 24, rats were subjected to sleep deprivation, maternal separation without sleep deprivation, sleep deprivation with 2 h recovery sleep, or no intervention. mRNA expression was quantified in the cortex and hippocampus. cFos was increased after sleep deprivation and was similar to control level after 2 h recovery sleep irrespective of age or brain region. BDNF was increased by sleep deprivation in the cortex at P20 and P24 and only at P24 in the hippocampus. FGF2 increased during recovery sleep at all ages in both brain regions. We conclude that cortical BDNF expression reflects the onset of adult sleep-homeostatic response, whereas the profile of expression of both growth factors suggests a trophic effect of mild sleep deprivation.

  18. Developmental Thyroid Hormone Insufficiency Reduces Expression of Brain-Derived Neurotrophic Factor (BDNF) in Adults But Not in Neonates

    Science.gov (United States)

    Brain-derived neurotrophic factor (BDNF) is a neurotrophin critical for many developmental and physiological aspects of CNS function. Severe hypothyroidism in the early neonatal period results in developmental and cognitive impairments and reductions in mRNA and protein expressio...

  19. Chronic stress induces upregulation of brain-derived neurotrophic factor (BDNF) mRNA and integrin alpha5 expression in the rat pineal gland.

    Science.gov (United States)

    Dagnino-Subiabre, Alexies; Zepeda-Carreño, Rodrigo; Díaz-Véliz, Gabriela; Mora, Sergio; Aboitiz, Francisco

    2006-05-01

    Chronic stress affects brain areas involved in learning and emotional responses. These alterations have been related with the development of cognitive deficits in major depression. Moreover, stress induces deleterious actions on the epithalamic pineal organ, a gland involved in a wide range of physiological functions. The aim of this study was to investigate whether the stress effects on the pineal gland are related with changes in the expression of neurotrophic factors and cell adhesion molecules. Using reverse transcription-polymerase chain reaction (RT-PCR) and Western blot, we analyzed the effect of chronic immobilization stress on the BDNF mRNA and integrin alpha5 expression in the rat pineal gland. We found that BDNF is produced in situ in the pineal gland. Chronic immobilization stress induced upregulation of BDNF mRNA and integrin alpha5 expression in the rat pineal gland but did not produce changes in beta-actin mRNA or in GAPDH expression. Stressed animals also evidenced an increase in anxiety-like behavior and acute gastric lesions. These results suggest that BDNF and integrin alpha5 may have a counteracting effect to the deleterious actions of immobilization stress on functionally stimulated pinealocytes. Furthermore, this study proposes that the pineal gland may be a target of glucocorticoid damage during stress.

  20. Metabotropic glutamate receptor 2 and corticotrophin-releasing factor receptor-1 gene expression is differently regulated by BDNF in rat primary cortical neurons

    DEFF Research Database (Denmark)

    Jørgensen, Christinna V; Klein, Anders B; El-Sayed, Mona;

    2013-01-01

    Brain-derived neurotrophic factor (BDNF) is important for neuronal survival and plasticity. Incorporation of matured receptor proteins is an integral part of synapse formation. However, whether BDNF increases synthesis and integration of receptors in functional synapses directly is unclear. We...... are particularly interested in the regulation of the 5-hydroxytryptamine receptor 2A (5-HT2A R). This receptor form a functional complex with the metabotropic glutamate receptor 2 (mGluR2) and is recruited to the cell membrane by the corticotrophin-releasing factor receptor 1 (CRF-R1). The effect of BDNF on gene...... expression for all these receptors, as well as a number of immediate-early genes, was pharmacologically characterized in primary neurons from rat frontal cortex. BDNF increased CRF-R1 mRNA levels up to fivefold, whereas mGluR2 mRNA levels were proportionally downregulated. No effect on 5-HT2A R mRNA was seen...

  1. Brain derived neurotrophic factor (BDNF contributes to the pain hypersensitivity following surgical incision in the rats

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    Zhang Jian-Yi

    2008-07-01

    Full Text Available Abstract Background The pathogenic role of brain derived neurotrophic factor (BDNF in the incisional pain is poorly understood. The present study explores the role of the BDNF in the incision-induced pain hypersensitivity. Methods A longitudinal incision was made in one plantar hind paw of isoflurane-anesthetized rats. Dorsal root ganglias (DRG and spinal cords were removed at various postoperative times (1–72 h. Expression pattern of BDNF was determined by immunohistochemistry and double-labeling immunofluorescence. Lidocaine-induced blockade of sciatic nerve function was used to determine the importance of afferent nerve activity on BDNF expression in the DRG and spinal cord after incision. BDNF antibody was administered intrathecally (IT or intraperitoneal (IP to modulate the spinal BDNF or peripheral BDNF after incision. Results After hind-paw incision, the BDNF was upregulated in the ipsilateral lumbar DRG and spinal cord whereas thoracic BDNF remained unchanged in response to incision. The upregulated BDNF was mainly expressed in the large-sized neurons in DRG and the neurons and the primary nerve terminals in the spinal cord. Sciatic nerve blockade prevented the increase of BDNF in the DRG and spinal cord. IT injection of BDNF antibody greatly inhibited the mechanical allodynia induced by incision whereas IP administration had only marginal effect. Conclusion The present study showed that incision induced the segmental upregulation of BDNF in the DRG and spinal cord through somatic afferent nerve transmission, and the upregulated BDNF contributed to the pain hypersensitivity induced by surgical incision.

  2. Differential Expression and Regulation of Brain-Derived Neurotrophic Factor (BDNF) mRNA Isoforms in Brain Cells from Mecp2(308/y) Mouse Model.

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    Rousseaud, Audrey; Delépine, Chloé; Nectoux, Juliette; Billuart, Pierre; Bienvenu, Thierry

    2015-08-01

    Rett syndrome (RTT) is a severe neurodevelopmental disease caused by mutations in methyl-CpG-binding protein 2 (MECP2), which encodes a transcriptional modulator of many genes including BDNF. BDNF comprises nine distinct promoter regions, each triggering the expression of a specific transcript. The role of this diversity of transcripts remains unknown. MeCP2 being highly expressed in neurons, RTT was initially considered as a neuronal disease. However, recent studies have shown that MeCP2 was also expressed in astrocytes. Though several studies explored Bdnf IV expression in Mecp2-deficient mice, the differential expression of Bdnf isoforms in Mecp2-deficient neurons and astrocytes was never studied. By using TaqMan technology and a mouse model expressing a truncated Mecp2 (Mecp2(308/y)), we firstly showed in neurons that Bdnf transcripts containing exon I, IIb, IIc, IV, and VI are prominently expressed, whereas in astrocytes, Bdnf transcript containing exon VI is preferentially expressed, suggesting a specific regulation of Bdnf expression at the cellular level. Secondly, we confirmed the repressive role of Mecp2 only on the expression of Bdnf VI in neurons. Our data suggested that the truncated Mecp2 protein maintains its function on Bdnf expression regulation in neurons and in astrocytes. Interestingly, we observed that Bdnf transcripts (I and IXA), regulated by neural activity induced by bicuculline in Mecp2(308/y) neurons, were not affected by histone deacetylase inhibition. In contrast, Bdnf transcripts (IIb, IIc, and VI), regulated by histone deacetylation, were not affected by bicuculline treatment in wild-type and Mecp2(308/y) neurons. All these results reflect the complexity of regulation of Bdnf gene.

  3. Neurokinin-1 (NK-1 receptor and brain-derived neurotrophic factor (BDNF gene expression is differentially modulated in the rat spinal dorsal horn and hippocampus during inflammatory pain

    Directory of Open Access Journals (Sweden)

    McCarson Kenneth E

    2007-10-01

    Full Text Available Abstract Persistent pain produces complex alterations in sensory pathways of the central nervous system (CNS through activation of various nociceptive mechanisms. However, the effects of pain on higher brain centers, particularly the influence of the stressful component of pain on the limbic system, are poorly understood. Neurokinin-1 (NK-1 receptors and brain-derived neurotrophic factor (BDNF, known neuromediators of hyperalgesia and spinal central sensitization, have also been implicated in the plasticity and neurodegeneration occurring in the hippocampal formation during exposures to various stressors. Results of this study showed that injections of complete Freund's adjuvant (CFA into the hind paw increased NK-1 receptor and BDNF mRNA levels in the ipsilateral dorsal horn, supporting an important role for these nociceptive mediators in the amplification of ascending pain signaling. An opposite effect was observed in the hippocampus, where CFA down-regulated NK-1 receptor and BDNF gene expression, phenomena previously observed in immobilization models of stress and depression. Western blot analyses demonstrated that in the spinal cord, CFA also increased levels of phosphorylated cAMP response element-binding protein (CREB, while in the hippocampus the activation of this transcription factor was significantly reduced, further suggesting that tissue specific transcription of either NK-1 or BDNF genes may be partially regulated by common intracellular transduction mechanisms mediated through activation of CREB. These findings suggest that persistent nociception induces differential regional regulation of NK-1 receptor and BDNF gene expression and CREB activation in the CNS, potentially reflecting varied roles of these neuromodulators in the spinal cord during persistent sensory activation vs. modulation of the higher brain structures such as the hippocampus.

  4. Neurokinin-1 (NK-1) receptor and brain-derived neurotrophic factor (BDNF) gene expression is differentially modulated in the rat spinal dorsal horn and hippocampus during inflammatory pain.

    Science.gov (United States)

    Duric, Vanja; McCarson, Kenneth E

    2007-10-31

    Persistent pain produces complex alterations in sensory pathways of the central nervous system (CNS) through activation of various nociceptive mechanisms. However, the effects of pain on higher brain centers, particularly the influence of the stressful component of pain on the limbic system, are poorly understood. Neurokinin-1 (NK-1) receptors and brain-derived neurotrophic factor (BDNF), known neuromediators of hyperalgesia and spinal central sensitization, have also been implicated in the plasticity and neurodegeneration occurring in the hippocampal formation during exposures to various stressors. Results of this study showed that injections of complete Freund's adjuvant (CFA) into the hind paw increased NK-1 receptor and BDNF mRNA levels in the ipsilateral dorsal horn, supporting an important role for these nociceptive mediators in the amplification of ascending pain signaling. An opposite effect was observed in the hippocampus, where CFA down-regulated NK-1 receptor and BDNF gene expression, phenomena previously observed in immobilization models of stress and depression. Western blot analyses demonstrated that in the spinal cord, CFA also increased levels of phosphorylated cAMP response element-binding protein (CREB), while in the hippocampus the activation of this transcription factor was significantly reduced, further suggesting that tissue specific transcription of either NK-1 or BDNF genes may be partially regulated by common intracellular transduction mechanisms mediated through activation of CREB. These findings suggest that persistent nociception induces differential regional regulation of NK-1 receptor and BDNF gene expression and CREB activation in the CNS, potentially reflecting varied roles of these neuromodulators in the spinal cord during persistent sensory activation vs. modulation of the higher brain structures such as the hippocampus.

  5. The human BDNF gene: peripheral gene expression and protein levels as biomarkers for psychiatric disorders

    Science.gov (United States)

    Cattaneo, A; Cattane, N; Begni, V; Pariante, C M; Riva, M A

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) regulates the survival and growth of neurons, and influences synaptic efficiency and plasticity. The human BDNF gene consists of 11 exons, and distinct BDNF transcripts are produced through the use of alternative promoters and splicing events. The majority of the BDNF transcripts can be detected not only in the brain but also in the blood cells, although no study has yet investigated the differential expression of BDNF transcripts at the peripheral level. This review provides a description of the human BDNF gene structure as well as a summary of clinical and preclinical evidence supporting the role of BDNF in the pathogenesis of psychiatric disorders. We will discuss several mechanisms as possibly underlying BDNF modulation, including epigenetic mechanisms. We will also discuss the potential use of peripheral BDNF as a biomarker for psychiatric disorders, focusing on the factors that can influence BDNF gene expression and protein levels. Within this context, we have also characterized, for we believe the first time, the expression of BDNF transcripts in the blood, with the aim to provide novel insights into the molecular mechanisms and signaling that may regulate peripheral BDNF gene expression levels. PMID:27874848

  6. Tissue-specific and neural activity-regulated expression of human BDNF gene in BAC transgenic mice

    Directory of Open Access Journals (Sweden)

    Palm Kaia

    2009-06-01

    Full Text Available Abstract Background Brain-derived neurotrophic factor (BDNF is a small secreted protein that has important roles in the developing and adult nervous system. Altered expression or changes in the regulation of the BDNF gene have been implicated in a variety of human nervous system disorders. Although regulation of the rodent BDNF gene has been extensively investigated, in vivo studies regarding the human BDNF gene are largely limited to postmortem analysis. Bacterial artificial chromosome (BAC transgenic mice harboring the human BDNF gene and its regulatory flanking sequences constitute a useful tool for studying human BDNF gene regulation and for identification of therapeutic compounds modulating BDNF expression. Results In this study we have generated and analyzed BAC transgenic mice carrying 168 kb of the human BDNF locus modified such that BDNF coding sequence was replaced with the sequence of a fusion protein consisting of N-terminal BDNF and the enhanced green fluorescent protein (EGFP. The human BDNF-BAC construct containing all BDNF 5' exons preceded by different promoters recapitulated the expression of endogenous BDNF mRNA in the brain and several non-neural tissues of transgenic mice. All different 5' exon-specific BDNF-EGFP alternative transcripts were expressed from the transgenic human BDNF-BAC construct, resembling the expression of endogenous BDNF. Furthermore, BDNF-EGFP mRNA was induced upon treatment with kainic acid in a promotor-specific manner, similarly to that of the endogenous mouse BDNF mRNA. Conclusion Genomic region covering 67 kb of human BDNF gene, 84 kb of upstream and 17 kb of downstream sequences is sufficient to drive tissue-specific and kainic acid-induced expression of the reporter gene in transgenic mice. The pattern of expression of the transgene is highly similar to BDNF gene expression in mouse and human. This is the first study to show that human BDNF gene is regulated by neural activity.

  7. Decreased expression of brain-derived neurotrophic factor in BDNF(+/-) mice is associated with enhanced recovery of motor performance and increased neuroblast number following experimental stroke.

    Science.gov (United States)

    Nygren, Josefine; Kokaia, Merab; Wieloch, Tadeusz

    2006-08-15

    Brain-derived neurotrophic factor (BDNF) is involved in brain plasticity and neuronal survival. Generally, BDNF enhances synaptic activity and neurite growth, although the effect of BDNF on neuronal survival and brain plasticity following injury is equivocal. Housing rats in an enriched environment after experimental stroke enhances recovery of sensory-motor function, which is associated with a decrease in the BDNF mRNA and protein levels. We used BDNF(+/-) mice and wild-type littermate mice to investigate whether the decrease in the brain levels of BDNF affected motor function or infarct volume following transient occlusion of the middle cerebral artery (tMCAO) for 40 min. We found that the BDNF(+/-) mice had a significantly improved motor function on the rotating pole test 2 weeks after tMCAO compared with wild-type mice. When intermittently exposed to an enriched environment following tMCAO, the wild-type mice improved motor function to the same degree as BDNF(+/-) mice. There was no effect of BDNF reduction on infarct volume. Neurogenesis is induced following experimental stroke, and in the striatum of BDNF(+/-) mice significantly increased numbers of neuroblasts compared with wild-type mice were seen, both in standard and in enriched conditions. We conclude that decreasing brain levels of BDNF enhances the recovery of function following experimental stroke.

  8. Regulation of Energy Balance via BDNF Expressed in Nonparaventricular Hypothalamic Neurons.

    Science.gov (United States)

    Yang, Haili; An, Juan Ji; Sun, Chao; Xu, Baoji

    2016-05-01

    Brain-derived neurotrophic factor (BDNF) expressed in the paraventricular hypothalamus (PVH) has been shown to play a key role in regulating energy intake and energy expenditure. BDNF is also expressed in other hypothalamic nuclei; however, the role in the control of energy balance for BDNF produced in these structures remains largely unknown. We found that deleting the Bdnf gene in the ventromedial hypothalamus (VMH) during embryogenesis using the Sf1-Cre transgene had no effect on body weight in mice. In contrast, deleting the Bdnf gene in the adult VMH using Cre-expressing virus led to significant hyperphagia and obesity. These observations indicate that the lack of a hyperphagia phenotype in the Sf1-Cre/Bdnf mutant mice is likely due to developmental compensation. To investigate the role of BDNF expressed in other hypothalamic areas, we employed the hypothalamus-specific Nkx2.1-Cre transgene to delete the Bdnf gene. We found that the Nkx2.1-Cre transgene could abolish BDNF expression in many hypothalamic nuclei, but not in the PVH, and that the resulting mutant mice developed modest obesity due to reduced energy expenditure. Thus, BDNF produced in the VMH plays a role in regulating energy intake. Furthermore, BDNF expressed in hypothalamic areas other than PVH and VMH is also involved in the control of energy expenditure.

  9. A novel BDNF gene promoter directs expression to skeletal muscle

    Directory of Open Access Journals (Sweden)

    Heinrich Gerhard

    2003-06-01

    Full Text Available Abstract Background Cell-specific expression of the gene that encodes brain-derived neurotrophic factor (BDNF is required for the normal development of peripheral sensory neurons and efficient synaptic transmission in the mature central and peripheral nervous system. The control of BDNF gene expression involves multiple tissue and cell-specific promoters that are differentially regulated. The molecular mechanisms that are responsible for tissue and cell-specific expression of these promoters are still incompletely understood. Results The cloning and analysis of three additional zebrafish (Danio rerio BDNF gene exons and two associated promoters, is reported. Among them are two exons that generate a novel tripartite mature transcript. The exons were located on the transcription unit, whose overall organization was determined by cloning, Southern blot hybridization and sequence analysis, and compared with the pufferfish (Fugu rubripes and mammalian BDNF loci, revealing a conserved but more compact organization. Structural and functional analysis of the exons, their adjacent promoters and 5' flanks, showed that they are expressed cell-specifically. The promoter associated with the 5' exon of the tripartite transcript is GC-rich, TATA-less and the 5' flank adjacent to it contains multiple Sp1, Mef2, and AP1 elements. A fusion gene containing the promoter and 1.5 KB of 5' flank is directed exclusively to skeletal muscle of transiently transfected embryos. The second promoter, whose associated 5' exon contains a 25-nucleotide segment of identity with a mammalian BDNF gene exon, was transiently expressed in yolk of the early embryo. RT-PCR analysis of total RNA from whole juvenile fish and adult female skeletal muscle revealed tissue-specific expression of the 5' exons but the novel exon could not be detected even after two rounds of nested PCR. Conclusion The zebrafish BDNF gene is as complex as the mammalian gene yet much more compact. Its exons are

  10. Dietary supplementation of soy germ phytoestrogens or estradiol improves spatial memory performance and increases gene expression of BDNF, TrkB receptor and synaptic factors in ovariectomized rats

    Directory of Open Access Journals (Sweden)

    Li Zhuoneng

    2010-09-01

    Full Text Available Abstract Background Estrogen or phytoestrogens treatment has been suggested to improve cognitive function of the brain in postmenopausal women. However, there is lack of information on the mechanism of such treatment on the central nervous system. The present study aimed to determine the effects of estradiol and soy germ phytoestrogens on spatial memory performance in ovariectomized rats and to explore the underlying mechanisms affecting the central nervous system. Methods Ovariectomized Sprague-Dawley rats were fed a basic diet supplemented with soy germ phytoestrogens (0.4 g/kg or 1.6 g/kg or 17β-estradiol (0.15 g/kg for 12 weeks. At the end of the experiment, animals were evaluated for their spatial learning and memory performance by the Morris Water Maze task. The expressions of brain-derived neurotrophic factor (BDNF and synaptic formation proteins in the hippocampal tissue were estimated using RT-PCR and ELISA. Results It was found that rats supplemented with soy germ phytoestrogens or estradiol performed significantly better in spatial memory acquisition and retention when compared to the rats fed on the control diet. Estradiol or the high dose of phytoestrogens treatment significantly increased BDNF concentration and the mRNA levels for BDNF and its TrkB receptors as well as the synaptic formation proteins, synaptophysin, spinophilin, synapsin 1 and PSD-95, in the hippocampal tissue of the experimental animals. It was also found that phytoestrogens, in contrast to estradiol, did not show any significant effect on the vaginal and uteri. Conclusion Soy germ phytoestrogens, which may be a substitute of estradiol, improved spatial memory performance in ovariectomized rats without significant side-effects on the vaginal and uteri. The memory enhancement effect may relate to the increase in BDNF and the synaptic formation proteins expression in the hippocampus of the brain.

  11. HuD promotes BDNF expression in brain neurons via selective stabilization of the BDNF long 3'UTR mRNA.

    Directory of Open Access Journals (Sweden)

    Megan Allen

    Full Text Available Complex regulation of brain-derived neurotrophic factor (BDNF governs its intricate functions in brain development and neuronal plasticity. Besides tight transcriptional control from multiple distinct promoters, alternative 3'end processing of the BDNF transcripts generates either a long or a short 3'untranslated region (3'UTR. Previous reports indicate that distinct RNA sequence in the BDNF 3'UTRs differentially regulates BDNF production in the brain to accommodate neuronal activity changes, conceivably through differential interactions with undefined trans-acting factors that regulate stability and translation of these BDNF mRNA isoforms. In this study, we report that the neuronal RNA-binding protein (RBP HuD interacts with a highly conserved AU-rich element (ARE specifically located in the BDNF long 3'UTR. Such interaction is necessary and sufficient for selective stabilization of mRNAs that contain the BDNF long 3'UTR in vitro and in vivo. Moreover, in a HuD transgenic mouse model, the BDNF long 3'UTR mRNA is increased in the hippocampal dentate granule cells (DGCs, leading to elevated expression of BDNF protein that is transported and stored in the mossy fiber (MF terminals. Our results identify HuD as the first trans-acting factor that enhances BDNF expression specifically through the long 3'UTR and a novel mechanism that regulates BDNF protein production in selected neuronal populations by HuD abundance.

  12. Glucocorticoids modulate BDNF mRNA expression in the rat hippocampus after traumatic brain injury.

    Science.gov (United States)

    Grundy, P L; Patel, N; Harbuz, M S; Lightman, S L; Sharples, P M

    2000-10-20

    Brain-derived neurotrophic factor (BDNF) expression in rat hippocampus is increased after experimental traumatic brain injury (TBI) and may be neuroprotective. Glucocorticoids are important regulators of brain neurotrophin levels and are often prescribed following TBI. The effect of adrenalectomy (ADX) on the expression of BDNF mRNA in the hippocampus after TBI has not been investigated to date. We used fluid percussion injury (FPI) and in situ hybridization to evaluate the expression of BDNF mRNA in the hippocampus 4 h after TBI in adrenal-intact or adrenalectomized rats (with or without corticosterone replacement). FPI and ADX independently increased expression of BDNF mRNA. In animals undergoing FPI, prior ADX caused further elevation of BDNF mRNA and this upregulation was prevented by corticosterone replacement in ADX rats. These findings suggest that glucocorticoids are involved in the modulation of the BDNF mRNA response to TBI.

  13. Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons.

    Science.gov (United States)

    Chen, Zhe-Yu; Patel, Paresh D; Sant, Gayatree; Meng, Chui-Xiang; Teng, Kenneth K; Hempstead, Barbara L; Lee, Francis S

    2004-05-05

    Brain-derived neurotrophic factor (BDNF) plays a critical role in nervous system and cardiovascular development and function. Recently, a common single nucleotide polymorphism in the bdnf gene, resulting in a valine to methionine substitution in the prodomain (BDNF(Met)), has been shown to lead to memory impairment and susceptibility to neuropsychiatric disorders in humans heterozygous for the variant BDNF. When expressed by itself in hippocampal neurons, less BDNF(Met) is secreted in an activity-dependent manner. The nature of the cellular defect when both BDNF(Met) and wild-type BDNF (BDNF(Val)) are present in the same cell is not known. Given that this is the predominant expression profile in humans, we examined the effect of coexpressed BDNF(Met) on BDNF(Val) intracellular trafficking and processing. Our data indicate that abnormal trafficking of BDNF(Met) occurred only in neuronal and neurosecretory cells and that BDNF(Met) could alter the intracellular distribution and activity-dependent secretion of BDNF(Val). We determined that, when coexpressed in the same cell, approximately 70% of the variant BDNF forms BDNF(Val).BDNF(Met) heterodimers, which are inefficiently sorted into secretory granules resulting in a quantitative decreased secretion. Finally, we determined the form of BDNF secreted in an activity-dependent manner and observed no differences in the forms of BDNF(Met) or the BDNF(Val).BDNF(Met) heterodimer compared with BDNF(Val). Together, these findings indicate that components of the regulated secretory machinery interacts specifically with a signal in the BDNF prodomain and that perturbations in BDNF trafficking may lead to selective impairment in CNS function.

  14. Cooperative roles of BDNF expression in neurons and Schwann cells are modulated by exercise to facilitate nerve regeneration.

    Science.gov (United States)

    Wilhelm, Jennifer C; Xu, Mei; Cucoranu, Delia; Chmielewski, Sarah; Holmes, Tiffany; Lau, Kelly Shukkwan; Bassell, Gary J; English, Arthur W

    2012-04-04

    After peripheral nerve injury, neurotrophins play a key role in the regeneration of damaged axons that can be augmented by exercise, although the distinct roles played by neurons and Schwann cells are unclear. In this study, we evaluated the requirement for the neurotrophin, brain-derived neurotrophic factor (BDNF), in neurons and Schwann cells for the regeneration of peripheral axons after injury. Common fibular or tibial nerves in thy-1-YFP-H mice were cut bilaterally and repaired using a graft of the same nerve from transgenic mice lacking BDNF in Schwann cells (BDNF(-/-)) or wild-type mice (WT). Two weeks postrepair, axonal regeneration into BDNF(-/-) grafts was markedly less than WT grafts, emphasizing the importance of Schwann cell BDNF. Nerve regeneration was enhanced by treadmill training posttransection, regardless of the BDNF content of the nerve graft. We further tested the hypothesis that training-induced increases in BDNF in neurons allow regenerating axons to overcome a lack of BDNF expression in cells in the pathway through which they regenerate. Nerves in mice lacking BDNF in YFP(+) neurons (SLICK) were cut and repaired with BDNF(-/-) and WT nerves. SLICK axons lacking BDNF did not regenerate into grafts lacking Schwann cell BDNF. Treadmill training could not rescue the regeneration into BDNF(-/-) grafts if the neurons also lacked BDNF. Both Schwann cell- and neuron-derived BDNF are thus important for axon regeneration in cut peripheral nerves.

  15. 3-Hydroxybutyrate regulates energy metabolism and induces BDNF expression in cerebral cortical neurons

    DEFF Research Database (Denmark)

    Marosi, Krisztina; Kim, Sang Woo; Moehl, Keelin

    2016-01-01

    . The mechanism by which 3OHB induces Bdnf gene expression involves generation of reactive oxygen species, activation of the transcription factor NF-κB, and activity of the histone acetyltransferase p300/EP300. Because BDNF plays important roles in synaptic plasticity and neuronal stress resistance, our findings...

  16. Effects of Chinese medicinal herbs on expression of brain-derived Neurotrophic factor (BDNF) and its interaction with human breast cancer MDA-MB-231 cells and endothelial HUVECs.

    Science.gov (United States)

    Chiu, Jen-Hwey; Chen, Fang-Pey; Tsai, Yi-Fang; Lin, Man-Ting; Tseng, Ling-Ming; Shyr, Yi-Ming

    2017-08-12

    Our previous study demonstrated that an up-regulation of the Brain-Derived Neurotrophic Factor (BDNF) signaling pathway is involved the mechanism causing the recurrence of triple negative breast cancer. The aim of this study is to investigate the effects of commonly used Chinese medicinal herbs on MDA-MB-231 and HUVEC cells and how they interact with BDNF. Human TNBC MDA-MB-231 cells and human endothelial HUVEC cells were used to explore the effect of commonly used Chinese herbal medicines on cancer cells alone, on endothelial cells alone and on cancer cell/endothelial cell interactions; this was done via functional studies, including migration and invasion assays. Furthermore, Western blot analysis and real-time PCR investigations were also used to investigate migration signal transduction, invasion signal transduction, and angiogenic signal transduction in these systems. Finally, the effect of the Chinese medicinal herbs on cancer cell/endothelial cell interactions was assessed using co-culture and ELISA. In terms of autoregulation, BDNF up-regulated TrkB gene expression in both MDA-MB-231 and HUVEC cells. Furthermore, BDNF enhanced migration by MDA-MB-231 cells via Rac, Cdc42 and MMP, while also increasing the migration of HUVEC cells via MMP and COX-2 expression. As measured by ELISA, the Chinese herbal medicinal herbs A. membranaceus, P. lactiflora, L. chuanxiong, P. suffruticosa and L. lucidum increased BDNF secretion by MDA-MB-231 cells. Similarly, using a co-culture system with MDA-MB-231 cells, A. membranaceus and L. lucidum modulated BDNF-TrkB signaling by HUVEC cells. We conclude that BDNF plays an important role in the metastatic interaction between MDA-MB-231 and HUVEC cells. Some Chinese medicinal herbs are able to enhance the BDNF-related metastatic potential of the interaction between cancer cells and endothelial cells. These findings provide important information that should help with the development of integrated medical therapies for breast

  17. [BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF): NEUROBIOLOGY AND MARKER VALUE IN NEUROPSYCHIATRY].

    Science.gov (United States)

    Levada, O A; Cherednichenko, N V

    2015-01-01

    In this review current publications about neurobiology and marker value of brain derived neurotrophic factor (BDNF) in neuropsychiatry are analyzed. It is shown that BDNF is an important member of the family of neurotrophins which widely represented in various structures of the CNS. In prenatal period BDNF is involved in all stages of neuronal networks formation, and in the postnatal period its main role is maintaining the normal brain architectonics, involvement in the processes of neurogenesis and realization of neuroprotective functions. BDNF plays an important role in learning and memory organization, food and motor behavior. BDNF brain expression decreases with age, as well as in degenerative and vascular dementias, affective, anxiety, and behavioral disorders. The reducing of BDNF serum, level reflects the decreasing of its cerebral expression and could be used as a neurobiological marker of these pathological processes but the rising of its concentration could indicate the therapy effectiveness.

  18. Lactoferrin up-regulates intestinal gene expression of brain-derived neurotrophic factors BDNF, UCHL1 and alkaline phosphatase activity to alleviate early weaning diarrhea in postnatal piglets.

    Science.gov (United States)

    Yang, Changwei; Zhu, Xi; Liu, Ni; Chen, Yue; Gan, Hexia; Troy, Frederic A; Wang, Bing

    2014-08-01

    The molecular mechanisms underlying how dietary lactoferrin (Lf) impacts gut development and maturation and protects against early weaning diarrhea are not well understood. In this study, we supplemented postnatal piglets with an Lf at a dose level of 155 and 285 mg/kg/day from 3 to 38 days following birth. Our findings show that the high dose of Lf up-regulated messenger RNA expression levels of genes encoding brain-derived neurotrophic factor (BDNF) and ubiquitin carboxy-terminal hydrolase L1 (ubiquitin thiolesterase (UCHL1) and, to a lesser extent, glial cell line-derived neurotrophic factor, in the duodenum (Pintestinal alkaline phosphatase activity (Pbrain-microbe axis that has not been previously reported.

  19. Effect of brain-derived neurotrophic factor and green fluorescent protein gene-transfected neural stem cells transplantation on brain-derived neurotrophic factor expression in rats with spinal cord injury%BDNF-GFP转染神经干细胞对脊髓损伤大鼠BDNF表达的影响

    Institute of Scientific and Technical Information of China (English)

    王岩松; 梅晰凡; 吕刚

    2011-01-01

    Objective To study the effect of brain-derived neurotrophic factor (BDNF) and green fluorescent protein (GFP)transfected neural stem cells (NSCs) transplantation on expression of BDNF in rats with spinal cord injury. Methods NSCs were transfected with adenovirus vector bearing BDNF and GFP. Expression of BDNF in BDNF and GFP-transfected NSCs was detected by immunohistochemistry and Western blot, respectively. Of the 40 healthy Wistar rats, 8 were selected as a sham-operation group, 32 served as a T9 left hemisection model. Then, the 32 rats were randomly divided into BDNF and GFP-transfected NSCs transplantation group, GFP-transfected NSCs transplantation group, single NSCs transplantation group and model groups, 8 rats in each group. Gene-transfected NSCs or non gene-transfected NSCs were microinjected into each side of the transection site in the 3 NSCs transplantation groups after spinal cord injury (SCI) was induced. An equal volume of PBS was injected into the model group through the same injection sites. Expression of BDNF was detected in each group after SCI by real-time PCR. Results Immunohistochemistry showed that BDNF and GFP-transfected NSCs could express BDNF (yellow fluorescence). Western blot demonstrated that BDNF and GFP-transfected NSCs could express immunoreactive bands with a relative molecular mass of 41kU. NSCs transplantation could significantly increase the expression level of BDNF (P<0.01). The expression level of BDNF was the highest in BDNF and GFPtransfected NSCs transplantation group (P<0.01). Conclusion BDNF and GFP-transfected NSCs can survive and highly express BDNF in hemisected spinal cord model of rats.%目的 探讨脑源性神经营养因子(Brain-Derived Neurotrophic Factor,BDNF)和绿色荧光蛋白(Green Fluorescent Protein,GFP)转染后神经干细胞(Neural Stem Cells,NSCs)移植对脊髓损伤大鼠BDNF表达的影响.方法 以携带BDNF-GFP基因的腺病毒转染NSCs,免疫组化及Western blot检测转染后NSCs BDNF

  20. Altered balance of glutamatergic/GABAergic synaptic input and associated changes in dendrite morphology after BDNF expression in BDNF-deficient hippocampal neurons

    OpenAIRE

    Singh, B; Henneberger, C.; Betances, D.; Arevalo, M. A.; Rodriguez-Tebar, A.; Meier, J C; Grantyn, R.

    2006-01-01

    Cultured neurons from bdnf-/- mice display reduced densities of synaptic terminals, although in vivo these deficits are small or absent. Here we aimed at clarifying the local responses to postsynaptic brain-derived neurotrophic factor (BDNF). To this end, solitary enhanced green fluorescent protein (EGFP)-labeled hippocampal neurons from bdnf-/- mice were compared with bdnf-/- neurons after transfection with BDNF, bdnf-/- neurons after transient exposure to exogenous BDNF, and bdnf+/+ neurons...

  1. Silencing Status Epilepticus-Induced BDNF Expression with Herpes Simplex Virus Type-1 Based Amplicon Vectors.

    Directory of Open Access Journals (Sweden)

    Chiara Falcicchia

    Full Text Available Brain-derived neurotrophic factor (BDNF has been found to produce pro- but also anti-epileptic effects. Thus, its validity as a therapeutic target must be verified using advanced tools designed to block or to enhance its signal. The aim of this study was to develop tools to silence the BDNF signal. We generated Herpes simplex virus type 1 (HSV-1 derived amplicon vectors, i.e. viral particles containing a genome of 152 kb constituted of concatameric repetitions of an expression cassette, enabling the expression of the gene of interest in multiple copies. HSV-1 based amplicon vectors are non-pathogenic and have been successfully employed in the past for gene delivery into the brain of living animals. Therefore, amplicon vectors should represent a logical choice for expressing a silencing cassette, which, in multiple copies, is expected to lead to an efficient knock-down of the target gene expression. Here, we employed two amplicon-based BDNF silencing strategies. The first, antisense, has been chosen to target and degrade the cytoplasmic mRNA pool of BDNF, whereas the second, based on the convergent transcription technology, has been chosen to repress transcription at the BDNF gene. Both these amplicon vectors proved to be effective in down-regulating BDNF expression in vitro, in BDNF-expressing mesoangioblast cells. However, only the antisense strategy was effective in vivo, after inoculation in the hippocampus in a model of status epilepticus in which BDNF mRNA levels are strongly increased. Interestingly, the knocking down of BDNF levels induced with BDNF-antisense was sufficient to produce significant behavioral effects, in spite of the fact that it was produced only in a part of a single hippocampus. In conclusion, this study demonstrates a reliable effect of amplicon vectors in knocking down gene expression in vitro and in vivo. Therefore, this approach may find broad applications in neurobiological studies.

  2. Effect of voluntary exercise on BDNF/TrkB gene expression and alcohol intake.

    OpenAIRE

    Jonsson, Josefine

    2012-01-01

    Voluntary wheel running is rewarding and believed to activate the same brain reward system as in alcohol and drug addiction. Brain-derived neurotrophic factor (BDNF), a well-known growth factor widely expressed in the brain, is modulated by both voluntary exercise and alcohol consumption. The aim of this study was to evaluate how voluntary exercise affects the expression levels of BDNF and its receptor TrkB in brain regions involved in positive and negative reinforcement. Additionally we want...

  3. ASPECTS OF CYCLON AND BDNF GENE EXPRESSION IN SCHIZOPHRENIA PATIENTS

    Directory of Open Access Journals (Sweden)

    Rinaldo Shishkov

    2012-08-01

    Full Text Available The pathogenesis of the schizophrenic illness is still not fully elucidated. Many studies have been conducted revealing different aspects but may be the studies of greatest significance are studying the genetic aspects of expression of trophic factors and enzymes associated with nervous system development and plasticity. In this relation we aimed at measuring the Cyclon and BDNF genes expression in blood of patients suffering from schizophrenia and to test for correlation between them. Our result did not reveal correlation in spite of their connection with the disease

  4. An evaluation of the effects of acute and chronic L-tyrosine administration on BDNF levels and BDNF mRNA expression in the rat brain.

    Science.gov (United States)

    Ferreira, Gabriela K; Scaini, Giselli; Jeremias, Isabela C; Carvalho-Silva, Milena; Gonçalves, Cinara L; Pereira, Talita C B; Oliveira, Giovanna M T; Kist, Luiza W; Bogo, Maurício R; Schuck, Patrícia F; Ferreira, Gustavo C; Streck, Emilio L

    2014-04-01

    Tyrosinemia type II, which is also known as Richner-Hanhart syndrome, is an inborn error of metabolism that is due to a block in the transamination reaction that converts tyrosine to p-hydroxyphenylpyruvate. Because the mechanisms of neurological dysfunction in hypertyrosinemic patients are poorly known and the symptoms of these patients are related to the central nervous system, the present study evaluated brain-derived neurotrophic factor (BDNF) levels and bdnf mRNA expression in young rats and during growth. In our acute protocol, Wistar rats (10 and 30 days old) were killed 1 h after a single intraperitoneal L-tyrosine injection (500 mg/kg) or saline. Chronic administration consisted of L-tyrosine (500 mg/kg) or saline injections 12 h apart for 24 days in Wistar rats (7 days old), and the rats were killed 12 h after the last injection. The brains were rapidly removed, and we evaluated the BDNF levels and bdnf mRNA expression. The present results showed that the acute administration of L-tyrosine decreased both BDNF and bdnf mRNA levels in the striatum of 10-day-old rats. In the 30-day-old rats, we observed decreased BDNF levels without modifications in bdnf transcript level in the hippocampus and striatum. Chronic administration of L-tyrosine increased the BDNF levels in the striatum of rats during their growth, whereas bdnf mRNA expression was not altered. We hypothesize that oxidative stress can interact with the BDNF system to modulate synaptic plasticity and cognitive function. The present results enhance our knowledge of the pathophysiology of hypertyrosinemia.

  5. BDNF promoter-mediated beta-galactosidase expression in the olfactory epithelium and bulb.

    Science.gov (United States)

    Clevenger, Amy C; Salcedo, Ernesto; Jones, Kevin R; Restrepo, Diego

    2008-07-01

    The neurotrophin brain-derived neurotrophic factor (BDNF) has been implicated in the generation and differentiation of new olfactory sensory neurons (OSNs) and in the regulation of branching of OSN axons in their target glomeruli. However, previous reports of BDNF mRNA and protein expression in olfactory epithelium and olfactory bulb (OB) have been inconsistent, raising questions on the proposed roles for BDNF. Here, we report on beta-galactosidase (beta-gal) expression in adult gene-targeted mice where the BDNF promoter drives expression of the Escherichia coli lacZ gene (BDNF(lacZneo) mice). We find that beta-gal is expressed in a small subset of OSNs with axons that reach the olfactory nerve layers throughout the OB. In the OB, we find expression of beta-gal in gamma-aminobutyric acidergic but not dopaminergic periglomerular cells and external tufted cells and in interneurons located in the mitral cell layer. Our results are inconsistent with the regulation of generation and differentiation of new OSNs elicited by the release of BDNF from horizontal basal cells. The results are consistent with a role for BDNF in competitive branching of OSN axons within the glomeruli of the OB.

  6. Recombinant AAV-mediated Expression of Human BDNF Protects Neurons against Cell Apoptosis in Aβ-induced Neuronal Damage Model

    Institute of Scientific and Technical Information of China (English)

    LIU Zhaohui; MA Dongliang; FENG Gaifeng; MA Yanbing; HU Haitao

    2007-01-01

    The human brain-derived neurotrophic factor (hBDNF) gene was cloned by polymerase chain reaction and the recombinant adeno-associated viral vector inserted with hBDNF gene (AAV-hBDNF) was constructed. Cultured rat hippocampal neurons were treated with Aβ25-35 and serued as the experimental Aβ-induced neuronal damage model (AD model), and the AD model was infected with AAV-hBDNF to explore neuroprotective effects of expression of BDNF. Cell viability was assayed by MTT. The expression of bcl-2 anti-apoptosis protein was detected by immunocytochemical staining. The change of intracellular free Ca ion ([Ca2+]i) was measured by laser scanning confocal microscopy. The results showed that BDNF had protective effects against Aβ-induced neuronal damage. The expression of the bcl-2 anti-apoptosis protein was raised significantly and the balance of [Ca2+]i was maintained in the AAV-hBDNF treatment group as compared with AD model group. These data suggested that recombinant AAV mediated a stable expression of hBDNF in cultured hippocampal neurons and resulted in significant neuron protective effects in AD model. The BDNF may reduce neuron apoptosis through increasing the expression of the bcl-2 anti-apoptosis protein and inhibiting intracellular calcium overload. The viral vector-mediated gene expression of BDNF may pave the way of a novel therapeutic strategy for the treatment of neurodegenerative diseases such as Alzheimer's disease.

  7. Chronic estradiol treatment decreases brain derived neurotrophic factor (BDNF) expression and monoamine levels in the amygdala--implications for behavioral disorders.

    Science.gov (United States)

    Balasubramanian, Priya; Subramanian, Madhan; Nunez, Joseph L; Mohankumar, Sheba M J; Mohankumar, P S

    2014-03-15

    Changes in serum estradiol levels are associated with mood disorders in women. However, the underlying mechanisms are not clear. Because alterations in Brain-Derived Neurotrophic Factor (BDNF) and monoamine levels in the hippocampus and amygdala have been associated with anxiety disorders, we hypothesized that chronic treatment with a low dose of estradiol would cause anxiety-like disorder by altering BDNF and monoamine levels in these regions. To test this hypothesis, female rats were sham-implanted (Controls) or implanted with pellets that release estradiol-17β (E2) for 90-days at the rate of 20 ng/day. Animals underwent behavioral tests such as the open field test and elevated plus maze test at the end of treatment. Brains from these animals were frozen, sectioned and the hippocampus, central amygdala and caudate putamen were microdissected and analyzed for monoamine levels using HPLC. BDNF protein levels in these areas were measured using ELISA and BDNF mRNA levels were analyzed using RT-PCR. In the open field test, animals chronically treated with E2 displayed anxiety-like behavior that was marked by a decrease in the number of inner zone crossings and increase in the rate of defecation compared to controls. However, no behavioral changes were observed in the elevated plus maze test. Chronic E2 treatment also decreased BDNF protein and mRNA levels in the central amygdala that was accompanied by a reduction in dopamine levels. No changes were observed in the hippocampus and caudate putamen. These results suggest that BDNF and dopamine in the central amygdala might possibly mediate chronic E2-induced behavioral alterations.

  8. Effects of Ethanol on the Expression Level of Various BDNF mRNA Isoforms and Their Encoded Protein in the Hippocampus of Adult and Embryonic Rats

    Directory of Open Access Journals (Sweden)

    Shahla Shojaei

    2015-12-01

    Full Text Available We aimed to compare the effects of oral ethanol (Eth alone or combined with the phytoestrogen resveratrol (Rsv on the expression of various brain-derived neurotrophic factor (BDNF transcripts and the encoded protein pro-BDNF in the hippocampus of pregnant and embryonic rats. A low (0.25 g/kg body weight (BW/day dose of Eth produced an increase in the expression of BDNF exons I, III and IV and a decrease in that of the exon IX in embryos, but failed to affect BDNF transcript and pro-BDNF protein expression in adults. However, co-administration of Eth 0.25 g/kg·BW/day and Rsv led to increased expression of BDNF exons I, III and IV and to a small but significant increase in the level of pro-BDNF protein in maternal rats. A high (2.5 g/kg·BW/day dose of Eth increased the expression of BDNF exons III and IV in embryos, but it decreased the expression of exon IX containing BDNF mRNAs in the maternal rats. While the high dose of Eth alone reduced the level of pro-BDNF in adults, it failed to change the levels of pro-BDNF in embryos. Eth differentially affects the expression pattern of BDNF transcripts and levels of pro-BDNF in the hippocampus of both adult and embryonic rats.

  9. Brain-derived neurotrophic factor (BDNF) and type 2 diabetes

    DEFF Research Database (Denmark)

    Krabbe, K. S.; Nielsen, A. R.; Krogh-Madsen, R.;

    2006-01-01

    Aims/hypothesis  Decreased levels of brain-derived neurotrophic factor (BDNF) have been implicated in the pathogenesis of Alzheimer's disease and depression. These disorders are associated with type 2 diabetes, and animal models suggest that BDNF plays a role in insulin resistance. We therefore...... explored whether BDNF plays a role in human glucose metabolism. Subjects and methods  We included (Study 1) 233 humans divided into four groups depending on presence or absence of type 2 diabetes and presence or absence of obesity; and (Study 2) seven healthy volunteers who underwent both a hyperglycaemic...... and a hyperinsulinaemic-euglycaemic clamp. Results  Plasma levels of BDNF in Study 1 were decreased in humans with type 2 diabetes independently of obesity. Plasma BDNF was inversely associated with fasting plasma glucose, but not with insulin. No association was found between the BDNF G196A (Val66Met) polymorphism...

  10. Increased expression of BDNF and proliferation of dentate granule cells after bacterial meningitis.

    Science.gov (United States)

    Tauber, Simone C; Stadelmann, Christine; Spreer, Annette; Brück, Wolfgang; Nau, Roland; Gerber, Joachim

    2005-09-01

    Proliferation and differentiation of neural progenitor cells is increased after bacterial meningitis. To identify endogenous factors involved in neurogenesis, expression of brain-derived neurotrophic factor (BDNF), TrkB, nerve growth factor (NGF), and glial cell line-derived neurotrophic factor (GDNF) was investigated. C57BL/6 mice were infected by intracerebral injection of Streptococcus pneumoniae. Mice were killed 30 hours later or treated with ceftriaxone and killed 4 days after infection. Hippocampal BDNF mRNA levels were increased 2.4-fold 4 days after infection (p = 0.026). Similarly, BDNF protein levels in the hippocampal formation were higher in infected mice than in control animals (p = 0.0003). This was accompanied by an elevated proliferation of dentate granule cells (p = 0.0002). BDNF protein was located predominantly in the hippocampal CA3/4 area and the hilus of the dentate gyrus. The density of dentate granule cells expressing the BDNF receptor TrkB as well as mRNA levels of TrkB in the hippocampal formation were increased 4 days after infection (p = 0.027 and 0.0048, respectively). Conversely, NGF mRNA levels at 30 hours after infection were reduced by approximately 50% (p = 0.004). No significant changes in GDNF expression were observed. In conclusion, increased synthesis of BDNF and TrkB suggests a contribution of this neurotrophic factor to neurogenesis after bacterial meningitis.

  11. Repeated exposure to sublethal doses of the organophosphorus compound VX activates BDNF expression in mouse brain.

    Science.gov (United States)

    Pizarro, Jose M; Chang, Wenling E; Bah, Mariama J; Wright, Linnzi K M; Saviolakis, George A; Alagappan, Arun; Robison, Christopher L; Shah, Jinesh D; Meyerhoff, James L; Cerasoli, Douglas M; Midboe, Eric G; Lumley, Lucille A

    2012-04-01

    The highly toxic organophosphorus compound VX [O-ethyl S-[2-(diisopropylamino)ethyl]methylphosphonate] is an irreversible inhibitor of the enzyme acetylcholinesterase (AChE). Prolonged inhibition of AChE increases endogenous levels of acetylcholine and is toxic at nerve synapses and neuromuscular junctions. We hypothesized that repeated exposure to sublethal doses of VX would affect genes associated with cell survival, neuronal plasticity, and neuronal remodeling, including brain-derived neurotrophic factor (BDNF). We examined the time course of BDNF expression in C57BL/6 mouse brain following repeated exposure (1/day × 5 days/week × 2 weeks) to sublethal doses of VX (0.2 LD(50) and 0.4 LD(50)). BDNF messenger RNA expression was significantly (p VX exposure. BDNF protein expression, however, was only increased in the CA3 region of the hippocampus. Whether increased BDNF in response to sublethal doses of VX exposure is an adaptive response to prevent cellular damage or a precursor to impending brain damage remains to be determined. If elevated BDNF is an adaptive response, exogenous BDNF may be a potential therapeutic target to reduce the toxic effects of nerve agent exposure.

  12. Brain-derived neurotrophic factor (BDNF) gene delivery into the CNS using bone marrow cells as vehicles in mice.

    Science.gov (United States)

    Makar, T K; Trisler, D; Eglitis, M A; Mouradian, M M; Dhib-Jalbut, S

    2004-02-19

    Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is protective in animal models of neurodegenerative diseases. However, BDNF has a short half-life and its efficacy in the CNS when delivered peripherally is limited due to the blood-brain barrier. In the present study, bone marrow cells were used as vehicles to deliver the BDNF gene into the CNS. Marrow cells obtained from 6 to 8 week-old SJL/J mice were transduced with BDNF expressing pro-virus. RT-PCR analysis revealed that BDNF mRNA was expressed in transduced but not in non-transduced marrow cells. Additionally, virus transduced marrow cells expressed the BDNF protein (296+/-1.2 unit/ml). BDNF-transduced marrow cells were then transplanted into irradiated mice through the tail vein. Three months post-transplantation, significant increases in BDNF as well as glutamic acid decarboxylase (GAD(67)) mRNA were detected in the brains of BDNF transplanted mice compared to untransplanted animals, indicating biological activity of the BDNF transgene. Thus, bone marrow cells can be used as vehicles to deliver the BDNF gene into the brain with implications for the treatment of neurological diseases.

  13. Electrical stimulation promotes BDNF expression in spinal cord neurons through Ca(2+)- and Erk-dependent signaling pathways.

    Science.gov (United States)

    Wenjin, Wang; Wenchao, Liu; Hao, Zhu; Feng, Li; Yan, Wo; Wodong, Shi; Xianqun, Fan; Wenlong, Ding

    2011-04-01

    Brief electrical stimulation has been shown to be effective in promoting neuronal regeneration following peripheral nerve injury. These effects are thought to be mediated largely by the upregulation of the expression of brain-derived neurotrophic factor (BDNF) in spinal cord neurons. However, the molecular mechanisms by which electrical stimulation can promote BDNF expression are not known. The mechanism involved in BDNF expression after electrical stimulation was explored in this study. Immunohistochemistry and Western blotting were used to test BDNF expression. Confocal microscopy was utilized to study intracellular Ca(2+) volume. Immunohistochemistry and Western blotting confirmed that brief electrical stimulation increased BDNF expression in spinal cord neurons both in vivo and in vitro. Treatment of cultured neurons with nifedipine, an inhibitor of voltage-gated calcium channels, significantly reduced the BDNF increase produced by electrical stimulation, and an inhibitor of Erk completely abolished the effect of electrical stimulation. Levels of BDNF expression in the presence of the Erk inhibitor were lower that in unstimulated and untreated controls, indicating that Erk activation is required to maintain baseline levels of BDNF. Confocal microscopy using a Ca(2+)-sensitive fluorochrome revealed that electrical stimulation is accompanied by an increase in intracellular Ca(2+) levels; the increase was partly blocked by nifedipine. These findings argue that electrical stimulation increases BDNF expression in spinal cord neurons by activating a Ca(2+)- and Erk-dependent signaling pathways.

  14. Brain-derived neurotrophic factor (BDNF) overexpression in the forebrain results in learning and memory impairments.

    Science.gov (United States)

    Cunha, Carla; Angelucci, Andrea; D'Antoni, Angela; Dobrossy, Mate D; Dunnett, Stephen B; Berardi, Nicoletta; Brambilla, Riccardo

    2009-03-01

    In this study we analyzed the effect on behavior of a chronic exposure to brain-derived neurotrophic factor (BDNF), by analysing a mouse line overexpressing BDNF under the alphaCaMKII promoter, which drives the transgene expression exclusively to principal neurons of the forebrain. BDNF transgenic mice and their WT littermates were examined with a battery of behavioral tests, in order to evaluate motor coordination, learning, short and long-term memory formation. Our results demonstrate that chronic BDNF overexpression in the central nervous system (CNS) causes learning deficits and short-term memory impairments, both in spatial and instrumental learning tasks. This observation suggests that a widespread increase in BDNF in forebrain networks may result in adverse effects on learning and memory formation.

  15. An AMPA receptor potentiator modulates hippocampal expression of BDNF: an in vivo study.

    Science.gov (United States)

    Mackowiak, Marzena; O'Neill, Michael J; Hicks, Caroline A; Bleakman, David; Skolnick, Phil

    2002-07-01

    AMPA receptor activation has been demonstrated to increase the neuronal expression of brain derived neurotrophic factor (BDNF). In the present study, we investigated the effect of a novel AMPA receptor potentiator (LY404187) and its active isomer (LY451646) on the expression of BDNF protein and mRNA, as well as TrkB mRNA in rat hippocampus. LY404187 administered for 7 days (1 mg/kg) significantly increased the number of BDNF immunopositive cells in the dentate gyrus, but not other hippocampal subfields. Chronic treatment (7 days) with LY451646 (0.5 mg/kg, comparable to 1 mg/kg of LY404187) increased the level of both BDNF and TrkB mRNA expression in the dentate gyrus, CA3 and CA4 of the hippocampus. However, chronic treatment with lower doses of LY451646 (0.125 and 0.25 mg/kg) decreased the level of BDNF and TrkB mRNA in hippocampus, whilst the highest used dose of LY451646 (1 mg/kg) had no effect on BDNF and TrkB mRNA in hippocampus. In contrast, acute treatment with LY451646 produced an increase in BDNF mRNA levels at doses of 0.125 and 0.25 mg/kg in the hippocampus (CA4, CA3 and dentate gyrus, but not in CA1). LY451646 at 0.5 mg/kg had no effect, but at 1.0 mg/kg decreased the level of BDNF mRNA in hippocampus. Acute treatment with LY451646 did not affect the TrkB receptor mRNA levels in hippocampus. Our results demonstrate that biarylpropylsulfonamide AMPA receptor potentiators are capable of modulating the expression of BDNF and TrkB mRNA in a dose- and time-dependent manner. The increase in both BDNF protein and mRNA expression in the dentate gyrus but not in CA1 indicates a specific role of AMPA receptors in the regulation of BDNF expression in this hippocampal subfield. The regulation of BDNF expression by biarylpropylsulfonamids such as LY451646 may have important therapeutical implications for this class of molecule in the treatment of depression and other CNS disorders.

  16. Increased BDNF protein expression after ischemic or PKC epsilon preconditioning promotes electrophysiologic changes that lead to neuroprotection

    OpenAIRE

    Neumann, Jake T.; Thompson, John W.; Raval, Ami P; Cohan, Charles H; Koronowski, Kevin B.; Perez-Pinzon, Miguel A

    2014-01-01

    Ischemic preconditioning (IPC) via protein kinase C epsilon (PKCɛ) activation induces neuroprotection against lethal ischemia. Brain-derived neurotrophic factor (BDNF) is a pro-survival signaling molecule that modulates synaptic plasticity and neurogenesis. Interestingly, BDNF mRNA expression increases after IPC. In this study, we investigated whether IPC or pharmacological preconditioning (PKCɛ activation) promoted BDNF-induced neuroprotection, if neuroprotection by IPC or PKCɛ activation al...

  17. Acute stress alters transcript expression pattern and reduces processing of proBDNF to mature BDNF in Dicentrarchus labrax

    Directory of Open Access Journals (Sweden)

    Saroglia Marco

    2010-01-01

    Full Text Available Abstract Background Stress involves alterations of brain functioning that may precipitate to mood disorders. The neurotrophin Brain Derived Neurotrophic Factor (BDNF has recently been involved in stress-induced adaptation. BDNF is a key regulator of neuronal plasticity and adaptive processes. Regulation of BDNF is complex and may reflect not only stress-specific mechanisms but also hormonal and emotional responses. For this reason we used, as an animal model of stress, a fish whose brain organization is very similar to that of higher vertebrates, but is generally considered free of emotional reactions. Results We provide a comprehensive characterization of BDNF gene in the Dicentrarchus labrax and its transcriptional, translational and post-translational regulation following acute stress. While total BDNF mRNA levels are unchanged, BDNF transcripts 1c and 1d resulted down regulated after acute stress. Acute stress induces also a significant increase in proBDNF levels and reduction in mature BDNF suggesting altered regulation of proBDNF proteolytic processing. Notably, we provide here the first evidence that fishes possess a simplified proteolytic regulation of BDNF since the pro28Kda form, generated by the SKI-1 protease in mammals, is absent in fishes because the cleavage site has first emerged in reptilians. Finally, we show that the proBDNF/totBDNF ratio is a highly predictive novel quantitative biomarker to detect stress in fishes with sensitivity = 100%, specificity = 87%, and Negative Predictive Value = 100%. Conclusion The high predictivity of proBDNF/totBDNF ratio for stress in lower vertebrates indicates that processing of BDNF is a central mechanism in adaptation to stress and predicts that a similar regulation of pro/mature BDNF has likely been conserved throughout evolution of vertebrates from fish to man.

  18. Neuronal release of proBDNF

    OpenAIRE

    Yang, Jianmin; Siao, Chia-Jen; Nagappan, Guhan; Marinic, Tina; Jing, Deqiang; McGrath, Kelly; Chen, Zhe-Yu; Mark, Willie; Tessarollo, Lino; Lee, Francis S.; Lu, Bai; Hempstead, Barbara L.

    2009-01-01

    Pro–brain-derived neurotrophic factor (proBDNF) and mature BDNF utilize distinct receptors to mediate divergent neuronal actions. Using new tools to quantitate endogenous BDNF isoforms, we found that mouse neurons secrete both proBDNF and mature BDNF. The highest levels of proBDNF and p75 were observed perinatally and declined, but were still detectable, in adulthood. Thus, BDNF actions are developmentally regulated by secretion of proBDNF or mature BDNF and by local expression of p75 and Trk...

  19. Sulforaphane epigenetically enhances neuronal BDNF expression and TrkB signaling pathways.

    Science.gov (United States)

    Kim, Jisung; Lee, Siyoung; Choi, Bo-Ryoung; Yang, Hee; Hwang, Youjin; Park, Jung Han Yoon; LaFerla, Frank M; Han, Jung-Soo; Lee, Ki Won; Kim, Jiyoung

    2017-02-01

    Brain-derived neurotrophic factor (BDNF) is a neurotrophin that supports the survival of existing neurons and encourages the growth and differentiation of new neurons and synapses. We investigated the effect of sulforaphane, a hydrolysis product of glucoraphanin present in Brassica vegetables, on neuronal BDNF expression and its synaptic signaling pathways. Mouse primary cortical neurons and a triple-transgenic mouse model of Alzheimer's disease (3 × Tg-AD) were used to study the effect of sulforaphane. Sulforaphane enhanced neuronal BDNF expression and increased levels of neuronal and synaptic molecules such as MAP2, synaptophysin, and PSD-95 in primary cortical neurons and 3 × Tg-AD mice. Sulforaphane elevated levels of synaptic TrkB signaling pathway components, including CREB, CaMKII, ERK, and Akt in both primary cortical neurons and 3 × Tg-AD mice. Sulforaphane increased global acetylation of histone 3 (H3) and H4, inhibited HDAC activity, and decreased the level of HDAC2 in primary cortical neurons. Chromatin immunoprecipitation analysis revealed that sulforaphane increased acetylated H3 and H4 at BDNF promoters, suggesting that sulforaphane regulates BDNF expression via HDAC inhibition. These findings suggest that sulforaphane has the potential to prevent neuronal disorders such as Alzheimer's disease by epigenetically enhancing neuronal BDNF expression and its TrkB signaling pathways. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. Hypermethylation of BDNF and SST Genes in the Orbital Frontal Cortex of Older Individuals: A Putative Mechanism for Declining Gene Expression with Age.

    Science.gov (United States)

    McKinney, Brandon C; Lin, Chien-Wei; Oh, Hyunjung; Tseng, George C; Lewis, David A; Sibille, Etienne

    2015-10-01

    Expression of brain-derived neurotrophic factor (BDNF) and somatostatin (SST) mRNAs in the brain decreases progressively and robustly with age, and lower BDNF and SST expression in the brain has been observed in many brain disorders. BDNF is known to regulate SST expression; however, the mechanisms underlying decreased expression of both genes are not understood. DNA methylation (DNAm) is an attractive candidate mechanism. To investigate the contribution of DNAm to the age-related decline in BDNF and SST expression, the Illumina Infinium HumanMethylation450 Beadchip Array was used to quantify DNAm of BDNF (26 CpG loci) and SST (9 CpG loci) in the orbital frontal cortices of postmortem brains from 22 younger (age 60 years) with known age-dependent BDNF and SST expression differences. Relative to the younger individuals, 10 of the 26 CpG loci in BDNF and 8 of the 9 CpG loci in SST were significantly hypermethylated in the older individuals. DNAm in BDNF exons/promoters I, II, and IV negatively correlated with BDNF expression (r=-0.37, pgenes exhibited similar age-related changes in DNAm and correlation with gene expression. These results suggest that DNAm may be a proximal mechanism for decreased expression of BDNF, SST, and other BDNF- and GABA-related genes with brain aging and, by extension, for brain disorders in which their expression is decreased.

  1. Antidepressive and BDNF effects of enriched environment treatment across ages in mice lacking BDNF expression through promoter IV

    Science.gov (United States)

    Jha, S; Dong, B E; Xue, Y; Delotterie, D F; Vail, M G; Sakata, K

    2016-01-01

    Reduced promoter IV-driven expression of brain-derived neurotrophic factor (BDNF) is implicated in stress and major depression. We previously reported that defective promoter IV (KIV) caused depression-like behavior in young adult mice, which was reversed more effectively by enriched environment treatment (EET) than antidepressants. The effects of promoter IV-BDNF deficiency and EET over the life stages remain unknown. Since early-life development (ED) involves dynamic epigenetic processes, we hypothesized that EET during ED would provide maximum antidepressive effects that would persist later in life due to enhanced, long-lasting BDNF induction. We tested this hypothesis by determining EET effects across three life stages: ED (0–2 months), young adult (2–4 months), and old adult (12–14 months). KIV mice at all life stages showed depression-like behavior in the open-field and tail-suspension tests compared with wild-type mice. Two months of EET reduced depression-like behavior in ED and young adult, but not old adult mice, with the largest effect in ED KIV mice. This effect lasted for 1 month after discontinuance of EET only in ED mice. BDNF protein induction by EET in the hippocampus and frontal cortex was also the largest in ED mice and persisted only in the hippocampus of ED KIV mice after discontinuance of EET. No gender-specific effects were observed. The results suggest that defective promoter IV causes depression-like behavior, regardless of age and gender, and that EET during ED is particularly beneficial to individuals with promoter IV-BDNF deficiency, while additional treatment may be needed for older adults. PMID:27648918

  2. Proteolytic Cleavage of ProBDNF into Mature BDNF in the Basolateral Amygdala Is Necessary for Defeat-Induced Social Avoidance

    Science.gov (United States)

    Dulka, Brooke N.; Ford, Ellen C.; Lee, Melissa A.; Donnell, Nathaniel J.; Goode, Travis D.; Prosser, Rebecca; Cooper, Matthew A.

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) is essential for memory processes. The present study tested whether proteolytic cleavage of proBDNF into mature BDNF (mBDNF) within the basolateral amygdala (BLA) regulates the consolidation of defeat-related memories. We found that acute social defeat increases the expression of mBDNF, but not proBDNF, in…

  3. Neuroprotection, Growth Factors and BDNF-TrkB Signalling in Retinal Degeneration

    Science.gov (United States)

    Kimura, Atsuko; Namekata, Kazuhiko; Guo, Xiaoli; Harada, Chikako; Harada, Takayuki

    2016-01-01

    Neurotrophic factors play key roles in the development and survival of neurons. The potent neuroprotective effects of neurotrophic factors, including brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), glial cell-line derived neurotrophic factor (GDNF) and nerve growth factor (NGF), suggest that they are good therapeutic candidates for neurodegenerative diseases. Glaucoma is a neurodegenerative disease of the eye that causes irreversible blindness. It is characterized by damage to the optic nerve, usually due to high intraocular pressure (IOP), and progressive degeneration of retinal neurons called retinal ganglion cells (RGCs). Current therapy for glaucoma focuses on reduction of IOP, but neuroprotection may also be beneficial. BDNF is a powerful neuroprotective agent especially for RGCs. Exogenous application of BDNF to the retina and increased BDNF expression in retinal neurons using viral vector systems are both effective in protecting RGCs from damage. Furthermore, induction of BDNF expression by agents such as valproic acid has also been beneficial in promoting RGC survival. In this review, we discuss the therapeutic potential of neurotrophic factors in retinal diseases and focus on the differential roles of glial and neuronal TrkB in neuroprotection. We also discuss the role of neurotrophic factors in neuroregeneration. PMID:27657046

  4. TUMOR NECROSIS FACTOR-α INCREASES BDNF EXPRESSION IN TRIGEMINAL GANGLION NEURONS IN AN ACTIVITY-DEPENDENT MANNER

    OpenAIRE

    2011-01-01

    Many chronic trigeminal pain conditions, such as migraine or temporo-mandibular disorders, are associated with inflammation within peripheral endings of trigeminal ganglion (TG) sensory neurons. A critical role in mechanisms of neuroinflammation is attributed to proinflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α (TNFα) that also contribute to mechanisms of persistent neuropathic pain resulting from nerve injury. However, the mechanisms of cytokine-mediated synaptic ...

  5. Effects of soft-diet feeding on BDNF expression in hippocampus of mice.

    Science.gov (United States)

    Yamamoto, Tetsu; Hirayama, Akihiko; Hosoe, Nobuo; Furube, Masaru; Hirano, Shusuke

    2008-11-01

    Our previous study showed that mice fed a soft diet after weaning had reduced synaptic connections in the hippocampal formation and impaired spatial learning ability after 3 months of age. We hypothesized that soft-diet feeding during development reduced levels of brain-derived neurotrophic factor (BDNF) protein in the hippocampus, resulting in lower synaptic densities in this region. Male pups of C57BL/6 mice were fed either a solid (hard-diet group) or powdered diet (soft-diet group), starting at weaning. Expression of BDNF protein in the hippocampus and cerebral cortex was evaluated quantitatively with enzyme-linked immunosorbent assay (ELISA) at 1, 3 and 6 months of age. Reduction in BDNF protein levels due to soft diet was detected markedly in the hippocampus of 3- and 6-month-old mice. On the other hand, a soft diet showed no significant effect on BDNF content in the cerebral cortex throughout the ages investigated. Immunohistochemistry of hippocampal formation in 3-month-old mice revealed that intensities of BDNF immunoreactivity in the dentate gyrus granule cell layer and CA1 and CA3 pyramidal cell layers appeared diminished in mice fed the soft diet compared with mice fed the hard diet. These results indicate that insufficient mastication activity during development reduces BDNF protein levels in the hippocampus and influences synaptic plasticity in this region.

  6. Changes in spatial memory and BDNF expression to concurrent dietary restriction and voluntary exercise.

    Science.gov (United States)

    Khabour, Omar F; Alzoubi, Karem H; Alomari, Mahmoud A; Alzubi, Mohammad A

    2010-05-01

    Substantial data suggest that cognitive function can be influenced by many lifestyle activities associated with changes in energy metabolism such as exercise and diet. In the current study, we investigated the combined effects of voluntary exercise (access to running wheels) and dietary restriction (every other day fasting, EODF) on spatial memory formation and on the levels of brain-derived neurotrophic factor (BDNF) in the hippocampus of Wistar male rats. Spatial learning and memory formation was assessed using the radial arm water maze (RAWM) paradigm, while BDNF protein was measured using ELISA test. Voluntary exercise and/or EODF were instituted for 6 weeks. Voluntary exercise alone significantly enhanced short-term, intermediate-term, and long-term memory formation, and increased BDNF protein levels in the hippocampus. EODF enhanced mean running wheel activity by approximately twofold. However, EODF did not modulate the effects of exercise on memory formation and expression of BDNF. In addition, EODF alone had no effect on memory and BDNF protein in the hippocampus. In conclusion, results of this study indicate that exercise enhanced while EODF had neutral effect on both spatial memory formation and hippocampus BDNF levels.

  7. Sonic Hedgehog Promotes Neurite Outgrowth of Primary Cortical Neurons Through Up-Regulating BDNF Expression.

    Science.gov (United States)

    He, Weiliang; Cui, Lili; Zhang, Cong; Zhang, Xiangjian; He, Junna; Xie, Yanzhao

    2016-04-01

    Sonic hedgehog (Shh), a secreted glycoprotein factor, can activate the Shh pathway, which has been implicated in neuronal polarization involving neurite outgrowth. However, little evidence is available about the effect of Shh on neurite outgrowth in primary cortical neurons and its potential mechanism. Here, we revealed that Shh increased neurite outgrowth in primary cortical neurons, while the Shh pathway inhibitor (cyclopamine, CPM) partially suppressed Shh-induced neurite outgrowth. Similar results were found for the expressions of Shh and Patched genes in Shh-induced primary cortical neurons. Moreover, Shh increased the levels of brain-derived neurotrophic factor (BDNF) not only in lysates and in culture medium but also in the longest neurites of primary cortical neurons, which was partially blocked by CPM. In addition, blocking of BDNF action suppressed Shh-mediated neurite elongation in primary cortical neurons. In conclusion, these findings suggest that Shh promotes neurite outgrowth in primary cortical neurons at least partially through modulating BDNF expression.

  8. Decreased expression of Sprouty2 in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder: a correlation with BDNF expression.

    Directory of Open Access Journals (Sweden)

    Anilkumar Pillai

    Full Text Available BACKGROUND: Current theories on the pathophysiology of schizophrenia suggest altered brain plasticity such as decreased neural proliferation and migration, delayed myelination, and abnormal synaptic modeling, in the brain of subjects with schizophrenia. Though functional alterations in BDNF, which plays important role in neuroplasticity, are implicated in many abnormalities found in schizophrenia, the regulatory mechanism(s involved in the abnormal signaling of BDNF in schizophrenia is not clear. The present study investigated whether Sprouty2, a regulator of growth factor signaling, is abnormally expressed in schizophrenia, and is associated with the changes in BDNF mRNA in this disorder. The potential effect of antipsychotic drugs on Sprouty2 expression was tested in adult rats. METHODS AND FINDINGS: Sprouty2 and BDNF gene expression were analyzed in dorsolateral prefrontal cortex samples from the Stanley Array Collection. Quantitative real-time PCR analysis of RNA in 100 individuals (35 with schizophrenia, 31 with bipolar disorder, and 34 psychiatrically normal controls showed significantly decreased expression of Sprouty2 and BDNF in both schizophrenia and bipolar disorder. Moreover, a significant correlation between these two genes existed in control, schizophrenia and bipolar subjects. Long-term treatment with antipsychotic drugs, haloperidol and olanzapine, showed differential effects on both Sprouty2 and BDNF mRNA and protein levels in the frontal cortex of rats. CONCLUSION: These findings demonstrating decreased expression of Sprouty2 associated with changes in BDNF, suggest the possibility that these decreases are secondary to treatment rather than to factors that are significant in the disease process of either schizophrenia and/or bipolar disorder. Further exploration of Sprouty2-related signal transduction pathways may be helpful to design novel treatment strategies for these disorders.

  9. The BDNF Val66Met polymorphism and plasma brain-derived neurotrophic factor levels in Han Chinese heroin-dependent patients.

    Science.gov (United States)

    Chen, Shiou-Lan; Lee, Sheng-Yu; Chang, Yun-Hsuan; Wang, Tzu-Yun; Chen, Shih-Heng; Chu, Chun-Hsien; Chen, Po See; Yang, Yen Kuang; Hong, Jau-Shyong; Lu, Ru-Band

    2015-02-02

    BDNF and its gene polymorphism may be important in synaptic plasticity and neuron survival, and may become a key target in the physiopathology of long-term heroin use. Thus, we investigated the relationships between brain-derived neurotrophic factor (BDNF) plasma concentrations and the BDNF Val66Met nucleotide polymorphism (SNP) in heroin-dependent patients. The pretreatment expression levels of plasma BDNF and the BDNF Val66Met SNP in 172 heroin-dependent patients and 102 healthy controls were checked. BDNF levels were significantly lower in patients (F = 52.28, p BDNF levels significantly different between Met/Met, Met/Val, and Val/Val carriers in each group, which indicated that the BDNF Val66Met SNP did not affect plasma BDNF levels in our participants. In heroin-dependent patients, plasma BDNF levels were negatively correlated with the length of heroin dependency. Long-term (>15 years) users had significantly lower plasma BDNF levels than did short-term (BDNF concentration in habitual heroin users are not affected by BDNF Val66Met gene variants, but by the length of the heroin dependency.

  10. AT2-receptor stimulation enhances axonal plasticity after spinal cord injury by upregulating BDNF expression

    DEFF Research Database (Denmark)

    Namsolleck, Pawel; Boato, Francesco; Schwengel, Katja;

    2013-01-01

    outgrowth was absent in neurons derived from AT2R-KO mice. In primary neurons, treatment with C21 further induced RNA expression of anti-apoptotic Bcl-2 (+75.7%), brain-derived neurotrophic factor (BDNF) (+53.7%), the neurotrophin receptors TrkA (+57.4%) and TrkB (+67.9%) and a marker for neurite growth...

  11. Increased BDNF protein expression after ischemic or PKC epsilon preconditioning promotes electrophysiologic changes that lead to neuroprotection.

    Science.gov (United States)

    Neumann, Jake T; Thompson, John W; Raval, Ami P; Cohan, Charles H; Koronowski, Kevin B; Perez-Pinzon, Miguel A

    2015-01-01

    Ischemic preconditioning (IPC) via protein kinase C epsilon (PKCɛ) activation induces neuroprotection against lethal ischemia. Brain-derived neurotrophic factor (BDNF) is a pro-survival signaling molecule that modulates synaptic plasticity and neurogenesis. Interestingly, BDNF mRNA expression increases after IPC. In this study, we investigated whether IPC or pharmacological preconditioning (PKCɛ activation) promoted BDNF-induced neuroprotection, if neuroprotection by IPC or PKCɛ activation altered neuronal excitability, and whether these changes were BDNF-mediated. We used both in vitro (hippocampal organotypic cultures and cortical neuronal-glial cocultures) and in vivo (acute hippocampal slices 48 hours after preconditioning) models of IPC or PKCɛ activation. BDNF protein expression increased 24 to 48 hours after preconditioning, where inhibition of the BDNF Trk receptors abolished neuroprotection against oxygen and glucose deprivation (OGD) in vitro. In addition, there was a significant decrease in neuronal firing frequency and increase in threshold potential 48 hours after preconditioning in vivo, where this threshold modulation was dependent on BDNF activation of Trk receptors in excitatory cortical neurons. In addition, 48 hours after PKCɛ activation in vivo, the onset of anoxic depolarization during OGD was significantly delayed in hippocampal slices. Overall, these results suggest that after IPC or PKCɛ activation, there are BDNF-dependent electrophysiologic modifications that lead to neuroprotection.

  12. Co-localization of brain-derived neurotrophic factor (BDNF) and wild-type huntingtin in normal and quinolinic acid-lesioned rat brain.

    Science.gov (United States)

    Fusco, Francesca R; Zuccato, Chiara; Tartari, Marzia; Martorana, Alessandro; De March, Zena; Giampà, Carmela; Cattaneo, Elena; Bernardi, Giorgio

    2003-09-01

    Loss of huntingtin-mediated brain-derived neurotrophic factor (BDNF) gene transcription has been described in Huntington's disease (HD) [Zuccato et al. (2001) Science, 293, 493-498]. It has been shown that BDNF is synthesized in the pyramidal layer of cerebral cortex and released in the striatum [Altar et al. (1997) Nature, 389, 856-860; Conner et al. (1997) J. Neurosci., 17, 2295-2313]. Here we show the cellular localization of BDNF in huntingtin-containing neurons in normal rat brain; our double-label immunofluorescence study shows that huntingtin and BDNF are co-contained in approximately 99% of pyramidal neurons of motor cortex. In the striatum, huntingtin is expressed in 75% of neurons containing BDNF. In normal striatum we also show that BDNF is contained in cholinergic and in NOS-containing interneurons, which are relatively resistant to HD degeneration. Furthermore, we show a reduction in huntingtin and in BDNF immunoreactivity in cortical neurons after striatal excitotoxic lesion. Our data are confirmed by an ELISA study of BDNF and by a Western blot analysis of huntingtin in cortex of quinolic acid (QUIN)-lesioned hemispheres. In the lesioned striatum we describe that the striatal subpopulation of cholinergic neurons, surviving degeneration, contain BDNF. The finding that BDNF is contained in nearly all neurons that contain huntingtin in the normal cortex, along with the reduced expression of BDNF after QUIN injection of the striatum, shows that huntingtin may be required for BDNF production in cortex.

  13. HBpF-proBDNF: A New Tool for the Analysis of Pro-Brain Derived Neurotrophic Factor Receptor Signaling and Cell Biology

    Science.gov (United States)

    Gaub, Perrine; de Léon, Andrès; Gibon, Julien; Soubannier, Vincent; Dorval, Geneviève; Séguéla, Philippe; Barker, Philip A.

    2016-01-01

    Neurotrophins activate intracellular signaling pathways necessary for neuronal survival, growth and apoptosis. The most abundant neurotrophin in the adult brain, brain-derived neurotrophic factor (BDNF), is first synthesized as a proBDNF precursor and recent studies have demonstrated that proBDNF can be secreted and that it functions as a ligand for a receptor complex containing p75NTR and sortilin. Activation of proBDNF receptors mediates growth cone collapse, reduces synaptic activity, and facilitates developmental apoptosis of motoneurons but the precise signaling cascades have been difficult to discern. To address this, we have engineered, expressed and purified HBpF-proBDNF, an expression construct containing a 6X-HIS tag, a biotin acceptor peptide (BAP) sequence, a PreScission™ Protease cleavage site and a FLAG-tag attached to the N-terminal part of murine proBDNF. Intact HBpF-proBDNF has activities indistinguishable from its wild-type counterpart and can be used to purify proBDNF signaling complexes or to monitor proBDNF endocytosis and retrograde transport. HBpF-proBDNF will be useful for characterizing proBDNF signaling complexes and for deciphering the role of proBDNF in neuronal development, synapse function and neurodegenerative disease. PMID:26950209

  14. BDNF over-expression increases olfactory bulb granule cell dendritic spine density in vivo.

    Science.gov (United States)

    McDole, B; Isgor, C; Pare, C; Guthrie, K

    2015-09-24

    Olfactory bulb granule cells (GCs) are axon-less, inhibitory interneurons that regulate the activity of the excitatory output neurons, the mitral and tufted cells, through reciprocal dendrodendritic synapses located on GC spines. These contacts are established in the distal apical dendritic compartment, while GC basal dendrites and more proximal apical segments bear spines that receive glutamatergic inputs from the olfactory cortices. This synaptic connectivity is vital to olfactory circuit function and is remodeled during development, and in response to changes in sensory activity and lifelong GC neurogenesis. Manipulations that alter levels of the neurotrophin brain-derived neurotrophic factor (BDNF) in vivo have significant effects on dendritic spine morphology, maintenance and activity-dependent plasticity for a variety of CNS neurons, yet little is known regarding BDNF effects on bulb GC spine maturation or maintenance. Here we show that, in vivo, sustained bulbar over-expression of BDNF in transgenic mice produces a marked increase in GC spine density that includes an increase in mature spines on their apical dendrites. Morphometric analysis demonstrated that changes in spine density were most notable in the distal and proximal apical domains, indicating that multiple excitatory inputs are potentially modified by BDNF. Our results indicate that increased levels of endogenous BDNF can promote the maturation and/or maintenance of dendritic spines on GCs, suggesting a role for this factor in modulating GC functional connectivity within adult olfactory circuitry.

  15. Reduction of BDNF expression in Fmr1 knockout mice worsens cognitive deficits but improves hyperactivity and sensorimotor deficits.

    Science.gov (United States)

    Uutela, M; Lindholm, J; Louhivuori, V; Wei, H; Louhivuori, L M; Pertovaara, A; Akerman, K; Castrén, E; Castrén, M L

    2012-07-01

    Fragile X syndrome (FXS) is a common cause of inherited intellectual disability and a well-characterized form of autism spectrum disorder. As brain-derived neurotrophic factor (BDNF) is implicated in the pathophysiology of FXS we examined the effects of reduced BDNF expression on the behavioral phenotype of an animal model of FXS, Fmr1 knockout (KO) mice, crossed with mice carrying a deletion of one copy of the Bdnf gene (Bdnf(+/-)). Fmr1 KO mice showed age-dependent alterations in hippocampal BDNF expression that declined after the age of 4 months compared to wild-type controls. Mild deficits in water maze learning in Bdnf(+/-) and Fmr1 KO mice were exaggerated and contextual fear learning significantly impaired in double transgenics. Reduced BDNF expression did not alter basal nociceptive responses or central hypersensitivity in Fmr1 KO mice. Paradoxically, the locomotor hyperactivity and deficits in sensorimotor learning and startle responses characteristic of Fmr1 KO mice were ameliorated by reducing BNDF, suggesting changes in simultaneously and in parallel working hippocampus-dependent and striatum-dependent systems. Furthermore, the obesity normally seen in Bdnf(+/-) mice was eliminated by the absence of fragile X mental retardation protein 1 (FMRP). Reduced BDNF decreased the survival of newborn cells in the ventral part of the hippocampus both in the presence and absence of FMRP. Since a short neurite phenotype characteristic of newborn cells lacking FMRP was not found in cells derived from double mutant mice, changes in neuronal maturation likely contributed to the behavioral phenotype. Our results show that the absence of FMRP modifies the diverse effects of BDNF on the FXS phenotype. © 2012 The Authors. Genes, Brain and Behavior © 2012 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

  16. Stress induces altered CRE/CREB pathway activity and BDNF expression in the hippocampus of glucocorticoid receptor-impaired mice.

    Science.gov (United States)

    Alboni, Silvia; Tascedda, Fabio; Corsini, Daniela; Benatti, Cristina; Caggia, Federica; Capone, Giacomo; Barden, Nicholas; Blom, Joan M C; Brunello, Nicoletta

    2011-06-01

    The gene coding for the neurotrophin Brain-Derived Neurotrophic Factor (BDNF) is a stress-responsive gene. Changes in its expression may underlie some of the pathological effects of stress-related disorders like depression. Data on the stress-induced regulation of the expression of BDNF in pathological conditions are rare because often research is conducted using healthy animals. In our experiments, we used transgenic mice with glucocorticoid receptor impaired (GR-i) expression in the hypothalamus created as a tool to study the neuroendocrine changes occurring in stress-related disorders. First, under basal condition, GR-i mice displayed lower levels of BDNF exons IX and IV and decreased CRE(BDNF) binding activity with respect to wild-type (WT) mice in the hippocampus. Then, we exposed GR-i and WT mice to an acute restraint stress (ARS) to test the hypothesis that GR-i mice display: 1] different ARS induced expression of BDNF, and 2] altered activation of signaling pathways implicated in regulating BDNF gene expression in the hippocampus with respect to WT mice. Results indicate that ARS enhanced BDNF mRNA expression mainly in the CA3 hippocampal sub-region of GR-i mice in the presence of enhanced levels of pro-BDNF protein, while no effect was observed in WT mice. Moreover, ARS reduced CREB signaling and binding to the BDNF promoter in GR-i mice but enhanced signaling and binding, possibly through ERK1/2 activation, in WT mice. Thus, life-long central GR dysfunction resulted in an altered sensitivity at the transcriptional level that may underlie an impaired response to an acute psycho-physical stress. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.

  17. Role of pro-brain-derived neurotrophic factor (proBDNF) to mature BDNF conversion in activity-dependent competition at developing neuromuscular synapses.

    Science.gov (United States)

    Je, H Shawn; Yang, Feng; Ji, Yuanyuan; Nagappan, Guhan; Hempstead, Barbara L; Lu, Bai

    2012-09-25

    Formation of specific neuronal connections often involves competition between adjacent axons, leading to stabilization of the active terminal, while retraction of the less active ones. The underlying molecular mechanisms remain unknown. We show that activity-dependent conversion of pro-brain-derived neurotrophic factor (proBDNF) to mature (m)BDNF mediates synaptic competition. Stimulation of motoneurons triggers proteolytic conversion of proBDNF to mBDNF at nerve terminals. In Xenopus nerve-muscle cocultures, in which two motoneurons innervate one myocyte, proBDNF-p75(NTR) signaling promotes retraction of the less active terminal, whereas mBDNF-tyrosine-related kinase B (TrkB) p75NTR (p75 neurotrophin receptor) facilitates stabilization of the active one. Thus, proBDNF and mBDNF may serve as potential "punishment" and "reward" signals for inactive and active terminals, respectively, and activity-dependent conversion of proBDNF to mBDNF may regulate synapse elimination.

  18. Expression of Brain-derived Neurotrophic Factor (BDNF) Gene in Rat Myoblast Cells%脑源性神经营养因子(BDNF)在成肌细胞中的稳定表达

    Institute of Scientific and Technical Information of China (English)

    刘健; 蒋琼; 戈凯; 孙兰英; 刘新垣; 郑仲承

    1999-01-01

    将bdnf基因克隆入逆转录病毒载体pLNCX, 构建得到pLNC/BDNF,经PA317细胞包装后,感染大鼠成肌细胞L-6TG,G418筛选2周后,得到稳定表达bdnf基因的细胞克隆L-6TG/BDNF.DNA印迹结果证实bdnf基因已经整合入L-6TG染色体中,RNA印迹和斑点印迹结果分别从mRNA水平和蛋白水平证明了bdnf基因的表达,且L-6TG/BDNF培养上清中BDNF的含量约为25ng(106细胞数每ml每24h).

  19. Effects of 1-bromopropane, a substitute for chlorofluorocarbons, on BDNF expression.

    Science.gov (United States)

    Yoshida, Yasuhiro; Nakano, Yoshiteru; Ueno, Susumu; Liu, Jiqin; Fueta, Yukiko; Ishidao, Toru; Kunugita, Naoki; Yanagihara, Nobuyuki; Sugiura, Tsutomu; Hori, Hajime; Yamashita, Uki

    2009-04-01

    1-Bromopropane (1-BP) has been widely used as an alternative to ozone-depleting chlorofluorocarbons in various industries. Although the neurotoxicity of 1-BP has been recently reported, there is little information about the effect of 1-BP on the cells in brain by experimental approach. Here we studied the effect of 1-BP on brain-derived neurotrophic factor (BDNF) expression in astrocytes in vitro. The BDNF mRNA level was remarkably decreased by 1-BP in a human astrocytoma cell line, U251, and in mouse primary astrocytes. The DNA-binding and specific reporter activity of cAMP response element-binding transcription factor (CREB), which is one of the key molecules regulating BDNF expression, were reduced by 1-BP in U251 and/or mouse primary astrocytes. Additionally, protein kinase A (PKA) activity was suppressed by 1-BP in U251. These results suggest that BDNF expression was affected by 1-BP through at least PKA.

  20. Yueju Pill Rapidly Induces Antidepressant-Like Effects and Acutely Enhances BDNF Expression in Mouse Brain

    Directory of Open Access Journals (Sweden)

    Wenda Xue

    2013-01-01

    Full Text Available The traditional antidepressants have a major disadvantage in delayed onset of efficacy, and the emerging fast-acting antidepressant ketamine has adverse behavioral and neurotoxic effects. Yueju pill, an herb medicine formulated eight hundred years ago by Doctor Zhu Danxi, has been popularly prescribed in China for alleviation of depression-like symptoms. Although several clinical outcome studies reported the relative short onset of antidepressant effects of Yueju, this has not been scientifically investigated. We, therefore, examined the rapid antidepressant effect of Yueju in mice and tested the underlying molecular mechanisms. We found that acute administration of ethanol extract of Yueju rapidly attenuated depressive-like symptoms in learned helpless paradigm, and the antidepressant-like effects were sustained for at least 24 hours in tail suspension test in ICR mice. Additionally, Yueju, like ketamine, rapidly increased the expression of brain-derived neurotrophic factor (BDNF in the hippocampus, whereas the BDNF mRNA expression remained unaltered. Yueju rapidly reduced the phosphorylation of eukaryotic elongation factor 2 (eEF2, leading to desuppression of BDNF synthesis. Unlike ketamine, both the BDNF expression and eEF2 phosphorylation were revered at 24 hours after Yueju administration. This study is the first to demonstrate the rapid antidepressant effects of an herb medicine, offering an opportunity to improve therapy of depression.

  1. Inhibition of the tyrosine phosphatase STEP61 restores BDNF expression and reverses motor and cognitive deficits in phencyclidine-treated mice.

    Science.gov (United States)

    Xu, Jian; Kurup, Pradeep; Baguley, Tyler D; Foscue, Ethan; Ellman, Jonathan A; Nairn, Angus C; Lombroso, Paul J

    2016-04-01

    Brain-derived neurotrophic factor (BDNF) and STriatal-Enriched protein tyrosine Phosphatase 61 (STEP61) have opposing functions in the brain, with BDNF supporting and STEP61 opposing synaptic strengthening. BDNF and STEP61 also exhibit an inverse pattern of expression in a number of brain disorders, including schizophrenia (SZ). NMDAR antagonists such as phencyclidine (PCP) elicit SZ-like symptoms in rodent models and unaffected individuals, and exacerbate psychotic episodes in SZ. Here we characterize the regulation of BDNF expression by STEP61, utilizing PCP-treated cortical culture and PCP-treated mice. PCP-treated cortical neurons showed both an increase in STEP61 levels and a decrease in BDNF expression. The reduction in BDNF expression was prevented by STEP61 knockdown or use of the STEP inhibitor, TC-2153. The PCP-induced increase in STEP61 expression was associated with the inhibition of CREB-dependent BDNF transcription. Similarly, both genetic and pharmacologic inhibition of STEP prevented the PCP-induced reduction in BDNF expression in vivo and normalized PCP-induced hyperlocomotion and cognitive deficits. These results suggest a mechanism by which STEP61 regulates BDNF expression, with implications for cognitive functioning in CNS disorders.

  2. Glycyrrhiza uralensis flavonoids inhibit brain microglial cell TNF-α secretion, p-IκB expression, and increase brain-derived neurotropic factor (BDNF secretion

    Directory of Open Access Journals (Sweden)

    Sangita P. Patil

    2014-07-01

    Conclusion: ASHMI and its effective flavonoid, isoliquiritigenin, inhibited TNF-α production by LPS stimulated microglial cells and elevated BDNF levels, which may prove to have anti-CNS inflammatory and anti-anxiety effects.

  3. Vergleichende Studie zur Expression von Neuropeptiden und von Calcium-bindenden Proteinen im Hippocampus von BDNF Knock-out Mäusen und den entsprechenden Wildtyp Geschwistertieren

    OpenAIRE

    Herrmann-Schwartzkopff, Katharina Helene

    2010-01-01

    Brain derived neurotrophic factor (BDNF) is well known for its positive effects on survival, development and differentiation of neurons in the central nervous system. It exerts its action through binding to its high (TrkB) and low (p75) affinity receptors. This work examines the expression of neuropeptides and calcium-binding proteins in the hippocampus of BDNF knockout mice (BDNF -/-) and their corresponding wild type littermates. With the use of highly specific antibodies the hippoca...

  4. Inhibition of the tyrosine phosphatase STEP61 restores BDNF expression and reverses motor and cognitive deficits in phencyclidine-treated mice

    OpenAIRE

    Xu, Jian; Kurup, Pradeep; Baguley, Tyler D.; Foscue, Ethan; Ellman, Jonathan A.; Nairn, Angus C.; Lombroso, Paul J.

    2015-01-01

    Brain-derived neurotrophic factor (BDNF) and STriatal-Enriched protein tyrosine Phosphatase 61 (STEP61) have opposing functions in the brain, with BDNF supporting and STEP61 opposing synaptic strengthening. BDNF and STEP61 also exhibit an inverse pattern of expression in a number of brain disorders, including schizophrenia (SZ). NMDAR antagonists such as phencyclidine (PCP) elicit SZ-like symptoms in rodent models and unaffected individuals, and exacerbate psychotic episodes in SZ. Here we ch...

  5. Expression and Dendritic Trafficking of BDNF-6 Splice Variant are Impaired in Knock-In Mice Carrying Human BDNF Val66Met Polymorphism

    OpenAIRE

    Mallei, A.; Baj, G.; Ieraci, A.; Corna, S.; Musazzi, L.; Lee, F S; Tongiorgi, E.; Popoli, M.

    2015-01-01

    Background: The human Val66Met polymorphism in brain-derived neurotrophic factor (BDNF), a key factor in neuroplasticity, synaptic function, and cognition, has been implicated in the pathophysiology of neuropsychiatric and neurodegenerative disorders. BDNF is encoded by multiple transcripts with distinct regulation and localization, but the impact of the Val66Met polymorphism on BDNF regulation remains unclear. Methods: In BDNF Val66Met knock-in mice, which recapitulate the phenotypic hallmar...

  6. Serum brain-derived neurotrophic factor (BDNF) levels in schizophrenia: A systematic review

    National Research Council Canada - National Science Library

    Cui, Huiru; Jin, Yi; Wang, Jijun; Weng, Xuchu; Li, Chunbo

    2012-01-01

    There is increasing interest in the role of brain-derived neurotrophic factor (BDNF) in the onset and course of schizophrenia, but there are conflicting reports about serum levels of BDNF in patients with schizophrenia...

  7. Effects of gravity changes on gene expression of BDNF and serotonin receptors in the mouse brain.

    Science.gov (United States)

    Ishikawa, Chihiro; Li, Haiyan; Ogura, Rin; Yoshimura, Yuko; Kudo, Takashi; Shirakawa, Masaki; Shiba, Dai; Takahashi, Satoru; Morita, Hironobu; Shiga, Takashi

    2017-01-01

    Spaceflight entails various stressful environmental factors including microgravity. The effects of gravity changes have been studied extensively on skeletal, muscular, cardiovascular, immune and vestibular systems, but those on the nervous system are not well studied. The alteration of gravity in ground-based animal experiments is one of the approaches taken to address this issue. Here we investigated the effects of centrifugation-induced gravity changes on gene expression of brain-derived neurotrophic factor (BDNF) and serotonin receptors (5-HTRs) in the mouse brain. Exposure to 2g hypergravity for 14 days showed differential modulation of gene expression depending on regions of the brain. BDNF expression was decreased in the ventral hippocampus and hypothalamus, whereas increased in the cerebellum. 5-HT1BR expression was decreased in the cerebellum, whereas increased in the ventral hippocampus and caudate putamen. In contrast, hypergravity did not affect gene expression of 5-HT1AR, 5-HT2AR, 5-HT2CR, 5-HT4R and 5-HT7R. In addition to hypergravity, decelerating gravity change from 2g hypergravity to 1g normal gravity affected gene expression of BDNF, 5-HT1AR, 5-HT1BR, and 5-HT2AR in various regions of the brain. We also examined involvement of the vestibular organ in the effects of hypergravity. Surgical lesions of the inner ear's vestibular organ removed the effects induced by hypergravity on gene expression, which suggests that the effects of hypergravity are mediated through the vestibular organ. In summary, we showed that gravity changes induced differential modulation of gene expression of BDNF and 5-HTRs (5-HT1AR, 5-HT1BR and 5-HT2AR) in some brain regions. The modulation of gene expression may constitute molecular bases that underlie behavioral alteration induced by gravity changes.

  8. Widespread expression of BDNF but not NT3 by target areas of basal forebrain cholinergic neurons

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    Phillips, H.S.; Hains, J.M.; Laramee, G.R.; Rosenthal, A.; Winslow, J.W. (Genentech, San Francisco, CA (USA))

    1990-10-12

    Brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3) are homologs of the well-known neurotrophic factor nerve growth factor. The three members of this family display distinct patterns of target specificity. To examine the distribution in brain of messenger RNA for these molecules, in situ hybridization was performed. Cells hybridizing intensely to antisense BDNF probe were located throughout the major targets of the rat basal forebrain cholinergic system, that is, the hippocampus, amygdala, and neocortex. Strongly hybridizing cells were also observed in structures associated with the olfactory system. The distribution of NT3 mRNA in forebrain was much more limited. Within the hippocampus, labeled cells were restricted to CA2, the most medial portion of CA1, and the dentate gyrus. In human hippocampus, cells expressing BDNF and mRNA are distributed in a fashion similar to that observed in the rat. These findings point to both basal forebrain cholinergic cells and olfactory pathways as potential central targets for BDNF.

  9. 在豌豆植物中瞬时表达大鼠神经营养因子BDNF%Brain derived neurotrophic factor (BDNF) of rat transient expression in pea plants

    Institute of Scientific and Technical Information of China (English)

    范亚军; 郑梅竹; 倪秀珍

    2016-01-01

    [目的]克隆大鼠神经营养因子BDNF基因,构建植物表达载体,在豌豆植物中表达BDNF蛋白.[方法]采用RT-PCR法克隆大鼠脑源性神经营养因子BDNF基因,构建豌豆植物表达载体pCAPE2-BDNF,利用豌豆发芽种子真空侵染法在豌豆植物中瞬时表达BDNF蛋白,以His标签抗体进行Western Blot检测目的蛋白.[结果]获得含有鼠源性神经营养因子BDNF基因的植物表达载体pCAPE2-BDNF,His标签抗体检测到目的条带.[结论]BDNF蛋白在豌豆植物中成功表达,有助于进一步对其功能活性进行分析.

  10. Innate BDNF expression is associated with ethanol intake in alcohol-preferring AA and alcohol-avoiding ANA rats.

    Science.gov (United States)

    Raivio, Noora; Miettinen, Pekka; Kiianmaa, Kalervo

    2014-09-04

    We have shown recently that acute administration of ethanol modulates the expression of brain-derived neurotrophic factor (BDNF) in several rat brain areas known to be involved in the development of addiction to ethanol and other drugs of abuse, suggesting that BDNF may be a factor contributing to the neuroadaptive changes set in motion by ethanol exposure. The purpose of the present study was to further clarify the role of BDNF in reinforcement from ethanol and in the development of addiction to ethanol by specifying the effect of acute administration of ethanol (1.5 or 3.0 g/kg i.p.) on the expression profile of BDNF mRNA in the ventral tegmental area and in the terminal areas of the mesolimbic dopamine pathway in the brain of alcohol-preferring AA and alcohol-avoiding ANA rats, selected for high and low voluntary ethanol intake, respectively. The level of BDNF mRNA expression was higher in the amygdala and ventral tegmental area of AA than in those of ANA rats, and there was a trend for a higher level in the nucleus accumbens. In the amygdala and hippocampus, a biphasic change in the BDNF mRNA levels was detected: the levels were decreased at 3 and 6h but increased above the basal levels at 24h. Furthermore, there was a difference between the AA and ANA lines in the effect of ethanol, the ANA rats showing an increase in BDNF mRNA levels while such a change was not seen in AA rats. These findings suggest that the innate levels of BDNF expression may play a role in the mediation of the reinforcing effects of ethanol and in the control of ethanol intake.

  11. Neurosteroids reduce social isolation-induced behavioral deficits: a proposed link with neurosteroid-mediated upregulation of BDNF expression

    Directory of Open Access Journals (Sweden)

    Mauricio Schüler Nin

    2011-11-01

    Full Text Available The pharmacological action of SSRI antidepressants may include a normalization of the decreased brain levels of neurosteroids such as that of the progesterone metabolite allopregnanolone and that of the brain-derived neurotrophic factor (BDNF, which are decreased in patients with depression and PTSD. Allopregnanolone and BDNF decrease in these patients is associated with behavioral symptom severity. Antidepressant treatment upregulates both allopregnanolone levels and the expression of BDNF in a manner that significantly correlates with improved symptomatology, which suggests that neurosteroid biosynthesis and BDNF expression may be interrelated. Preclinical studies using the socially isolated mouse as an animal model of behavioral deficits that resemble some of the symptoms observed in PTSD patients have shown that fluoxetine and derivatives improve anxiety-like behavior, fear responses, and aggressive behavior by elevating the corticolimbic levels of allopregnanolone and BDNF mRNA expression. These actions appeared to be independent and more selective from the action of these drugs on 5-HT reuptake inhibition.Hence, this review addresses the hypothesis that in PTSD or depressed patients brain allopregnanolone levels and BDNF expression upregulation may be part of the mechanisms involved in the beneficial actions of antidepressants or other selective brain steroidogenic stimulant (SBSS molecules.

  12. Postnatal BDNF Expression Profiles in Prefrontal Cortex and Hippocampus of a Rat Schizophrenia Model Induced by MK-801 Administration

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    Chunmei Guo

    2010-01-01

    Full Text Available Neonatal blockade of N-methyl-D-aspartic acid (NMDA receptors represents one of experimental animal models for schizophrenia. This study is to investigate the long-term brain-derived neurotrophic factor (BDNF expression profiles in different regions and correlation with “schizophrenia-like” behaviors in the adolescence and adult of this rat model. The NMDA receptor antagonist MK801 was administered to female Sprague-Dawley rats on postnatal days (PND 5 through 14. Open-field test was performed on PND 42, and PND 77 to examine the validity of the current model. BDNF protein levels in hippocampus and prefrontal cortex (PFC were analyzed on PND 15, PND 42, and PND 77. Results showed that neonatal challenge with MK-801 persistently elevated locomotor activity as well as BDNF expression; the alterations in BDNF expression varied at different developing stages and among brain regions. However, these findings provide neurochemical evidence that the blockade of NMDA receptors during brain development results in long-lasting alterations in BDNF expression and might contribute to neurobehavioral pathology of the present animal model for schizophrenia. Further study in the mechanisms and roles of the BDNF may lead to better understanding of the pathophysiology of schizophrenia.

  13. Highest trkB mRNA expression in the entorhinal cortex among hippocampal subregions in the adult rat: contrasting pattern with BDNF mRNA expression.

    Science.gov (United States)

    Tokuyama, W; Hashimoto, T; Li, Y X; Okuno, H; Miyashita, Y

    1998-11-20

    Brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, regulate synaptic functions in the hippocampus of the adult rodent. In previous studies, in situ hybridization methods have been used to evaluate regional differences in BDNF and trkB mRNA expression levels in hippocampal subregions. However, these studies have failed to reach consensus regarding the regional differences in the mRNA expression levels. In the present study, we quantitated mRNA expression levels using two different methods, ribonuclease protection assays and a quantitative reverse-transcription polymerase chain reaction technique, in four hippocampal subregions: the entorhinal cortex, dentate gyrus (DG), CA3 and CA1. These two methods yielded the same results. We found that BDNF and trkB mRNA expression levels did not covary in the four subregions. BDNF and full length trkB (trkB FL) mRNA in the entorhinal cortex and the DG show contrasting expression patterns. The expression level of BDNF mRNA was highest in the DG among the hippocampal subregions and low in the entorhinal cortex and the CA1, whereas the trkB FL mRNA expression level was highest in the entorhinal cortex, low in the DG and lowest in the CA3. These results suggest regional differences in BDNF/TrkB signaling for maintenance and modifiability of neuronal connections in the hippocampal formation.

  14. Expression and localisation of BDNF, NT4 and TrkB in proliferative vitreoretinopathy.

    Science.gov (United States)

    Ghazi-Nouri, Seyed M S; Ellis, James S; Moss, Stephen; Limb, G Astrid; Charteris, David G

    2008-05-01

    Exogenous brain derived neurotrophic factor (BDNF) is known to rescue ganglion cell death after optic nerve injury. Its mechanism of action is believed to be indirect via glial cells in the retina. In this study we investigated the changes in expression and localisation of BDNF, neurotrophin-4 (NT4) and their common receptor (TrkB) in retinectomy sections of patients with proliferative vitreoretinopathy (PVR). Nine full-thickness retinectomy specimens obtained at retinal reattachment surgery for PVR were fixed in 4% paraformaldehyde immediately after excision and compared to similarly processed normal donor retinas (4 eyes). Agarose-embedded sections (100 microm thick) were double labelled for immunohistochemistry by confocal microscopy, with antibodies against BDNF, NT4, TrkB, rod opsin, glial fibrillary acidic protein (GFAP), cellular retinaldehyde binding protein (CRALBP) and Brn3. This study demonstrates expression of NT4 by ganglion cells and shows expression of BDNF and NT4 in the outer photoreceptor segments is downregulated during PVR, whilst NT4 is markedly upregulated throughout the retina during this condition. The findings here suggest that NT4 may play a neural protective role during the development of PVR. It also shows that upregulation of NT4 in PVR is localised to Müller glial cells, indicating either over-expression of this factor by Müller cells or that Müller cells internalise NT4 for trafficking across the retina. TrkB expression was not observed in PVR retina. The observations that Müller glia demonstrate upregulation of NT4 suggests that retinal injury may lead to activation of this neurotrophin by Müller cells as part of their neuroprotective functions.

  15. Therapeutic potential of brain-derived neurotrophic factor (BDNF) and a small molecular mimics of BDNF for traumatic brain injury

    Science.gov (United States)

    Wurzelmann, Mary; Romeika, Jennifer; Sun, Dong

    2017-01-01

    Traumatic brain injury (TBI) is a major health problem worldwide. Following primary mechanical insults, a cascade of secondary injuries often leads to further neural tissue loss. Thus far there is no cure to rescue the damaged neural tissue. Current therapeutic strategies primarily target the secondary injuries focusing on neuroprotection and neuroregeneration. The neurotrophin brain-derived neurotrophic factor (BDNF) has significant effect in both aspects, promoting neuronal survival, synaptic plasticity and neurogenesis. Recently, the flavonoid 7,8-dihydroxyflavone (7,8-DHF), a small TrkB agonist that mimics BDNF function, has shown similar effects as BDNF in promoting neuronal survival and regeneration following TBI. Compared to BDNF, 7,8-DHF has a longer half-life and much smaller molecular size, capable of penetrating the blood-brain barrier, which makes it possible for non-invasive clinical application. In this review, we summarize functions of the BDNF/TrkB signaling pathway and studies examining the potential of BDNF and 7,8-DHF as a therapy for TBI.

  16. Therapeutic potential of brain-derived neurotrophic factor (BDNF) and a small molecular mimics of BDNF for traumatic brain injury.

    Science.gov (United States)

    Wurzelmann, Mary; Romeika, Jennifer; Sun, Dong

    2017-01-01

    Traumatic brain injury (TBI) is a major health problem worldwide. Following primary mechanical insults, a cascade of secondary injuries often leads to further neural tissue loss. Thus far there is no cure to rescue the damaged neural tissue. Current therapeutic strategies primarily target the secondary injuries focusing on neuroprotection and neuroregeneration. The neurotrophin brain-derived neurotrophic factor (BDNF) has significant effect in both aspects, promoting neuronal survival, synaptic plasticity and neurogenesis. Recently, the flavonoid 7,8-dihydroxyflavone (7,8-DHF), a small TrkB agonist that mimics BDNF function, has shown similar effects as BDNF in promoting neuronal survival and regeneration following TBI. Compared to BDNF, 7,8-DHF has a longer half-life and much smaller molecular size, capable of penetrating the blood-brain barrier, which makes it possible for non-invasive clinical application. In this review, we summarize functions of the BDNF/TrkB signaling pathway and studies examining the potential of BDNF and 7,8-DHF as a therapy for TBI.

  17. Effect of Boric Acid Supplementation on the Expression of BDNF in African Ostrich Chick Brain.

    Science.gov (United States)

    Tang, Juan; Zheng, Xing-ting; Xiao, Ke; Wang, Kun-lun; Wang, Jing; Wang, Yun-xiao; Wang, Ke; Wang, Wei; Lu, Shun; Yang, Ke-li; Sun, Peng-Peng; Khaliq, Haseeb; Zhong, Juming; Peng, Ke-Mei

    2016-03-01

    The degree of brain development can be expressed by the levels of brain brain-derived neurotrophic factor (BDNF). BDNF plays an irreplaceable role in the process of neuronal development, protection, and restoration. The aim of the present study was to evaluate the effects of boric acid supplementation in water on the ostrich chick neuronal development. One-day-old healthy animals were supplemented with boron in drinking water at various concentrations, and the potential effects of boric acid on brain development were tested by a series of experiments. The histological changes in brain were observed by hematoxylin and eosin (HE) staining and Nissl staining. Expression of BDNF was analyzed by immunohistochemistry, quantitative real-time PCR (QRT-PCR), and enzyme linked immunosorbent assay (ELISA). Apoptosis was evaluated with Dutp-biotin nick end labeling (TUNEL) reaction, and caspase-3 was detected with QRT-PCR. The results were as follows: (1) under the light microscope, the neuron structure was well developed with abundance of neurites and intact cell morphology when animals were fed with less than 160 mg/L of boric acid (groups II, III, IV). Adversely, when boric acid doses were higher than 320 mg/L(groups V, VI), the high-dose boric acid neuron structure was damaged with less neurites, particularly at 640 mg/L; (2) the quantity of BDNF expression in groups II, III, and IV was increased while it was decreased in groups V and VI when compared with that in group I; (3) TUNEL reaction and the caspase-3 mRNA level showed that the amount of cell apoptosis in group II, group III, and group IV were decreased, but increased in group V and group VI significantly. These results indicated that appropriate supplementation of boric acid, especially at 160 mg/L, could promote ostrich chicks' brain development by promoting the BDNF expression and reducing cell apoptosis. Conversely, high dose of boric acid particularly in 640 mg/L would damage the neuron structure of

  18. Pharmacological profile of brain-derived neurotrophic factor (BDNF) splice variant translation using a novel drug screening assay: a "quantitative code".

    Science.gov (United States)

    Vaghi, Valentina; Polacchini, Alessio; Baj, Gabriele; Pinheiro, Vera L M; Vicario, Annalisa; Tongiorgi, Enrico

    2014-10-03

    The neurotrophin brain-derived neurotrophic factor (BDNF) is a key regulator of neuronal development and plasticity. BDNF is a major pharmaceutical target in neurodevelopmental and psychiatric disorders. However, pharmacological modulation of this neurotrophin is challenging because BDNF is generated by multiple, alternatively spliced transcripts with different 5'- and 3'UTRs. Each BDNF mRNA variant is transcribed independently, but translation regulation is unknown. To evaluate the translatability of BDNF transcripts, we developed an in vitro luciferase assay in human neuroblastoma cells. In unstimulated cells, each BDNF 5'- and 3'UTR determined a different basal translation level of the luciferase reporter gene. However, constructs with either a 5'UTR or a 3'UTR alone showed poor translation modulation by BDNF, KCl, dihydroxyphenylglycine, AMPA, NMDA, dopamine, acetylcholine, norepinephrine, or serotonin. Constructs consisting of the luciferase reporter gene flanked by the 5'UTR of one of the most abundant BDNF transcripts in the brain (exons 1, 2c, 4, and 6) and the long 3'UTR responded selectively to stimulation with the different receptor agonists, and only transcripts 2c and 6 were increased by the antidepressants desipramine and mirtazapine. We propose that BDNF mRNA variants represent "a quantitative code" for regulated expression of the protein. Thus, to discriminate the efficacy of drugs in stimulating BDNF synthesis, it is appropriate to use variant-specific in vitro screening tests.

  19. Brain-derived neurotrophic factor (BDNF)-induced tropomyosin-related kinase B (Trk B) signaling is a potential therapeutic target for peritoneal carcinomatosis arising from colorectal cancer.

    Science.gov (United States)

    Tanaka, Koji; Okugawa, Yoshinaga; Toiyama, Yuji; Inoue, Yasuhiro; Saigusa, Susumu; Kawamura, Mikio; Araki, Toshimitsu; Uchida, Keiichi; Mohri, Yasuhiko; Kusunoki, Masato

    2014-01-01

    Tropomyosin-related receptor kinase B (TrkB) signaling, stimulated by brain-derived neurotrophic factor (BDNF) ligand, promotes tumor progression, and is related to the poor prognosis of various malignancies. We sought to examine the clinical relevance of BDNF/TrkB expression in colorectal cancer (CRC) tissues, its prognostic value for CRC patients, and its therapeutic potential in vitro and in vivo. Two hundred and twenty-three CRC patient specimens were used to determine both BDNF and TrkB mRNA levels. The expression of these proteins in their primary and metastatic tumors was investigated by immunohistochemistry. CRC cell lines and recombinant BDNF and K252a (a selective pharmacological pan-Trk inhibitor) were used for in vitro cell viability, migration, invasion, anoikis resistance and in vivo peritoneal metastasis assays. Tissue BDNF mRNA was associated with liver and peritoneal metastasis. Tissue TrkB mRNA was also associated with lymph node metastasis. The co-expression of BDNF and TrkB was associated with liver and peritoneal metastasis. Patients with higher BDNF, TrkB, and co-expression of BDNF and TrkB had a significantly poor prognosis. BDNF increased tumor cell viability, migration, invasion and inhibited anoikis in the TrkB-expressing CRC cell lines. These effects were suppressed by K252a. In mice injected with DLD1 co-expressing BDNF and TrkB, and subsequently treated with K252a, peritoneal metastatic nodules was found to be reduced, as compared with control mice. BDNF/TrkB signaling may thus be a potential target for treating peritoneal carcinomatosis arising from colorectal cancer.

  20. RNA interference-mediated knockdown of brain-derived neurotrophic factor (BDNF) promotes cell cycle arrest and apoptosis in B-cell lymphoma cells.

    Science.gov (United States)

    Xia, D; Li, W; Zhang, L; Qian, H; Yao, S; Qi, X

    2014-01-01

    Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin superfamily that has been reported to be involved in a number of neurological and psychological situations. Recently, high expression level of BDNF is observed in diverse human malignancies, delineating a role of BDNF in tumorigenesis. Nevertheless, its effect on B-cell lymphoma remains unclear. In this study, RNA interference technology mediated by short hairpin RNA (shRNA) was performed to inhibit endogenous BDNF expression in B-cell lymphoma cells. Results showed that knockdown of BDNF reduced cell growth and proliferation of Raji and Ramos cells. Furthermore, down-regulation of BDNF induced a cell cycle arrest at G0/G1 phase in Raji cells, and consequently led to cell apoptosis in vitro. Meanwhile, down-regulation of Bcl-2 and up-regulation of Bax, activated caspase-3 and caspase-9 and cleaved poly (ADP-ribose) polymerase (PARP) were observed in Raji cells when endogenous BDNF was inhibited. Besides, we also found that suppression of BDNF in Raji cells increased their sensitivity to chemotherapeutic drug, 5-Fluorouracil (5-FU). Our research provides a promising therapeutic strategy for human B-cell lymphoma by targeting BDNF.

  1. BDNF activates mTOR to regulate GluR1 expression required for memory formation.

    Directory of Open Access Journals (Sweden)

    Leandro Slipczuk

    Full Text Available BACKGROUND: The mammalian target of Rapamycin (mTOR kinase plays a key role in translational control of a subset of mRNAs through regulation of its initiation step. In neurons, mTOR is present at the synaptic region, where it modulates the activity-dependent expression of locally-translated proteins independently of mRNA synthesis. Indeed, mTOR is necessary for different forms of synaptic plasticity and long-term memory (LTM formation. However, little is known about the time course of mTOR activation and the extracellular signals governing this process or the identity of the proteins whose translation is regulated by this kinase, during mnemonic processing. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that consolidation of inhibitory avoidance (IA LTM entails mTOR activation in the dorsal hippocampus at the moment of and 3 h after training and is associated with a rapid and rapamycin-sensitive increase in AMPA receptor GluR1 subunit expression, which was also blocked by intra-hippocampal delivery of GluR1 antisense oligonucleotides (ASO. In addition, we found that pre- or post-training administration of function-blocking anti-BDNF antibodies into dorsal CA1 hampered IA LTM retention, abolished the learning-induced biphasic activation of mTOR and its readout, p70S6K and blocked GluR1 expression, indicating that BDNF is an upstream factor controlling mTOR signaling during fear-memory consolidation. Interestingly, BDNF ASO hindered LTM retention only when given into dorsal CA1 1 h after but not 2 h before training, suggesting that BDNF controls the biphasic requirement of mTOR during LTM consolidation through different mechanisms: an early one involving BDNF already available at the moment of training, and a late one, happening around 3 h post-training that needs de novo synthesis of this neurotrophin. CONCLUSIONS/SIGNIFICANCE: IN CONCLUSION, OUR FINDINGS DEMONSTRATE THAT: 1 mTOR-mediated mRNA translation is required for memory consolidation during

  2. Correlation between Nerve Growth Factor (NGF) with Brain Derived Neurotropic Factor (BDNF) in Ischemic Stroke Patient

    OpenAIRE

    Islam, Andi Asadul

    2016-01-01

    - The neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) is a family of polypeptides that play critical role during neuronal development, appear to mediate protective role on neurorepair in ischemic stroke. Naturally in adult brain neurorepair process consist of: angiogenesis, neurogenesis, and neuronal plasticity, it can also be stimulated by endogenous neurorepair. In this study we observed correlation between NGF and BDNF ischemic stroke patient's onset...

  3. Correlation between Nerve Growth Factor (NGF with Brain Derived Neurotropic Factor (BDNF in Ischemic Stroke Patient

    Directory of Open Access Journals (Sweden)

    Joko Widodo

    2016-05-01

    Full Text Available Background: The neurotrophins nerve growth factor (NGF and brain-derived neurotrophic factor (BDNF is a family of polypeptides that play critical role during neuronal development, appear to mediate protective role on neurorepair in ischemic stroke. Naturally in adult brain neurorepair process consist of: angiogenesis, neurogenesis, and neuronal plasticity, it can also be stimulated by endogenous neurorepair. In this study we observed correlation between NGF and BDNF ischemic stroke patient’s onset: 7-30 and over 30 days. Methods: This is cross sectional study on 46 subjects aged 38 – 74 years old with ischemic stroke from The Indonesian Central Hospital of Army Gatot Subroto Jakarta. Diagnosis of ischemic stroke was made using clinical examination and magnetic resonance imaging (MRI by neurologist. Subjects were divided into 2 groups based on stroke onset: 7 – 30 days (Group A: 19 subjects and > 30 days (Group B: 27 Subjects. Serum NGF levels were measured with ELISA method and BDNF levels were measured using multiplex method with Luminex Magpix. Results: Levels of NGF and BDNF were significantly different between onset group A and B (NGF p= 0.022, and BDNF p=0.008, with mean levels NGF in group A higher than group B, indicating that BDNF levels is lower in group A than group B. There was no significant correlation between NGF and BDNF levels in all groups. Conclusion: The variations in neurotrophic factor levels reflect an endogenous attempt at neuroprotection against biochemical and molecular changes after ischemic stroke. NGF represents an early marker of brain injury while BDNF recovery is most prominent during the first 14 days after onsite but continuous for more than 30 days. There is no significant correlation between NGF and BDNF in each group.  

  4. Modulation of BDNF and TrkB expression in rat hippocampus in response to acute neurotoxicity by diethyldithiocarbamate.

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    Micheli, M R; Bova, R; Laurenzi, M A; Bazzucchi, M; Grassi Zucconi, G

    2006-12-13

    In this study, we examined the expression profile of brain-derived neurotrophic factor (BDNF) and its receptor TrkB in adult rat hippocampus following acute administration of diethyldithiocarbamate (DDTC), a neurotoxic compound which was previously shown to induce microglia activation and cell death. Semiquantitative RT-PCR analysis detected significant variations of BDNF mRNA levels in whole hippocampus homogenates, with a peak at 24h after DDTC injection. Increased BDNF protein expression was demonstrated by immunohistochemistry in various hippocampal subfields. The most relevant increase was observed in the hilus of the dentate gyrus where BDNF levels at 120h were found to be almost four times those of basal levels. Full-length TrkB (TrkB.FL) encoding mRNA was also shown to undergo an earlier increase in the hippocampus of DDTC-treated rats. TrkB immunostaining with an antibody binding both full-length and truncated (TrkB.T) isoforms was found to increase at 120h in the hippocampal CA2 and CA3 regions. These results demonstrate that DDTC modulates the expression of BDNF and its receptor in the adult rat hippocampus and suggest a possible involvement of this neurotrophin in the protective response to DDTC-induced neuronal damage.

  5. Identification of a novel brain derived neurotrophic factor (BDNF)-inhibitory factor: regulation of BDNF by teneurin C-terminal associated peptide (TCAP)-1 in immortalized embryonic mouse hypothalamic cells.

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    Ng, Tiffany; Chand, Dhan; Song, Lifang; Al Chawaf, Arij; Watson, John D; Boutros, Paul C; Belsham, Denise D; Lovejoy, David A

    2012-02-10

    The teneurins are a family of four large transmembrane proteins that are highly expressed in the central nervous system (CNS) where they have been implicated in development and CNS function. At the tip of the carboxyl terminus of each teneurin lies a 43-amino acid sequence, that when processed, could liberate an amidated 41-residue peptide. We have called this region the teneurin C-terminal associated peptide (TCAP). Picomolar concentrations of the synthetic version of TCAP-1 inhibit stress-induced cocaine reinstatement in rats. Because cocaine-seeking is associated with increased brain derived neurotrophic factor (BDNF) in the brain, we examined whether synthetic mouse TCAP-1 has the potential to regulate BDNF expression in immortalized mouse neurons. Immortalized mouse neurons (N38; mHypoE38) show strong FITC-labeled [K(8)]-TCAP-1 uptake and BDNF labeling in the cytosol. Moreover, FITC-labeled [K(8)]-TCAP-1 bound competitively to membrane fractions. In culture, the labeled TCAP-1 peptide could be detected on cell membranes within 15 min and subsequently became internalized in the cytosol and trafficked toward the nucleus. Administration of 10(-8)M unlabeled TCAP-1 to cultures of the N38 cells resulted in a significant decrease of total cell BDNF immunoreactivity over 4h as determined by western blot and ELISA analyses. Real-time PCR, utilizing primers to the various BDNF transcripts showed a significant decline of promoter IIB- and VI-driven transcripts. Taken together, these studies indicated that in vitro, TCAP-1 induces a significant decline in BDNF transcription and protein labeling in embyronic mouse immortalized hypothalamic neurons. Thus, TCAP-1 may act as a novel BDNF inhibitory factor.

  6. BDNF regulates spontaneous correlated activity at early developmental stages by increasing synaptogenesis and expression of the K+/Cl- co-transporter KCC2.

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    Aguado, Fernando; Carmona, Maria A; Pozas, Esther; Aguiló, Agustín; Martínez-Guijarro, Francisco J; Alcantara, Soledad; Borrell, Victor; Yuste, Rafael; Ibañez, Carlos F; Soriano, Eduardo

    2003-04-01

    Spontaneous neural activity is a basic property of the developing brain, which regulates key developmental processes, including migration, neural differentiation and formation and refinement of connections. The mechanisms regulating spontaneous activity are not known. By using transgenic embryos that overexpress BDNF under the control of the nestin promoter, we show here that BDNF controls the emergence and robustness of spontaneous activity in embryonic hippocampal slices. Further, BDNF dramatically increases spontaneous co-active network activity, which is believed to synchronize gene expression and synaptogenesis in vast numbers of neurons. In fact, BDNF raises the spontaneous activity of E18 hippocampal neurons to levels that are typical of postnatal slices. We also show that BDNF overexpression increases the number of synapses at much earlier stages (E18) than those reported previously. Most of these synapses were GABAergic, and GABAergic interneurons showed hypertrophy and a 3-fold increase in GAD expression. Interestingly, whereas BDNF does not alter the expression of GABA and glutamate ionotropic receptors, it does raise the expression of the recently cloned K(+)/Cl(-) KCC2 co-transporter, which is responsible for the conversion of GABA responses from depolarizing to inhibitory, through the control of the Cl(-) potential. Together, results indicate that both the presynaptic and postsynaptic machineries of GABAergic circuits may be essential targets of BDNF actions to control spontaneous activity. The data indicate that BDNF is a potent regulator of spontaneous activity and co-active networks, which is a new level of regulation of neurotrophins. Given that BDNF itself is regulated by neuronal activity, we suggest that BDNF acts as a homeostatic factor controlling the emergence, complexity and networking properties of spontaneous networks.

  7. Enriched Environment Attenuates Surgery-Induced Impairment of Learning, Memory, and Neurogenesis Possibly by Preserving BDNF Expression.

    Science.gov (United States)

    Fan, Dan; Li, Jun; Zheng, Bin; Hua, Lei; Zuo, Zhiyi

    2016-01-01

    Postoperative cognitive dysfunction (POCD) is a significant clinical syndrome. Neurogenesis contributes to cognition. It is known that enriched environment (EE) enhances neurogenesis. We determined whether EE attenuated surgery-induced cognitive impairment and whether growth factors and neurogenesis played a role in the EE effect. Eight-week-old C57BL/6J mice were subjected to carotid artery exposure. Their learning and memory were assessed by Barnes maze, and fear conditioning started 2 weeks after the surgery. Growth factor expression and cell genesis were determined at various times after the surgery. Surgery increased the time for the mice to identify the target hole in the Barnes maze and reduced context-related freezing behavior. Surgery also reduced the expression of brain-derived neurotrophic factor (BDNF) and neurogenesis in the hippocampus. These effects were attenuated by EE. EE also attenuated surgery-induced reduction of phosphorylated/activated tropomyosin-related kinase B (TrkB) and extracellular signal-regulated kinases (ERK), components of BDNF signaling pathway. ANA-12, a selective TrkB antagonist, blocked the effects of EE on cognition, phosphorylation of TrkB and ERK, and neurogenesis. These results provide initial evidence that surgery reduces BDNF expression and neurogenesis in the hippocampus. Our results suggest that EE reduces surgery-induced impairment of learning, memory, and neurogenesis by preserving BDNF expression.

  8. Increased brain-derived neurotrophic factor (BDNF) protein concentrations in mice lacking brain serotonin.

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    Kronenberg, Golo; Mosienko, Valentina; Gertz, Karen; Alenina, Natalia; Hellweg, Rainer; Klempin, Friederike

    2016-04-01

    The interplay between BDNF signaling and the serotonergic system remains incompletely understood. Using a highly sensitive enzyme-linked immunosorbent assay, we studied BDNF concentrations in hippocampus and cortex of two mouse models of altered serotonin signaling: tryptophan hydroxylase (Tph)2-deficient (Tph2 (-/-)) mice lacking brain serotonin and serotonin transporter (SERT)-deficient (SERT(-/-)) mice lacking serotonin re-uptake. Surprisingly, hippocampal BDNF was significantly elevated in Tph2 (-/-) mice, whereas no significant changes were observed in SERT(-/-) mice. Furthermore, BDNF levels were increased in the prefrontal cortex of Tph2 (-/-) but not of SERT(-/-) mice. Our results emphasize the interaction between serotonin signaling and BDNF. Complete lack of brain serotonin induces BDNF expression.

  9. BDNF regulates the expression and distribution of vesicular glutamate transporters in cultured hippocampal neurons.

    Directory of Open Access Journals (Sweden)

    Carlos V Melo

    Full Text Available BDNF is a pro-survival protein involved in neuronal development and synaptic plasticity. BDNF strengthens excitatory synapses and contributes to LTP, presynaptically, through enhancement of glutamate release, and postsynaptically, via phosphorylation of neurotransmitter receptors, modulation of receptor traffic and activation of the translation machinery. We examined whether BDNF upregulated vesicular glutamate receptor (VGLUT 1 and 2 expression, which would partly account for the increased glutamate release in LTP. Cultured rat hippocampal neurons were incubated with 100 ng/ml BDNF, for different periods of time, and VGLUT gene and protein expression were assessed by real-time PCR and immunoblotting, respectively. At DIV7, exogenous application of BDNF rapidly increased VGLUT2 mRNA and protein levels, in a dose-dependent manner. VGLUT1 expression also increased but only transiently. However, at DIV14, BDNF stably increased VGLUT1 expression, whilst VGLUT2 levels remained low. Transcription inhibition with actinomycin-D or α-amanitine, and translation inhibition with emetine or anisomycin, fully blocked BDNF-induced VGLUT upregulation. Fluorescence microscopy imaging showed that BDNF stimulation upregulates the number, integrated density and intensity of VGLUT1 and VGLUT2 puncta in neurites of cultured hippocampal neurons (DIV7, indicating that the neurotrophin also affects the subcellular distribution of the transporter in developing neurons. Increased VGLUT1 somatic signals were also found 3 h after stimulation with BDNF, further suggesting an increased de novo transcription and translation. BDNF regulation of VGLUT expression was specifically mediated by BDNF, as no effect was found upon application of IGF-1 or bFGF, which activate other receptor tyrosine kinases. Moreover, inhibition of TrkB receptors with K252a and PLCγ signaling with U-73122 precluded BDNF-induced VGLUT upregulation. Hippocampal neurons express both isoforms during

  10. BDNF — EDRN Public Portal

    Science.gov (United States)

    BDNF (brain-derived neurotrophic factor) is a member of the nerve growth factor family. It is induced by cortical neurons, and is necessary for survival of striatal neurons in the brain. During development, BDNF promotes the survival and differentiation of selected neuronal populations of the peripheral and central nervous systems. Decreased expression of the BDNF gene is seen in both Alzheimer's and Huntington disease patients. BDNF may play a role in the regulation of stress response and in the biology of mood disorders. Multiple transcript variants encoding distinct isoforms have been described for this gene.

  11. Critical role of promoter IV-driven BDNF transcription in GABAergic transmission and synaptic plasticity in the prefrontal cortex

    OpenAIRE

    Sakata, Kazuko; Woo, Newton H.; Martinowich, Keri; Greene, Joshua S.; Schloesser, Robert J.; Shen, Liya; Lu, Bai

    2009-01-01

    Transcription of Bdnf is controlled by multiple promoters, which drive expression of multiple transcripts encoding for the same protein. Promoter IV contributes significantly to activity-dependent brain-derived neurotrophic factor (BDNF) transcription. We have generated promoter IV mutant mice (BDNF-KIV) by inserting a GFP-STOP cassette within the Bdnf exon IV locus. This genetic manipulation results in disruption of promoter IV-mediated Bdnf expression. BDNF-KIV animals exhibited significant...

  12. Differential distribution of the expression of neuropeptides and calcium-binding proteins in the hippocampus of BDNF knock-out mice and the corresponding wild type brother and sister animals

    OpenAIRE

    Herrmann-Schwartzkopff, Katharina Helene

    2010-01-01

    Brain derived neurotrophic factor (BDNF) is well known for its positive effects on survival, development and differentiation of neurons in the central nervous system. It exerts its action through binding to its high (TrkB) and low (p75) affinity receptors. This work examines the expression of neuropeptides and calcium-binding proteins in the hippocampus of BDNF knockout mice (BDNF -/-) and their corresponding wild type littermates. With the use of highly specific antibodies the hippoca...

  13. Increased expression of BDNF transcript with exon VI in hippocampi of patients with pharmaco-resistant temporal lobe epilepsy.

    Science.gov (United States)

    Martínez-Levy, G A; Rocha, L; Lubin, F D; Alonso-Vanegas, M A; Nani, A; Buentello-García, R M; Pérez-Molina, R; Briones-Velasco, M; Recillas-Targa, F; Pérez-Molina, A; San-Juan, D; Cienfuegos, J; Cruz-Fuentes, C S

    2016-02-01

    A putative role of the brain-derived neurotrophic factor (BDNF) in epilepsy has emerged from in vitro and animal models, but few studies have analyzed human samples. We assessed the BDNF expression of transcripts with exons I (BDNFI), II (BDNFII), IV (BDNFIV) and VI (BDNFVI) and methylation levels of promoters 4 and 6 in the hippocampi of patients with pharmaco-resistant temporal lobe epilepsy (TLE) (n=24). Hippocampal sclerosis (HS) and pre-surgical pharmacological treatment were considered as clinical independent variables. A statistical significant increase for the BDNFVI (p<0.05) was observed in TLE patients compared to the autopsy control group (n=8). BDNFVI was also increased in anxiety/depression TLE (N=4) when compared to autopsies or to the remaining group of patients (p<0.05). In contrast, the use of the antiepileptic drug Topiramate (TPM) (N=3) was associated to a decrease in BDNFVI expression (p<0.05) when compared to the remaining group of patients. Methylation levels at the BDNF promoters 4 and 6 were similar between TLE and autopsies and in relation to the use of either Sertraline (SRT) or TPM. These results suggest an up-regulated expression of a specific BDNF transcript in patients with TLE, an effect that seems to be dependent on the use of specific drugs.

  14. The brain-uterus connection: brain derived neurotrophic factor (BDNF) and its receptor (Ntrk2) are conserved in the mammalian uterus.

    Science.gov (United States)

    Wessels, Jocelyn M; Wu, Liang; Leyland, Nicholas A; Wang, Hongmei; Foster, Warren G

    2014-01-01

    The neurotrophins are neuropeptides that are potent regulators of neurite growth and survival. Although mainly studied in the brain and nervous system, recent reports have shown that neurotrophins are expressed in multiple target tissues and cell types throughout the body. Additionally, dysregulation of neurotrophins has been linked to several disease conditions including Alzheimer's, Parkinson's, Huntington's, psychiatric disorders, and cancer. Brain derived neurotrophic factor (BDNF) is a member of the neurotrophin family that elicits its actions through the neurotrophic tyrosine receptor kinase type 2 (Ntrk2). Together BDNF and Ntrk2 are capable of activating the adhesion, angiogenesis, apoptosis, and proliferation pathways. These pathways are prominently involved in reproductive physiology, yet a cross-species examination of BDNF and Ntrk2 expression in the mammalian uterus is lacking. Herein we demonstrated the conserved nature of BDNF and Ntrk2 across several mammalian species by mRNA and protein sequence alignment, isolated BDNF and Ntrk2 transcripts in the uterus by Real-Time PCR, localized both proteins to the glandular and luminal epithelium, vascular smooth muscle, and myometrium of the uterus, determined that the major isoforms expressed in the human endometrium were pro-BDNF, and truncated Ntrk2, and finally demonstrated antibody specificity. Our findings suggest that BDNF and Ntrk2 are transcribed, translated, and conserved across mammalian species including human, mouse, rat, pig, horse, and the bat.

  15. The brain-uterus connection: brain derived neurotrophic factor (BDNF and its receptor (Ntrk2 are conserved in the mammalian uterus.

    Directory of Open Access Journals (Sweden)

    Jocelyn M Wessels

    Full Text Available The neurotrophins are neuropeptides that are potent regulators of neurite growth and survival. Although mainly studied in the brain and nervous system, recent reports have shown that neurotrophins are expressed in multiple target tissues and cell types throughout the body. Additionally, dysregulation of neurotrophins has been linked to several disease conditions including Alzheimer's, Parkinson's, Huntington's, psychiatric disorders, and cancer. Brain derived neurotrophic factor (BDNF is a member of the neurotrophin family that elicits its actions through the neurotrophic tyrosine receptor kinase type 2 (Ntrk2. Together BDNF and Ntrk2 are capable of activating the adhesion, angiogenesis, apoptosis, and proliferation pathways. These pathways are prominently involved in reproductive physiology, yet a cross-species examination of BDNF and Ntrk2 expression in the mammalian uterus is lacking. Herein we demonstrated the conserved nature of BDNF and Ntrk2 across several mammalian species by mRNA and protein sequence alignment, isolated BDNF and Ntrk2 transcripts in the uterus by Real-Time PCR, localized both proteins to the glandular and luminal epithelium, vascular smooth muscle, and myometrium of the uterus, determined that the major isoforms expressed in the human endometrium were pro-BDNF, and truncated Ntrk2, and finally demonstrated antibody specificity. Our findings suggest that BDNF and Ntrk2 are transcribed, translated, and conserved across mammalian species including human, mouse, rat, pig, horse, and the bat.

  16. BDNF Expression in the Central Nervous System of Tree Shrews (Tupaia Belangeri Chinensis)%BDNF在树鼩中枢神经系统的表达

    Institute of Scientific and Technical Information of China (English)

    何保丽; 刘汝文; 陈丽玲; 李波; 李进涛; 角建林

    2011-01-01

    Objective To detect BDNF expression in the central nervous system(hippocampus and brainstem) of tree shrews. Method RT-PCR was used to detect BDNF expression in the central nervous system(hippocampus and brainstem) of tree shrews from embryo to adult. Results BDNF expressed in hippocampus and brainstem of tree shrews from embryo to adult. The expression level of BDNF mRNA in adult was significantly higher than that of embryo and newborn tree shrews (F< 0.05) . Conclusion The expression level of BDNF is still high in adult tree shrews.%目的 观测脑源性神经营养因子(6rain-derived neurotrophic factor,BDNF)在树鼩中枢神经系统的表达.方法 用RT—PCR技术探讨从胎儿、新生到成年过程中,观察树鼩中枢神经系统海马和脑干BDNF的表达变化.结果 BDNF在胎儿、新生和成年树鼩的海马和脑干均有表达,成年树鼩海马中的表达量显著高于胎儿和新生树鼩,差异有统计学意义(P<0.05).结论 BDNF在成年树鼩仍有较高的表达量.

  17. Trophic factors GDNF and BDNF improve function of retinal sheet transplants.

    Science.gov (United States)

    Yang, Pamela B; Seiler, Magdalene J; Aramant, Robert B; Yan, Fengrong; Mahoney, Melissa J; Kitzes, Leonard M; Keirstead, Hans S

    2010-11-01

    The aim of this study was to compare glial-derived neurotrophic factor (GDNF) treatment with brain-derived neurotrophic factor (BDNF) treatment of retinal transplants on restoration of visual responses in the superior colliculus (SC) of the S334ter line 3 rat model of rapid retinal degeneration (RD). RD rats (age 4-6 weeks) received subretinal transplants of intact sheets of fetal retina expressing the marker human placental alkaline phosphatase (hPAP). Experimental groups included: (1) untreated retinal sheet transplants, (2) GDNF-treated transplants, (3) BDNF-treated transplants, (4) none surgical, age-matched RD rats, (5) sham surgery RD controls, (6) progenitor cortex transplant RD controls, and (7) normal pigmented rat controls. At 2-8 months after transplantation, multi-unit visual responses were recorded from the SC using a 40 ms full-field stimulus (-5.9 to +1 log cd/m(2)) after overnight dark-adaptation. Responses were analyzed for light thresholds, spike counts, response latencies, and location within the SC. Transplants were grouped into laminated or rosetted (more disorganized) transplants based on histological analysis. Visual stimulation of control RD rats evoked no responses. In RD rats with retinal transplants, a small area of the SC corresponding to the position of the transplant in the host retina, responded to light stimulation between -4.5 and -0.08 log cd/m(2), whereas the light threshold of normal rats was at or below -5 log cd/m(2) all over the SC. Overall, responses in the SC in rats with laminated transplants had lower response thresholds and were distributed over a wider area than rats with rosetted transplants. BDNF treatment improved responses (spike counts, light thresholds and responsive areas) of rats with laminated transplants whereas GDNF treatment improved responses from rats with both laminated and rosetted (more disorganized) transplants. In conclusion, treatment of retinal transplants with GDNF and BDNF improved the restoration

  18. Expression of BDNF and TrkB Phosphorylation in the Rat Frontal Cortex During Morphine Withdrawal are NO Dependent.

    Science.gov (United States)

    Peregud, Danil I; Yakovlev, Alexander A; Stepanichev, Mikhail Yu; Onufriev, Mikhail V; Panchenko, Leonid F; Gulyaeva, Natalia V

    2016-08-01

    Nitric oxide (NO) mediates pharmacological effects of opiates including dependence and abstinence. Modulation of NO synthesis during the induction phase of morphine dependence affects manifestations of morphine withdrawal syndrome, though little is known about mechanisms underlying this phenomenon. Neurotrophic and growth factors are involved in neuronal adaptation during opiate dependence. NO-dependent modulation of morphine dependence may be mediated by changes in expression and activity of neurotrophic and/or growth factors in the brain. Here, we studied the effects of NO synthesis inhibition during the induction phase of morphine dependence on the expression of brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and insulin-like growth factor 1 (IGF1) as well as their receptors in rat brain regions after spontaneous morphine withdrawal in dependent animals. Morphine dependence in rats was induced within 6 days by 12 injections of morphine in increasing doses (10-100 mg/kg), and NO synthase inhibitor L-N(G)-nitroarginine methyl ester (L-NAME) (10 mg/kg) was given 1 h before each morphine injection. The expression of the BDNF, GDNF, NGF, IGF1, and their receptors in the frontal cortex, striatum, hippocampus, and midbrain was assessed 40 h after morphine withdrawal. L-NAME treatment during morphine intoxication resulted in an aggravation of the spontaneous morphine withdrawal severity. Morphine withdrawal was accompanied by upregulation of BDNF, IGF1, and their receptors TrkB and IGF1R, respectively, on the mRNA level in the frontal cortex, and only BDNF in hippocampus and midbrain. L-NAME administration during morphine intoxication decreased abstinence-induced upregulation of these mRNAs in the frontal cortex, hippocampus and midbrain. L-NAME prevented from abstinence-induced elevation of mature but not pro-form of BDNF polypeptide in the frontal cortex. While morphine abstinence did not affect Trk

  19. BDNF modifies hippocampal KCC2 and NKCC1 expression in a temporal lobe epilepsy model.

    Science.gov (United States)

    Eftekhari, Sanaz; Mehrabi, Soraya; Soleimani, Mansooreh; Hassanzadeh, Gholamreza; Shahrokhi, Amene; Mostafavi, Hossein; Hayat, Parisa; Barati, Mahmood; Mehdizadeh, Hajar; Rahmanzadeh, Reza; Hadjighassem, Mahmoud Reza; Joghataei, Mohammad Taghi

    2014-01-01

    Excitatory GABA actions, induced by altered expression of chloride transporters (KCC2/NKCC1), can contribute to seizure generation in temporal lobe epilepsy. In the present study, we evaluated whether BDNF administration can affect KCC2/NKCC1 expression, ictogenesis and behavioral alterations in this paradigm. Status epilepticus was induced in male rats with pilocarpine, followed by a treatment of either a single high dose or multiple injections of BDNF during the latent phase of temporal lobe epilepsy. Chloride transporters expression, spontaneous recurrent seizures, and hyperexcitability post-seizural behaviors were evaluated after treatment. NKCC1 protein expression was markedly upregulated, whereas that of KCC2 was significantly downregulated in epileptic hippocampi compared to intact controls. Application of BDNF (both single high dose and multiple injections) increased KCC2 expression in epileptic hippocampi, while NKCC1 expression was downregulated exclusively by the single high dose injection of BDNF. Development of spontaneous recurrent seizures was delayed but not prevented by the treatment, and hyperexcitability behaviors were ameliorated for a short period of time. To prevent GABA-A mediated depolarization and design appropriate treatment strategies for temporal lobe epilepsy, chloride transporters can be considered as a target. Future studies are warranted to investigate any possible therapeutic effects of BDNF via altering chloride transporters expression.

  20. Area-specific effects of brain-derived neurotrophic factor (BDNF) genetic ablation on various neuronal subtypes of the mouse brain.

    Science.gov (United States)

    Grosse, Gisela; Djalali, Susann; Deng, Dong Rui; Höltje, Markus; Hinz, Britta; Schwartzkopff, Katharina; Cygon, Marcel; Rothe, Thomas; Stroh, Thomas; Hellweg, Rainer; Ahnert-Hilger, Gudrun; Hörtnag, Heide

    2005-05-12

    The effects of brain-derived neurotrophic factor (BDNF) on the development of presynaptic terminals and of neuronal subtypes in various brain areas were studied in BDNF-knockout (BDNF-/-) mice at postnatal days 15-17. Western analysis revealed no changes in the overall amount of a variety of synaptic proteins in BDNF-/- mice as compared to wild type mice. In addition, the complex between the vesicular proteins, synaptophysin and synaptobrevin, as well as their respective homodimers were unaltered. Moreover, no changes in the density of neurons were found in, e.g., the CA3 region of the hippocampus and the nucleus nervi facialis of BDNF-/- mice. However, cholinergic cells were reduced by 20% in the medial septum of BDNF-/- mice associated with a decrease in the activity of choline acetyltransferase and protein levels of nerve growth factor in the hippocampus by 16% and 44%, respectively. In the striatum, however, the total number of cholinergic cells were comparable in both groups, although the activity of choline acetyltransferase was decreased by 46%. In GABAergic interneurons, the expression of neuropeptides in various brain areas was differentially affected by BDNF deletion as revealed by immunohistochemistry. In the hippocampus and cortex of BDNF-/- mice, the density of neuropeptide Y-, somatostatin-, and parvalbumin-immunoreactive cells was drastically reduced, whereas the density of calretinin-positive cells was increased. The extent of these changes in neuropeptide-containing cells varied among hippocampal subregions. In the striatum, only the density of parvalbumin-immunoreactive cells was decreased by approximately 45%. In conclusion, BDNF deficiency is accompanied by a differential dysregulation in the expression of neuropeptides and calcium-binding proteins in otherwise intact GABAergic and glutamatergic neurons in a region-specific manner.

  1. Brain-derived neurotrophic factor (BDNF)-induced mitochondrial motility arrest and presynaptic docking contribute to BDNF-enhanced synaptic transmission.

    Science.gov (United States)

    Su, Bo; Ji, Yun-Song; Sun, Xu-lu; Liu, Xiang-Hua; Chen, Zhe-Yu

    2014-01-17

    Appropriate mitochondrial transport and distribution are essential for neurons because of the high energy and Ca(2+) buffering requirements at synapses. Brain-derived neurotrophic factor (BDNF) plays an essential role in regulating synaptic transmission and plasticity. However, whether and how BDNF can regulate mitochondrial transport and distribution are still unclear. Here, we find that in cultured hippocampal neurons, application of BDNF for 15 min decreased the percentage of moving mitochondria in axons, a process dependent on the activation of the TrkB receptor and its downstream PI3K and phospholipase-Cγ signaling pathways. Moreover, the BDNF-induced mitochondrial stopping requires the activation of transient receptor potential canonical 3 and 6 (TRPC3 and TRPC6) channels and elevated intracellular Ca(2+) levels. The Ca(2+) sensor Miro1 plays an important role in this process. Finally, the BDNF-induced mitochondrial stopping leads to the accumulation of more mitochondria at presynaptic sites. Mutant Miro1 lacking the ability to bind Ca(2+) prevents BDNF-induced mitochondrial presynaptic accumulation and synaptic transmission, suggesting that Miro1-mediated mitochondrial motility is involved in BDNF-induced mitochondrial presynaptic docking and neurotransmission. Together, these data suggest that mitochondrial transport and distribution play essential roles in BDNF-mediated synaptic transmission.

  2. The relationship between serum brain-derived neurotrophic factor (BDNF) and cardiometabolic indices in schizophrenia.

    Science.gov (United States)

    Nurjono, Milawaty; Tay, Yi Hang; Lee, Jimmy

    2014-08-01

    Brain derived neurotrophic factor (BDNF), which has been implicated in the pathogenesis of schizophrenia, has been recently shown to be involved in the regulation of metabolism and energy homeostasis. This study seeks to examine the relationship between BDNF, metabolic indices and cardiovascular (CVD) risk in patients with schizophrenia. Medical histories, demographic information and anthropometric measurements were collected and analyzed from 61 participants with schizophrenia. Fasting glucose and lipids were measured in a central laboratory, and serum BDNF was analyzed using commercially available enzyme-linked immunosorbent assay (ELISA). The 10-year CVD risk for each participant was computed using the Framingham risk score (FRS). Linear regressions were performed to examine the relationships between serum BDNF with body mass index (BMI), blood pressure (BP), triglycerides (TG), total cholesterol, high-density lipoprotein cholesterol (HDL-C) and glucose. To examine the relationship between serum BDNF and FRS, serum BDNF was categorized into quartiles, and a multiple regression was performed. After adjusting for age, gender and current smoking status, diastolic BP (dBP) (p=0.045) and TG (p=0.015) were found to be significantly associated with serum BDNF. Participants in the highest quartile of serum BDNF had a 3.3 times increase in FRS over those in the lowest quartile. Our findings support the possible regulatory role of BDNF in metabolism and cardiovascular homeostasis among patients with schizophrenia similar to that observed among the non-mentally ill. Serum BDNF not only present itself as a candidate biomarker of schizophrenia but also might be a viable marker of metabolic co-morbidities associated with schizophrenia.

  3. Brain insults in rats induce increased expression of the BDNF gene through differential use of multiple promoters.

    Science.gov (United States)

    Kokaia, Z; Metsis, M; Kokaia, M; Bengzon, J; Elmér, E; Smith, M L; Timmusk, T; Siesjö, B K; Persson, H; Lindvall, O

    1994-04-01

    The rat brain-derived neurotrophic factor (BDNF) gene consists of four short 5'-exons linked to separate promoters and one 3'-exon encoding the mature BDNF protein. Using in situ hybridization we demonstrate here that kindling-induced seizures, cerebral ischaemia and insulin-induced hypoglycaemic coma increase BDNF mRNA levels through insult- and region-specific usage of three promoters within the BDNF gene. Both brief (2 min) and longer (10 min) periods of forebrain ischaemia induced significant and major increases only of exon III mRNA in the dentate gyrus. Following hypoglycaemic coma (1 and 30 min), exon III mRNA was markedly elevated in the dentate gyrus and, in addition, exon I mRNA showed a moderate increase. Single and recurrent (n = 40) hippocampal seizures significantly increased expression of exon I, II and III mRNAs in the dentate gyrus granule cells. After recurrent seizures, including generalized convulsions, there were also major increases of both exon I and III mRNAs in the CA3 region, amygdala, piriform cortex and neocortex, whereas in the hippocampal CA1 sector marked elevations were detected only for exon III mRNA. The insults had no effect on the level of exon IV mRNA in the brain. The region- and insult-specific pattern of promoter activation might be of importance for the effectiveness of protective responses as well as for the regulation of plastic changes following brain insults.

  4. BDNF 和TrkB 在肝细胞癌中的表达及其功能研究%Expression and Functions of BDNF and TrkB in Hepatocellular Carcinoma

    Institute of Scientific and Technical Information of China (English)

    郭大伟; 侯学忠; 张弘彬; 孙文郁; 朱磊; 姜晓峰; 梁健

    2012-01-01

    Objective: To investigate the expression of brain-derived neurotrophic factor ( BDNF ) and its primary receptor, tropo-mysin-related kinase B ( TrkB ) in hepatocellular carcinoma ( HCC ) tissues, and to evaluate the functions of these proteins in the onco-genesis and progression of HCC. Methods: The expression of BDNF and TrkB in 65 HCC cases was evaluated via immunohistochemi-cal staining. In the human HCC HepG2 cell lines, the secretory BDNF in the supernatant liquid was measured using enzyme-linked im-munosorbent assay ( ELISA ). The effects of BDNF-neutralizing antibody and the Trk tyrosine kinase inhibitor K252a on apoptosis and invasion were examined using flow cytometry and a Transwell assay, respectively. Results: Higher BDNF expression ( 63.1% ) or positive TrkB expression ( 55.4% ) was found in the HCC specimens. More cases of intrahepatic multiple tumors were found in HCCs with higher BDNF expression (P< 0.01 ). Similarly, HCCs with negative for TrkB tended to be solitary tumors (P< 0.05 ). In addition, patients with higher levels of BDNF expression or positive TrkB expression had more advanced stages of HCC ( P < 0.05 ). The level of BDNF secretion in HepG2 cells was 88.56 pg/ml ± 7.45 pg/ml. Both anti-BDNF and K252a antibodies effectively induced apoptosis and suppressed the invasion of the HepG2 cells. Conclusion: BDNF and TrkB are essential for the survival and invasion of the HCC cells. BDNF/TrkB signaling may be an effective target for promoting HCC advancement.%目的:研究BDNF及其受体TrkB在人肝细胞癌(HCC)中的表达,并探讨二者在HCC发生、发展中的作用.方法:采用免疫组织化学方法检测BDNF和TrkB在65例HCC组织中的表达.在人HCC细胞系HepG2中,采用ELISA方法检测BDNF在培养上清中的分泌水平,分别采用流式细胞术和Transwell细胞侵袭方法测定BDNF中和抗体或TrkB激酶活性抑制剂K252a处理对细胞凋亡和侵袭的影响.结果:65例HCC组织标本中,41例(63.1%)

  5. Impact of prenatal polycyclic aromatic hydrocarbon exposure on behavior, cortical gene expression, and DNA methylation of the Bdnf gene

    Directory of Open Access Journals (Sweden)

    Rachel L. Miller

    2016-03-01

    Full Text Available Prenatal exposure to polycyclic aromatic hydrocarbons (PAH has been associated with sustained effects on the brain and behavior in offspring. However, the mechanisms have yet to be determined. We hypothesized that prenatal exposure to ambient PAH in mice would be associated with impaired neurocognition, increased anxiety, altered cortical expression of Bdnf and Grin2b, and greater DNA methylation of Bdnf. Our results indicated that during open-field testing, prenatal PAH–exposed offspring spent more time immobile and less time exploring. Females produced more fecal boli. Offspring prenatally exposed to PAH displayed modest reductions in overall exploration of objects. Further, prenatal PAH exposure was associated with lower cortical expression of Grin2b and Bdnf in males and greater Bdnf IV promoter methylation. Epigenetic differences within the Bdnf IV promoter correlated with Bdnf gene expression but not with the observed behavioral outcomes, suggesting that additional targets may account for these PAH-associated effects.

  6. Neuropeptide S and BDNF gene expression in the amygdala are influenced by social decision-making under stress.

    Science.gov (United States)

    Smith, Justin P; Achua, Justin K; Summers, Tangi R; Ronan, Patrick J; Summers, Cliff H

    2014-01-01

    In a newly developed conceptual model of stressful social decision-making, the Stress-Alternatives Model (SAM; used for the 1st time in mice) elicits two types of response: escape or remain submissively. Daily (4d) aggressive social interaction in a neutral arena between a C57BL6/N test mouse and a larger, novel aggressive CD1 mouse, begin after an audible tone (conditioned stimulus; CS). Although escape holes (only large enough for smaller test animals) are available, and the aggressor is unremittingly antagonistic, only half of the mice tested utilize the possibility of escape. During training, for mice that choose to leave the arena and social interaction, latency to escape dramatically decreases over time; this is also true for control C57BL6/N mice which experienced no aggression. Therefore, the open field of the SAM apparatus is intrinsically anxiogenic. It also means that submission to the aggressor is chosen despite this anxiety and the high intensity of the aggressive attacks and defeat. While both groups that received aggression displayed stress responsiveness, corticosterone levels were significantly higher in animals that chose submissive coexistence. Although both escaping and non-escaping groups of animals experienced aggression and defeat, submissive animals also exhibited classic fear conditioning, freezing in response to the CS alone, while escaping animals did not. In the basolateral amygdala (BLA), gene expression of brain-derived neurotrophic factor (BDNF) was diminished, at the same time neuropeptide S (NPS) expression was significantly elevated, but only in submissive animals. This increase in submission-evoked NPS mRNA expression was greatest in the central amygdala (CeA), which coincided with decreased BDNF expression. Reduced expression of BDNF was only found in submissive animals that also exhibit elevated NPS expression, despite elevated corticosterone in all socially interacting animals. The results suggest an interwoven relationship

  7. Serum brain-derived neurotrophic factor (BDNF) levels in attention deficit-hyperactivity disorder (ADHD).

    Science.gov (United States)

    Scassellati, Catia; Zanardini, Roberta; Tiberti, Alessandra; Pezzani, Marco; Valenti, Vera; Effedri, Paola; Filippini, Elena; Conte, Stefano; Ottolini, Alberto; Gennarelli, Massimo; Bocchio-Chiavetto, Luisella

    2014-03-01

    It has been proposed that the neurotrophin brain-derived neurotrophic factor (BDNF) may be involved in attention deficit-hyperactivity disorder (ADHD) etiopathogenesis. Alterations in BDNF serum levels have been observed in childhood/adulthood neurodevelopmental pathologies, but no evidence is available for BDNF serum concentrations in ADHD. The study includes 45 drug-naïve ADHD children and 45 age-sex matched healthy subjects. Concentration of serum BDNF was determined by the ELISA method. BDNF serum levels in patients with ADHD were not different from those of controls (mean ± SD; ADHD: 39.33 ± 10.41 ng/ml; controls: 38.82 ± 8.29 ng/ml, t = -0.26, p = 0.80). Our findings indicate no alteration of serum BDNF levels in untreated patients with ADHD. A further stratification for cognitive, neuropsychological and psychopathological assessment in a larger sample could be useful to clarify the role of BDNF in the endophenotype characterization of ADHD.

  8. Plasma brain derived neurotrophic factor (BDNF) and response to ketamine in treatment-resistant depression.

    Science.gov (United States)

    Haile, C N; Murrough, J W; Iosifescu, D V; Chang, L C; Al Jurdi, R K; Foulkes, A; Iqbal, S; Mahoney, J J; De La Garza, R; Charney, D S; Newton, T F; Mathew, S J

    2014-02-01

    Ketamine produces rapid antidepressant effects in treatment-resistant depression (TRD), but the magnitude of response varies considerably between individual patients. Brain-derived neurotrophic factor (BDNF) has been investigated as a biomarker of treatment response in depression and has been implicated in the mechanism of action of ketamine. We evaluated plasma BDNF and associations with symptoms in 22 patients with TRD enrolled in a randomized controlled trial of ketamine compared to an anaesthetic control (midazolam). Ketamine significantly increased plasma BDNF levels in responders compared to non-responders 240 min post-infusion, and Montgomery-Åsberg Depression Rating Scale (MADRS) scores were negatively correlated with BDNF (r=-0.701, p = 0.008). Plasma BDNF levels at 240 min post-infusion were highly negatively associated with MADRS scores at 240 min (r = -0.897, p=.002), 24 h (r = -0.791, p = 0.038), 48 h (r = -0.944, p = 0.001) and 72 h (r = -0.977, p = 0.010). No associations with BDNF were found for patients receiving midazolam. These data support plasma BDNF as a peripheral biomarker relevant to ketamine antidepressant response.

  9. Spontaneous sleep-wake cycle and sleep deprivation differently induce Bdnf1, Bdnf4 and Bdnf9a DNA methylation and transcripts levels in the basal forebrain and frontal cortex in rats.

    Science.gov (United States)

    Ventskovska, Olena; Porkka-Heiskanen, Tarja; Karpova, Nina N

    2015-04-01

    Brain-derived neurotrophic factor (Bdnf) regulates neuronal plasticity, slow wave activity and sleep homeostasis. Environmental stimuli control Bdnf expression through epigenetic mechanisms, but there are no data on epigenetic regulation of Bdnf by sleep or sleep deprivation. Here we investigated whether 5-methylcytosine (5mC) DNA modification at Bdnf promoters p1, p4 and p9 influences Bdnf1, Bdnf4 and Bdnf9a expression during the normal inactive phase or after sleep deprivation (SD) (3, 6 and 12 h, end-times being ZT3, ZT6 and ZT12) in rats in two brain areas involved in sleep regulation, the basal forebrain and cortex. We found a daytime variation in cortical Bdnf expression: Bdnf1 expression was highest at ZT6 and Bdnf4 lowest at ZT12. Such variation was not observed in the basal forebrain. Also Bdnf p1 and p9 methylation levels differed only in the cortex, while Bdnf p4 methylation did not vary in either area. Factorial analysis revealed that sleep deprivation significantly induced Bdnf1 and Bdnf4 with the similar pattern for Bdnf9a in both basal forebrain and cortex; 12 h of sleep deprivation decreased 5mC levels at the cortical Bdnf p4 and p9. Regression analysis between the 5mC promoter levels and the corresponding Bdnf transcript expression revealed significant negative correlations for the basal forebrain Bdnf1 and cortical Bdnf9a transcripts in only non-deprived rats, while these correlations were lost after sleep deprivation. Our results suggest that Bdnf transcription during the light phase of undisturbed sleep-wake cycle but not after SD is regulated at least partially by brain site-specific DNA methylation. © 2014 European Sleep Research Society.

  10. Morphological differences in adipose tissue and changes in BDNF/Trkb expression in brain and gut of a diet induced obese zebrafish model.

    Science.gov (United States)

    Montalbano, Giuseppe; Mania, Manuela; Guerrera, Maria Cristina; Abbate, Francesco; Laurà, Rosaria; Navarra, Michele; Vega, Jose A; Ciriaco, Emilia; Germanà, Antonino

    2016-03-01

    Obesity is a multifactorial disease generated by an alteration in balance between energy intake and expenditure, also dependent on genetic and non-genetic factors. Moreover, various nuclei of the hypothalamus receive and process peripheral stimuli from the gastrointestinal tract, controlling food intake and therefore energy balance. Among anorexigenic molecules, brain-derived neurotrophic factor (BDNF) acts through the tyrosine-kinase receptor TrkB. Numerous data demonstrate that the BDNF/TrkB system has a fundamental role in the control of food intake and body weight. Quantitative PCR and immunohistochemistry for both BDNF and TrkB were used to determine changes in levels in the brain and gastro-intestinal tract of an experimental zebrafish model of diet-induced obesity. Overfed animals showed increased weight and body mass index as well as accumulation of adipose tissue in the visceral, subcutaneous and hepatic areas. These changes were concomitant with decreased levels of BDNF mRNA in the gastro-intestinal tract and increased expression of TrkB mRNA in the brain. Overfeeding did not change the density of cells displaying immunoreactivity for BDNF or TrkB in the brain although both were significantly diminished in the gastro-intestinal tract. These results suggest an involvement of the BDNF/TrkB system in the regulation of food intake and energy balance in zebrafish, as in mammals.

  11. Targeted brain derived neurotropic factors (BDNF delivery across the blood-brain barrier for neuro-protection using magnetic nano carriers: an in-vitro study.

    Directory of Open Access Journals (Sweden)

    Sudheesh Pilakka-Kanthikeel

    Full Text Available Parenteral use of drugs; such as opiates exert immunomodulatory effects and serve as a cofactor in the progression of HIV-1 infection, thereby potentiating HIV related neurotoxicity ultimately leading to progression of NeuroAIDS. Morphine exposure is known to induce apoptosis, down regulate cAMP response element-binding (CREB expression and decrease in dendritic branching and spine density in cultured cells. Use of neuroprotective agent; brain derived neurotropic factor (BDNF, which protects neurons against these effects, could be of therapeutic benefit in the treatment of opiate addiction. Previous studies have shown that BDNF was not transported through the blood brain barrier (BBB in-vivo.; and hence it is not effective in-vivo. Therefore development of a drug delivery system that can cross BBB may have significant therapeutic advantage. In the present study, we hypothesized that magnetically guided nanocarrier may provide a viable approach for targeting BDNF across the BBB. We developed a magnetic nanoparticle (MNP based carrier bound to BDNF and evaluated its efficacy and ability to transmigrate across the BBB using an in-vitro BBB model. The end point determinations of BDNF that crossed BBB were apoptosis, CREB expression and dendritic spine density measurement. We found that transmigrated BDNF was effective in suppressing the morphine induced apoptosis, inducing CREB expression and restoring the spine density. Our results suggest that the developed nanocarrier will provide a potential therapeutic approach to treat opiate addiction, protect neurotoxicity and synaptic density degeneration.

  12. Brain-derived neurotrophic factor increases vascular endothelial growth factor expression and enhances angiogenesis in human chondrosarcoma cells.

    Science.gov (United States)

    Lin, Chih-Yang; Hung, Shih-Ya; Chen, Hsien-Te; Tsou, Hsi-Kai; Fong, Yi-Chin; Wang, Shih-Wei; Tang, Chih-Hsin

    2014-10-15

    Chondrosarcomas are a type of primary malignant bone cancer, with a potent capacity for local invasion and distant metastasis. Brain-derived neurotrophic factor (BDNF) is commonly upregulated during neurogenesis. The aim of the present study was to examine the mechanism involved in BDNF-mediated vascular endothelial growth factor (VEGF) expression and angiogenesis in human chondrosarcoma cells. Here, we knocked down BDNF expression in chondrosarcoma cells and assessed their capacity to control VEGF expression and angiogenesis in vitro and in vivo. We found knockdown of BDNF decreased VEGF expression and abolished chondrosarcoma conditional medium-mediated angiogenesis in vitro as well as angiogenesis effects in vivo in the chick chorioallantoic membrane and Matrigel plug nude mouse models. In addition, in the xenograft tumor angiogenesis model, the knockdown of BDNF significantly reduced tumor growth and tumor-associated angiogenesis. BDNF increased VEGF expression and angiogenesis through the TrkB receptor, PLCγ, PKCα, and the HIF-1α signaling pathway. Finally, we analyzed samples from chondrosarcoma patients by immunohistochemical staining. The expression of BDNF and VEGF protein in 56 chondrosarcoma patients was significantly higher than in normal cartilage. In addition, the high level of BDNF expression correlated strongly with VEGF expression and tumor stage. Taken together, our results indicate that BDNF increases VEGF expression and enhances angiogenesis through a signal transduction pathway that involves the TrkB receptor, PLCγ, PKCα, and the HIF-1α. Therefore, BDNF may represent a novel target for anti-angiogenic therapy for human chondrosarcoma.

  13. Rapid Antidepressant Activity of Ethanol Extract of Gardenia jasminoides Ellis Is Associated with Upregulation of BDNF Expression in the Hippocampus

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    Hailou Zhang

    2015-01-01

    Full Text Available Ethanol extract of Yueju pill, a Traditional Chinese Medicine herbal formula widely used to treat mood disorders, demonstrates rapid antidepressant effects similar to ketamine, likely via instant enhancement of brain-derived neurotrophic factor (BDNF expression in the hippocampus. Here we investigated ethanol extracts of the constituent herbs of Yueju responsible for rapid antidepressant effects. Screening with tail suspension test in Kunming mice at 24 hours after a single administration of five individual constituent herbs of Yueju, we found that only Gardenia jasminoides Ellis (GJ showed a significant effect. The antidepressant response started at 2 hours after GJ administration. Similar to Yueju and ketamine, a single administration of GJ significantly reduced the number of escape failures in the learned helplessness test. Furthermore, GJ decreased latency of food consumption in the novelty suppressed-feeding test. Additionally, starting from 2 hours and continuing for over 20 hours after GJ administration, BDNF expression in the hippocampus was upregulated, temporally linked with the antidepressant response. These findings suggest that GJ has rapid antidepressant effects, which are associated with the elevated expression of BDNF in the hippocampus. In Yueju formula, Yue represents GJ, as thus our study demonstrates the primary role of GJ in rapid antidepressant efficacy of Yueju.

  14. Changes in expression of BDNF and its receptors TrkB and p75NTR in the hippocampus of a dog model of chronic alcoholism and abstinence

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    Xu, R.; Duan, S.R.; Zhao, J.W.; Wang, C.Y. [Neurology Ward of Internal Medicine, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province (China)

    2015-06-23

    Chronic ethanol consumption can produce learning and memory deficits. Brain-derived neurotrophic factor (BDNF) and its receptors affect the pathogenesis of alcoholism. In this study, we examined the expression of BDNF, tropomyosin receptor kinase B (TrkB) and p75 neurotrophin receptor (p75NTR) in the hippocampus of a dog model of chronic alcoholism and abstinence. Twenty domestic dogs (9-10 months old, 15-20 kg; 10 males and 10 females) were obtained from Harbin Medical University. A stable alcoholism model was established through ad libitum feeding, and anti-alcohol drug treatment (Zhong Yao Jie Jiu Ling, the main ingredient was the stems of watermelon; developed in our laboratory), at low- and high-doses, was carried out. The Zhong Yao Jie Jiu Ling was effective for the alcoholism in dogs. The morphology of hippocampal neurons was evaluated using hematoxylin-eosin staining. The number and morphological features of BDNF, TrkB and p75NTR-positive neurons in the dentate gyrus (DG), and the CA1, CA3 and CA4 regions of the hippocampus were observed using immunohistochemistry. One-way ANOVA was used to determine differences in BDNF, TrkB and p75NTR expression. BDNF, TrkB and p75NTR-positive cells were mainly localized in the granular cell layer of the DG and in the pyramidal cell layer of the CA1, CA3 and CA4 regions (DG>CA1>CA3>CA4). Expression levels of both BDNF and TrkB were decreased in chronic alcoholism, and increased after abstinence. The CA4 region appeared to show the greatest differences. Changes in p75NTR expression were the opposite of those of BDNF and TrkB, with the greatest differences observed in the DG and CA4 regions.

  15. Changes in expression of BDNF and its receptors TrkB and p75NTR in the hippocampus of a dog model of chronic alcoholism and abstinence.

    Science.gov (United States)

    Xu, R; Duan, S R; Zhao, J W; Wang, C Y

    2015-08-01

    Chronic ethanol consumption can produce learning and memory deficits. Brain-derived neurotrophic factor (BDNF) and its receptors affect the pathogenesis of alcoholism. In this study, we examined the expression of BDNF, tropomyosin receptor kinase B (TrkB) and p75 neurotrophin receptor (p75NTR) in the hippocampus of a dog model of chronic alcoholism and abstinence. Twenty domestic dogs (9-10 months old, 15-20 kg; 10 males and 10 females) were obtained from Harbin Medical University. A stable alcoholism model was established through ad libitum feeding, and anti-alcohol drug treatment (Zhong Yao Jie Jiu Ling, the main ingredient was the stems of watermelon; developed in our laboratory), at low- and high-doses, was carried out. The Zhong Yao Jie Jiu Ling was effective for the alcoholism in dogs. The morphology of hippocampal neurons was evaluated using hematoxylin-eosin staining. The number and morphological features of BDNF, TrkB and p75NTR-positive neurons in the dentate gyrus (DG), and the CA1, CA3 and CA4 regions of the hippocampus were observed using immunohistochemistry. One-way ANOVA was used to determine differences in BDNF, TrkB and p75NTR expression. BDNF, TrkB and p75NTR-positive cells were mainly localized in the granular cell layer of the DG and in the pyramidal cell layer of the CA1, CA3 and CA4 regions (DG>CA1>CA3>CA4). Expression levels of both BDNF and TrkB were decreased in chronic alcoholism, and increased after abstinence. The CA4 region appeared to show the greatest differences. Changes in p75NTR expression were the opposite of those of BDNF and TrkB, with the greatest differences observed in the DG and CA4 regions.

  16. Changes in expression of BDNF and its receptors TrkB and p75NTR in the hippocampus of a dog model of chronic alcoholism and abstinence

    Directory of Open Access Journals (Sweden)

    R. Xu

    2015-08-01

    Full Text Available Chronic ethanol consumption can produce learning and memory deficits. Brain-derived neurotrophic factor (BDNF and its receptors affect the pathogenesis of alcoholism. In this study, we examined the expression of BDNF, tropomyosin receptor kinase B (TrkB and p75 neurotrophin receptor (p75NTR in the hippocampus of a dog model of chronic alcoholism and abstinence. Twenty domestic dogs (9-10 months old, 15-20 kg; 10 males and 10 females were obtained from Harbin Medical University. A stable alcoholism model was established through ad libitum feeding, and anti-alcohol drug treatment (Zhong Yao Jie Jiu Ling, the main ingredient was the stems of watermelon; developed in our laboratory, at low- and high-doses, was carried out. The Zhong Yao Jie Jiu Ling was effective for the alcoholism in dogs. The morphology of hippocampal neurons was evaluated using hematoxylin-eosin staining. The number and morphological features of BDNF, TrkB and p75NTR-positive neurons in the dentate gyrus (DG, and the CA1, CA3 and CA4 regions of the hippocampus were observed using immunohistochemistry. One-way ANOVA was used to determine differences in BDNF, TrkB and p75NTR expression. BDNF, TrkB and p75NTR-positive cells were mainly localized in the granular cell layer of the DG and in the pyramidal cell layer of the CA1, CA3 and CA4 regions (DG>CA1>CA3>CA4. Expression levels of both BDNF and TrkB were decreased in chronic alcoholism, and increased after abstinence. The CA4 region appeared to show the greatest differences. Changes in p75NTR expression were the opposite of those of BDNF and TrkB, with the greatest differences observed in the DG and CA4 regions.

  17. Striatal modulation of BDNF expression using microRNA124a-expressing lentiviral vectors impairs ethanol-induced conditioned-place preference and voluntary alcohol consumption.

    Science.gov (United States)

    Bahi, Amine; Dreyer, Jean-Luc

    2013-07-01

    Alcohol abuse is a major health, economic and social concern in modern societies, but the exact molecular mechanisms underlying ethanol addiction remain elusive. Recent findings show that small non-coding microRNA (miRNA) signaling contributes to complex behavioral disorders including drug addiction. However, the role of miRNAs in ethanol-induced conditioned-place preference (CPP) and voluntary alcohol consumption has not yet been directly addressed. Here, we assessed the expression profile of miR124a in the dorsal striatum of rats upon ethanol intake. The results show that miR124a was downregulated in the dorso-lateral striatum (DLS) following alcohol drinking. Then, we identified brain-derived neurotrophic factor (BDNF) as a direct target of miR124a. In fact, BDNF mRNA was upregulated following ethanol drinking. We used lentiviral vector (LV) gene transfer technology to further address the role of miR124a and its direct target BDNF in ethanol-induced CPP and alcohol consumption. Results reveal that stereotaxic injection of LV-miR124a in the DLS enhances ethanol-induced CPP as well as voluntary alcohol consumption in a two-bottle choice drinking paradigm. Moreover, miR124a-silencer (LV-siR124a) as well as LV-BDNF infusion in the DLS attenuates ethanol-induced CPP as well as voluntary alcohol consumption. Importantly, LV-miR124a, LV-siR124a and LV-BDNF have no effect on saccharin and quinine intake. Our findings indicate that striatal miR124a and BDNF signaling have crucial roles in alcohol consumption and ethanol conditioned reward.

  18. Disruption of the brain-derived neurotrophic factor (BDNF immunoreactivity in the human Kölliker-Fuse nucleus in victims of unexplained fetal and infant death

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    Anna Maria Lavezzi

    2014-09-01

    Full Text Available Experimental studies have demonstrated that the neurotrophin brain-derived neutrophic factor (BDNF is required for the appropriate development of the central respiratory network, a neuronal complex in the brainstem of vital importance to sustaining life. The pontine Kölliker-Fuse nucleus (KFN is a fundamental component of this circuitry with strong implications in the pre- and postnatal breathing control. This study provides detailed account for the cytoarchitecture, the physiology and the BDNF behaviour of the human KFN in perinatal age. We applied immunohistochemistry in formalin-fixed and paraffin-embedded brainstem samples (from 45 fetuses and newborns died of both known and unknown causes, to analyze BDNF, gliosis and apoptosis patterns of manifestation. The KFN showed clear signs of developmental immaturity, prevalently associated to BDNF altered expression, in high percentages of sudden intrauterine unexplained death syndrome (SIUDS and sudden infant death syndrome (SIDS victims. Our results indicate that BDNF pathway dysfunctions can derange the normal KFN development so preventing the breathing control in the sudden perinatal death.The data presented here are also relevant to a better understanding of how the BDNF expression in the KFN can be involved in several human respiratory pathologies such as the Rett’s and the congenital central hypoventilation syndromes.

  19. Brain derived neurotrophic factor

    DEFF Research Database (Denmark)

    Mitchelmore, Cathy; Gede, Lene

    2014-01-01

    Brain Derived Neurotrophic Factor (BDNF) is a neurotrophin with important functions in neuronal development and neuroplasticity. Accumulating evidence suggests that alterations in BDNF expression levels underlie a variety of psychiatric and neurological disorders. Indeed, BDNF therapies are curre......Brain Derived Neurotrophic Factor (BDNF) is a neurotrophin with important functions in neuronal development and neuroplasticity. Accumulating evidence suggests that alterations in BDNF expression levels underlie a variety of psychiatric and neurological disorders. Indeed, BDNF therapies...

  20. BDNF in sleep, insomnia, and sleep deprivation.

    Science.gov (United States)

    Schmitt, Karen; Holsboer-Trachsler, Edith; Eckert, Anne

    2016-01-01

    The protein brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors involved in plasticity of neurons in several brain regions. There are numerous evidence that BDNF expression is decreased by experiencing psychological stress and that, accordingly, a lack of neurotrophic support causes major depression. Furthermore, disruption in sleep homeostatic processes results in higher stress vulnerability and is often associated with stress-related mental disorders. Recently, we reported, for the first time, a relationship between BDNF and insomnia and sleep deprivation (SD). Using a biphasic stress model as explanation approach, we discuss here the hypothesis that chronic stress might induce a deregulation of the hypothalamic-pituitary-adrenal system. In the long-term it leads to sleep disturbance and depression as well as decreased BDNF levels, whereas acute stress like SD can be used as therapeutic intervention in some insomniac or depressed patients as compensatory process to normalize BDNF levels. Indeed, partial SD (PSD) induced a fast increase in BDNF serum levels within hours after PSD which is similar to effects seen after ketamine infusion, another fast-acting antidepressant intervention, while traditional antidepressants are characterized by a major delay until treatment response as well as delayed BDNF level increase. Key messages Brain-derived neurotrophic factor (BDNF) plays a key role in the pathophysiology of stress-related mood disorders. The interplay of stress and sleep impacts on BDNF level. Partial sleep deprivation (PSD) shows a fast action on BDNF level increase.

  1. Plasma levels of mature brain-derived neurotrophic factor (BDNF) and matrix metalloproteinase-9 (MMP-9) in treatment-resistant schizophrenia treated with clozapine.

    Science.gov (United States)

    Yamamori, Hidenaga; Hashimoto, Ryota; Ishima, Tamaki; Kishi, Fukuko; Yasuda, Yuka; Ohi, Kazutaka; Fujimoto, Michiko; Umeda-Yano, Satomi; Ito, Akira; Hashimoto, Kenji; Takeda, Masatoshi

    2013-11-27

    Brain-derived neurotrophic factor (BDNF) regulates the survival and growth of neurons, and influences synaptic efficiency and plasticity. Peripheral BDNF levels in patients with schizophrenia have been widely reported in the literature. However, it is still controversial whether peripheral levels of BDNF are altered in patients with schizophrenia. The peripheral BDNF levels previously reported in patients with schizophrenia were total BDNF (proBDNF and mature BDNF) as it was unable to specifically measure mature BDNF due to limited BDNF antibody specificity. In this study, we examined whether peripheral levels of mature BDNF were altered in patients with treatment-resistant schizophrenia. Matrix metalloproteinase-9 (MMP-9) levels were also measured, as MMP-9 plays a role in the conversion of proBDNF to mature BDNF. Twenty-two patients with treatment-resistant schizophrenia treated with clozapine and 22 age- and sex-matched healthy controls were enrolled. The plasma levels of mature BDNF and MMP-9 were measured using ELISA kits. No significant difference was observed for mature BDNF however, MMP-9 was significantly increased in patients with schizophrenia. The significant correlation was observed between mature BDNF and MMP-9 plasma levels. Neither mature BDNF nor MMP-9 plasma levels were associated clinical variables. Our results do not support the view that peripheral BDNF levels are associated with schizophrenia. MMP-9 may play a role in the pathophysiology of schizophrenia and serve as a biomarker for schizophrenia.

  2. Effects of chronic forced swim stress on hippocampal brain-derived neutrophic factor (BDNF) and its receptor (TrkB) immunoreactive cells in juvenile and aged rats.

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    Badowska-Szalewska, Ewa; Spodnik, Edyta; Klejbor, Ilona; Morys, Janusz

    2010-01-01

    A type of stress stimulation and age are claimed to affect the expression of brain-derived neurotrophic factor (BDNF) and its receptor - tyrosine kinase B (TrkB) in the hippocampal regions differentially. This study aimed to explore the influence of chronic (15 min daily for 21 days) forced swim stress (FS) exposure on the BDNF and TrkB containing neurons in the hippocampal CA1, CA3 pyramidal cell layers and dentate gyrus (DG) granule cell layer in juvenile (P28) and aged (P360) rats. An immunofluorescence (-ir) method was used to detect BDNF-ir and TrkB-ir cells. Under chronic FS exposure, in the group of juvenile rats a significant decrease in the density of BDNF immunoreactive neurons was observed in CA1 and DG (P less than CA3, where it remained unaltered just as the density of TrkB-ir cells in CA1 and DG, but in CA3 the number of TrkB-ir cells was found to grow (P less than 0.05) in comparison with control groups. After chronic FS exposure of aged (P360) rats, the density of BDNF-ir and TrkB-ir cells did not decline in any of the subregions of the hippocampus. In all subfields of the hippocampus, the denseness of BDNF-positive neurons was significantly higher in P360 stressed group, compared with P28 stressed group, but the density of TrkB-ir fell more markedly in P360 than in P28. In conclusion, chronic FS stress influenced the number of BDNF and TrkB immunoreactive neurons only in juvenile animals. The age of rats tested in the chronic forced swim test was a decisive factor determining changes in the density of BDNF-ir and TrkB-ir in the hippocampal structures.

  3. Involvement of brain-derived neurotrophic factor (BDNF) in MP4-induced autoimmune encephalomyelitis.

    Science.gov (United States)

    Javeri, Sita; Rodi, Michael; Tary-Lehmann, Magdalena; Lehmann, Paul V; Addicks, Klaus; Kuerten, Stefanie

    2010-11-01

    The role of brain-derived neurotrophic factor (BDNF) in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) is still unclear. Here we investigate the clinical course, CNS histopathology and peripheral antigen-specific immunity in MP4-induced EAE of BDNF (-/+) mice. We demonstrate that these mice displayed less severe disease compared to BDNF (+/+) mice, reflected by decreased inflammation and demyelination. In correspondence to diminished frequencies of T and B cells in CNS infiltrates, the peripheral MP4-specific T(H)1/T(H)17 response was attenuated in BDNF (-/+), but not in wild-type animals. In contrast, immunization with ovalbumin triggered similar frequencies of IFN-γ- and IL-17-secreting T cells in both groups. The cytokine secretion and proliferative activity upon mitogen stimulation did not reveal any global defect of T cell function in BDNF (-/+) mice. By influencing the antigen-specific immune response in autoimmune encephalomyelitis, BDNF may support and maintain the disease in ways that go beyond its alleged neuroprotective role.

  4. Essential Role for Vav GEFs in Brain-derived Neurotrophic Factor (BDNF)-induced Dendritic Spine Growth and Synapse Plasticity

    OpenAIRE

    Hale, Carly F.; Dietz, Karen C.; Varela, Juan A.; Wood, Cody B.; Zirlin, Benjamin C.; Leah S. Leverich; Greene, Robert W.; Cowan, Christopher W.

    2011-01-01

    Brain-derived neurotrophic factor (BDNF) and its cognate receptor, TrkB, regulate a wide range of cellular processes, including dendritic spine formation and functional synapse plasticity. However, the signaling mechanisms that link BDNF-activated TrkB to F-actin remodeling enzymes and dendritic spine morphological plasticity remain poorly understood. We report here that BDNF/TrkB signaling in neurons activates the Vav family of Rac/RhoA guanine nucleotide exchange factors (GEFs) through a no...

  5. Effects of Duloxetine Treatment on Cognitive Flexibility and BDNF Expression in the mPFC of Adult Male Mice Exposed to Social Stress during Adolescence

    Science.gov (United States)

    Xu, Hang; Zhang, Yu; Zhang, Fan; Yuan, San-na; Shao, Feng; Wang, Weiwen

    2016-01-01

    Early stress is a significant risk factor for the onset of mood disorders such as depression during adulthood. Impairments in cognitive flexibility mediated by prefrontal cortex (PFC) dysfunction are increasingly recognized as important etiological and pathological factors in the development of depression. Our previous study demonstrated that social defeat stress during early adolescence produced delayed deficits in cognitive flexibility in adult mice. The potential molecular mechanisms underlying these long-term consequences remain unclear. One candidate molecule is brain-derived neurotrophic factor (BDNF), which plays a vital role in neural development and synaptic plasticity. In this study, we initially examined the effects of adolescent social stress on cognitive flexibility and PFC BDNF expression within a week after the last stress exposure and 6 weeks later during adulthood. Adolescent (PND 28) male mice were subjected to stress or control manipulation for 10 days. The attentional set-shifting task (AST) was used to assess cognitive flexibility. Levels of BDNF mRNA and protein in the PFC were examined after behavioral testing. The results demonstrated that previously stressed mice exhibited delayed extra-dimensional set-shifting deficits in AST when tested as adults but not when tested as adolescents. Consistent with the cognitive alterations, adolescent stress induced dynamic alterations in BDNF expression in the medial PFC (mPFC), with a transient increase observed shortly after the stress, followed by a decrease 6 weeks later during adulthood. Next, we further determined the effects of chronic treatment with the antidepressant duloxetine during early adulthood on cognitive and molecular alterations induced by adolescent stress. Compared with the controls, duloxetine treatment reversed the cognitive deficits and increased the BDNF protein expression in the mPFC during adulthood in previously stressed mice. These findings demonstrated that BDNF expression

  6. Social isolation mediated anxiety like behavior is associated with enhanced expression and regulation of BDNF in the female mouse brain.

    Science.gov (United States)

    Kumari, Anita; Singh, Padmanabh; Baghel, Meghraj Singh; Thakur, M K

    2016-05-01

    Adverse early life experience is prominent risk factors for numerous psychiatric illnesses, including mood and anxiety disorders. It imposes serious long-term costs on the individual as well as health and social systems. Hence, developing therapies that prevent the long-term consequences of early life stress is of utmost importance, and necessitates a better understanding of the mechanisms by which early life stress triggers long-lasting alterations in gene expression and behavior. Post-weaning isolation rearing of rodents models the behavioral consequences of adverse early life experiences in humans and it is reported to cause anxiety like behavior which is more common in case of females. Therefore, in the present study, we have studied the impact of social isolation of young female mice for 8weeks on the anxiety like behavior and the underlying molecular mechanism. Elevated plus maze and open field test revealed that social isolation caused anxiety like behavior. BDNF, a well-known molecule implicated in the anxiety like behavior, was up-regulated both at the message and protein level in cerebral cortex by social isolation. CREB-1 and CBP, which play a crucial role in BDNF transcription, were up-regulated at mRNA level in cerebral cortex by social isolation. HDAC-2, which negatively regulates BDNF expression, was down-regulated at mRNA and protein level in cerebral cortex by social isolation. Furthermore, BDNF acts in concert with Limk-1, miRNA-132 and miRNA-134 for the regulation of structural and morphological plasticity. Social isolation resulted in up-regulation of Limk-1 mRNA and miRNA-132 expression in the cerebral cortex. MiRNA-134, which inhibits the translation of Limk-1, was decreased in cerebral cortex by social isolation. Taken together, our study suggests that social isolation mediated anxiety like behavior is associated with up-regulation of BDNF expression and concomitant increase in the expression of CBP, CREB-1, Limk-1 and miRNA-132, and decrease

  7. Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism affects sympathetic tone in a gender-specific way.

    Science.gov (United States)

    Chang, Chuan-Chia; Chang, Hsin-An; Chen, Tien-Yu; Fang, Wen-Hui; Huang, San-Yuan

    2014-09-01

    The Val/Val genotype of the brain-derived neurotrophic factor (BDNF) polymorphism (Val66Met) has been reported to affect human anxiety-related phenotypes. Substantial research has demonstrated that anxiety is associated with sympathetic activation, while sex steroid hormones have been shown to exert differential actions in regulating BDNF expression. Thus, we examined whether the BDNF variant modulates autonomic function in a gender-dependent manner. From 708 adults initially screened for medical and psychiatric illnesses, a final cohort of 583 drug-free healthy Han Chinese (355 males, 228 females; age 34.43±8.42 years) was recruited for BDNF genotyping (Val/Val: 136, 23.3%, Val/Met: 294, 50.4%, and Met/Met: 153, 26.2%). Time- and frequency-domain analyses of heart rate variability (HRV) were used to assess autonomic outflow to the heart. Significant genotype-by-gender interaction effects were found on HRV indices. Even after adjusting for possible confounders, male participants bearing the Val/Val genotype had significant increases in low frequency (LF), LF% and LF/high frequency (HF) ratio, indicating altered sympathovagal balance with increased sympathetic modulation, compared to male Met/Met homozygotes. Females, however, showed an opposite but non-significant pattern. These results suggest that the studied BDNF polymorphism is associated with sympathetic control in a gender-specific way. The findings here support the view that male subjects with the Val/Val genotype have increased risk of anxiety by association with sympathetic activation.

  8. Elevated IKKα accelerates the differentiation of human neuronal progenitor cells and induces MeCP2-dependent BDNF expression.

    Directory of Open Access Journals (Sweden)

    Ali Khoshnan

    Full Text Available The IκB kinase α (IKKα is implicated in the differentiation of epithelial and immune cells. We examined whether IKKα also plays a role in the differentiation and maturation of embryonic human neuronal progenitor cells (NPCs. We find that expression of an extra copy of IKKα (IKKα+ blocks self-renewal and accelerates the differentiation of NPCs. This coincides with reduced expression of the Repressor Element Silencing Transcription Factor/Neuron-Restrictive Silencing Factor (REST/NRSF, which is a prominent inhibitor of neurogenesis, and subsequent induction of the pro-differentiation non-coding RNA, miR-124a. However, the effects of IKKα on REST/NRSF and miR-124a expression are likely to be indirect. IKKα+ neurons display extensive neurite outgrowth and accumulate protein markers of neuronal maturation such as SCG10/stathmin-2, postsynaptic density 95 (PSD95, syntaxin, and methyl-CpG binding protein 2 (MeCP2. Interestingly, IKKα associates with MeCP2 in the nuclei of human neurons and can phosphorylate MeCP2 in vitro. Using chromatin immunoprecipitation assays, we find that IKKα is recruited to the exon-IV brain-derived neurotrophic factor (BDNF promoter, which is a well-characterized target of MeCP2 activity. Moreover, IKKα induces the transcription of BDNF and knockdown expression of MeCP2 interferes with this event. These studies highlight a role for IKKα in accelerating the differentiation of human NPCs and identify IKKα as a potential regulator of MeCP2 function and BDNF expression.

  9. Regulation of brain-derived neurotrophic factor (BDNF) in the chronic unpredictable stress rat model and the effects of chronic antidepressant treatment.

    Science.gov (United States)

    Larsen, Marianne H; Mikkelsen, Jens D; Hay-Schmidt, Anders; Sandi, Carmen

    2010-10-01

    Chronic unpredictable stress (CUS) is a widely used animal model of depression. The present study was undertaken to investigate behavioral, physiological and molecular effects of CUS and/or chronic antidepressant treatment (venlafaxine or imipramine) in the same set of animals. Anhedonia, a core symptom of depression, was assessed by measuring consumption of a palatable solution. Exposure to CUS reduced intake of a palatable solution and this effect was prevented by chronic antidepressant treatment. Moreover, chronic antidepressant treatment decreased depressive-like behavior in a modified forced swim test in stressed rats. Present evidence suggests a role for brain-derived neurotrophic factor (BDNF) in depression. BDNF mRNA levels in the ventral and dorsal hippocampus were assessed by in situ hybridization. Exposure to CUS was not correlated with a decrease but rather with an increase in BDNF mRNA expression in both the dentate gyrus of the dorsal hippocampus and the CA3 region of the ventral hippocampus indicating that there is no simple link between depression-like behaviors per se and brain BDNF levels in rats. However, a significant increase in BDNF mRNA levels in the dentate gyrus of the dorsal hippocampus correlated with chronic antidepressant treatment emphasizing a role for BDNF in the mechanisms underlying antidepressant activity.

  10. Reduced expression of brain-derived neurotrophic factor protein in Parkinson's disease substantia nigra.

    Science.gov (United States)

    Parain, K; Murer, M G; Yan, Q; Faucheux, B; Agid, Y; Hirsch, E; Raisman-Vozari, R

    1999-02-25

    Several in vitro and in vivo studies have shown that brain-derived neurotrophic factor (BDNF) promotes survival of damaged mesencephalic dopaminergic neurons. Using a specific antibody directed against human recombinant BDNF, we studied the expression of the protein at the cellular level in the post-mortem mesencephalon of control subjects and patients with Parkinson's disease (PD). In control subjects, BDNF was expressed in all mesencephalic regions containing dopaminergic neurons, and in the substantia nigra pars compacta (SNpc) 65% of the melanized neurons expressed BDNF. In the PD SNpc, the total number of pigmented neurons containing BDNF was reduced to 9.6% of the corresponding control value. In contrast, the number of pigmented neurons non-immunoreactive for BDNF was reduced to 23.9% of the corresponding control value. This result appears to indicate that SNpc melanized neurons not expressing BDNF have a 2.5-fold greater probability of surviving than BDNF-positive melanized neurons. Furthermore, we found that in parkinsonian mesencephalon almost all dopaminergic neurons containing Lewy bodies were immunoreactive for BDNF. These findings demonstrate a reduced expression of BDNF in PD and suggest that BDNF protein expression does not protect melanized SNpc neurons from the degenerative process in this disease.

  11. Effect of dehydroepiandrosterone (DHEA) on memory and brain derived neurotrophic factor (BDNF) in a rat model of vascular dementia.

    Science.gov (United States)

    Sakr, H F; Khalil, K I; Hussein, A M; Zaki, M S A; Eid, R A; Alkhateeb, M

    2014-02-01

    The effect of dehydroepiandrosterone (DHEA) on memory and cognition in experimental animals is well known, but its efficacy in clinical dementia is unproven. So, the aim of the present study was to investigate the effect of DHEA on learning and memory activities in a rat model of vascular dementia (VD). Forty-eight male rats that positively passed the holeboard memory test were chosen for the study before bilateral permanent occlusion of the common carotid artery. They were divided into four groups (n=12, each) as follows (i) untreated control, (ii) rats exposed to surgical permanent bilateral occlusion of the common carotid arteries (BCCAO) leading to chronic cerebral hypoperfusion, (iii) rats exposed to BCCAO then received DHEA (BCCAO + DHEA) and (i.v.) rats exposed to BCCAO then received donepezil (BCCAO + DON). Holeboard memory test was used to assess the time, latency, working memory and reference memory. Central level of acetylcholine, norepinephrine and dopamine in the hippocampus were measured. Furthermore, the expression of brain derived neurotrophic factor (BDNF) in the hippocampus was determined. Histopathological studies of the cerebral cortex and transmission electron microscope of the hippocampus were performed. BCCAO decreased the learning and memory activities in the holeboard memory. Also, it decreased the expression of BDNF as well as the central level of acetylcholine, noradrenaline and dopamine as compared to control rats. Treatment with DHEA and donepezil increased the working and reference memories, BDNF expression as well as the central acetylcholine in the hippocampus as compared to BCCAO rats. DHEA produced neuroprotective effects through increasing the expression of BDNF as well as increasing the central level of acetylcholine and catecholamines which are non-comparable to donepezil effects.

  12. The role of brain-derived neurotrophic factor (BDNF) in the development of neurogenic detrusor overactivity (NDO).

    Science.gov (United States)

    Frias, Bárbara; Santos, João; Morgado, Marlene; Sousa, Mónica Mendes; Gray, Susannah M Y; McCloskey, Karen D; Allen, Shelley; Cruz, Francisco; Cruz, Célia Duarte

    2015-02-04

    Neurogenic detrusor overactivity (NDO) is a well known consequence of spinal cord injury (SCI), recognizable after spinal shock, during which the bladder is areflexic. NDO emergence and maintenance depend on profound plastic changes of the spinal neuronal pathways regulating bladder function. It is well known that neurotrophins (NTs) are major regulators of such changes. NGF is the best-studied NT in the bladder and its role in NDO has already been established. Another very abundant neurotrophin is BDNF. Despite being shown that, acting at the spinal cord level, BDNF is a key mediator of bladder dysfunction and pain during cystitis, it is presently unclear if it is also important for NDO. This study aimed to clarify this issue. Results obtained pinpoint BDNF as an important regulator of NDO appearance and maintenance. Spinal BDNF expression increased in a time-dependent manner together with NDO emergence. In chronic SCI rats, BDNF sequestration improved bladder function, indicating that, at later stages, BDNF contributes NDO maintenance. During spinal shock, BDNF sequestration resulted in early development of bladder hyperactivity, accompanied by increased axonal growth of calcitonin gene-related peptide-labeled fibers in the dorsal horn. Chronic BDNF administration inhibited the emergence of NDO, together with reduction of axonal growth, suggesting that BDNF may have a crucial role in bladder function after SCI via inhibition of neuronal sprouting. These findings highlight the role of BDNF in NDO and may provide a significant contribution to create more efficient therapies to manage SCI patients.

  13. Oligomeric amyloid-{beta} inhibits the proteolytic conversion of brain-derived neurotrophic factor (BDNF), AMPA receptor trafficking, and classical conditioning.

    Science.gov (United States)

    Zheng, Zhaoqing; Sabirzhanov, Boris; Keifer, Joyce

    2010-11-01

    Amyloid-β (Aβ) peptide is thought to have a significant role in the progressive memory loss observed in patients with Alzheimer disease and inhibits synaptic plasticity in animal models of learning. We previously demonstrated that brain-derived neurotrophic factor (BDNF) is critical for synaptic AMPA receptor delivery in an in vitro model of eyeblink classical conditioning. Here, we report that acquisition of conditioned responses was significantly attenuated by bath application of oligomeric (200 nm), but not fibrillar, Aβ peptide. Western blotting revealed that BDNF protein expression during conditioning is significantly reduced by treatment with oligomeric Aβ, as were phosphorylation levels of cAMP-response element-binding protein (CREB), Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), Ca(2+)/calmodulin-dependent protein kinase IV (CaMKIV), and ERK. However, levels of PKA and PKCζ/λ were unaffected, as was PDK-1. Protein localization studies using confocal imaging indicate that oligomeric Aβ, but not fibrillar or scrambled forms, suppresses colocalization of GluR1 and GluR4 AMPA receptor subunits with synaptophysin, indicating that trafficking of these subunits to synapses during the conditioning procedure is blocked. In contrast, coapplication of BDNF with oligomeric Aβ significantly reversed these findings. Interestingly, a tolloid-like metalloproteinase in turtle, tTLLs (turtle tolloid-like protein), which normally processes the precursor proBDNF into mature BDNF, was found to degrade oligomeric Aβ into small fragments. These data suggest that an Aβ-induced reduction in BDNF, perhaps due to interference in the proteolytic conversion of proBDNF to BDNF, results in inhibition of synaptic AMPA receptor delivery and suppression of the acquisition of conditioning.

  14. Increased serum brain-derived neurotrophic factor (BDNF) levels in patients with narcolepsy

    DEFF Research Database (Denmark)

    Klein, Anders B; Jennum, Poul; Knudsen, Stine

    2013-01-01

    in hypocretin neurons in hypothalamus in post-mortem tissue. Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are important for activity-dependent neuronal function and synaptic modulation and it is considered that these mechanisms are important in sleep regulation. We hypothesised......Narcolepsy is a lifelong sleep disorder characterized by excessive daytime sleepiness, sudden loss of muscle tone (cataplexy), fragmentation of nocturnal sleep and sleep paralysis. The symptoms of the disease strongly correlate with a reduction in hypocretin levels in CSF and a reduction...... that serum levels of these factors are altered in patients with narcolepsy compared to healthy controls without sleep disturbances. Polysomnography data was obtained and serum BDNF and NGF levels measured using ELISA, while hypocretin was measured using RIA. Serum BDNF levels were significantly higher...

  15. Expression and physiological regulation of BDNF receptors in the neuroendocrine melanotrope cell of Xenopus laevis

    NARCIS (Netherlands)

    Kidane, A.H.; Dooren, S.H. van; Roubos, E.W.; Jenks, B.G.

    2007-01-01

    Brain-derived neurotrophic factor (BDNF) and alpha-melanophore-stimulating hormone (alpha-MSH) are co-sequestered in secretory granules in melanotrope cells of the pituitary pars intermedia of the amphibian Xenopus laevis. alpha-MSH is responsible for pigment dispersion in dermal melanophores during

  16. Sex and stress hormone influences on the expression and activity of brain-derived neurotrophic factor.

    Science.gov (United States)

    Carbone, D L; Handa, R J

    2013-06-03

    The neurotrophin, brain-derived neurotrophic factor (BDNF), is recognized as a key component in the regulation of CNS ontogeny, homeostasis and adult neuroplasticity. The importance of BDNF in CNS development and function is well documented by numerous reports from animal studies linking abnormal BDNF signaling to metabolic disturbances and anxiety or depressive-like behavior. Despite the diverse roles for BDNF in nearly all aspects of CNS physiology, the regulation of BDNF expression, as well as our understanding of the signaling mechanisms associated with this neurotrophin, remains incomplete. However, links between sex hormones such as estradiol and testosterone, as well as endogenous and synthetic glucocorticoids (GCs), have emerged as important mediators of BDNF expression and function. Examples of such regulation include brain region-specific induction of Bdnf mRNA in response to estradiol. Additional studies have also documented regulation of the expression of the high-affinity BDNF receptor Tropomyosin-Related Kinase B by estradiol, thus implicating sex steroids not only in the regulation of BDNF expression, but also in mechanisms of signaling associated with it. In addition to gonadal steroids, further evidence also suggests functional interaction between BDNF and GCs, such as in the regulation of corticotrophin-releasing hormone and other important neuropeptides. In this review, we provide an overview of the roles played by selected sex or stress hormones in the regulation of BDNF expression and signaling in the CNS.

  17. Changes in expression of BDNF and its receptors TrkB and p75NTR in the hippocampus of a dog model of chronic alcoholism and abstinence

    OpenAIRE

    Xu, R.; S.R. Duan; Zhao, J.W.; Wang, C Y

    2015-01-01

    Chronic ethanol consumption can produce learning and memory deficits. Brain-derived neurotrophic factor (BDNF) and its receptors affect the pathogenesis of alcoholism. In this study, we examined the expression of BDNF, tropomyosin receptor kinase B (TrkB) and p75 neurotrophin receptor (p75NTR) in the hippocampus of a dog model of chronic alcoholism and abstinence. Twenty domestic dogs (9-10 months old, 15-20 kg; 10 males and 10 females) were obtained from Harbin Medical University. A stable a...

  18. BDNF and trkB mRNA expression in the rat hippocampus following entorhinal cortex lesions.

    Science.gov (United States)

    Lapchak, P A; Araujo, D M; Hefti, F

    1993-02-01

    Quantitative in situ hybridization was used to determine whether the prevalence or topographical distribution of brain-derived neurotrophic factor (BDNF) or tyrosine receptor kinase (trk) B mRNA is altered in the hippocampal formation following lesions of excitatory afferents from the entorhinal cortex which provides an external source of innervation for the hippocampal formation. BDNF mRNA levels were not altered in the hippocampal formation up to 10 days following entorhinal cortex lesions (ECLs). The levels of mRNA coding for all known forms of trkB receptors also remained unchanged. The prevalence of the synaptic plasticity marker SNAP-25 mRNA was increased in the CA2 and CA3 pyramidal cell layers and the dentate gyrus by 6 days following ECLs and remained elevated at 10 days following ECLs. Our findings indicate that hippocampal neuron sprouting which occurs in response to ECLs is not the result of changes in the expression of the BDNF or trkB mRNA.

  19. Tranquilizing and Allaying Excitement Needling Method Affects BDNF and SYP Expression in Hippocampus

    Directory of Open Access Journals (Sweden)

    Peng Zheng

    2017-01-01

    Full Text Available Sleep disorder is a state of sleep loss caused by various reasons, which leads to a series of changes, such as emotion, learning and memory, and immune function. “Tranquilizing and allaying excitement” was widely used in clinical treatment of insomnia; however, the mechanism was still not very clear. We randomly divided rats into three groups: control group, sleep deprivation group, and acupuncture treatment group. We observed BDNF and SYP expression in hippocampus in these three groups. Both protein contents and mRNA contents of BDNF and SYP were measured by western blot, immunohistochemistry, and RT-PCR analysis. The sleep deprivation model was established using modified multiple platform sleep deprivation method (MMPM. Our study explored the BDNF and SYP abnormality in hippocampus caused by sleep deprivation and “tranquilizing and allaying excitement” intervention regulated the abnormal expression of BDNF and SYP caused by sleep deprivation on the short run and the long run. Our study provided a molecular evidence that “tranquilizing and allaying excitement” treatment in rats with sleep disorder affects learning and memory ability.

  20. Combined neonatal stress and young-adult glucocorticoid stimulation in rats reduce BDNF expression in hippocampus: effects on learning and memory.

    Science.gov (United States)

    Choy, Kwok Ho Christopher; de Visser, Yvonne; Nichols, Nancy R; van den Buuse, Maarten

    2008-01-01

    Epidemiological studies suggest that multiple developmental disruptions are involved in the etiology of psychiatric illnesses including schizophrenia. In addition, altered expression of brain-derived neurotrophic factor (BDNF) has been implicated in these illnesses. In the present study, we examined the combined long-term effect of an early stress, in the form of maternal deprivation, and a later stress, simulated by chronic young-adult treatment with the stress hormone, corticosterone, on BDNF expression in the hippocampus of rats. To assess whether there were behavioral effects, which may correlate with the BDNF changes, learning and memory was tested in the Y-maze test for short term spatial memory, the Morris water maze for long-term spatial memory, and the T-maze test for working memory. Four groups of rats received either no stress, maternal deprivation, corticosterone treatment, or both. Dorsal hippocampus sections obtained from parallel groups were used for BDNF mRNA in situ hybridization. Rats which had undergone both maternal deprivation and corticosterone treatment displayed a unique and significant 25-35% reduction of BDNF expression in the dentate gyrus (DG), and similar trends in the CA1 and CA3 regions of the hippocampus. These "two-hit" animals exhibited a learning delay in the Morris water maze test, a marked deficit in the Y-maze, but little change in the T-maze test. However, some aspects of cognition were also altered in rats with either maternal deprivation or corticosterone treatment. This study demonstrates a persistent effect of two developmental disruptions on BDNF expression in the hippocampus, with parallel, but not completely correlative changes in learning and memory.

  1. Modulation of c-Fos and BDNF Protein Expression in Pentylenetetrazole-Kindled Mice following the Treatment with Novel Antiepileptic Compound HHL-6

    Directory of Open Access Journals (Sweden)

    Saima Mahmood Malhi

    2014-01-01

    Full Text Available Brain-derived neurotrophic factor (BDNF and c-Fos are shown to promote epileptogenesis and are taken as a marker of neuronal activity. The present study investigated the expression of BDNF and c-Fos in mice brain with pentylenetetrazol- (PTZ- induced generalized seizure and evaluated the effect of novel tryptamine derivative HHL-6 on the expression of these two markers. The subconvulsive dose of PTZ (50 mg/kg was administered on alternate days in the experimental groups until the seizure scores 4-5 developed in the PTZ-control group. At the end of each experiment, animals were sacrificed, brain samples were collected and cryosectioned, and immunohistochemical analysis of BDNF and c-Fos protein was performed. Data obtained from two sections per mouse (n=12 animals/group is presented as means ± S.E.M. The test compound HHL-6 demonstrated a potent anticonvulsant activity in the PTZ-induced seizure in mice. Significant reduction in the BDNF (P<0.003 and c-Fos (P<0.01 protein expression was observed in the HHL-6 treated group. Based on these results we suggest that one of the possible mechanisms of HHL-6 to inhibit epileptogenesis might be due to its controlling effect on the cellular and molecular expression of the factors that contribute to the development of epileptogenic plasticity in the CNS.

  2. Chronic prenatal stress epigenetically modifies spinal cord BDNF expression to induce sex specific visceral hypersensitivity in offspring

    Science.gov (United States)

    Winston, John H.; Li, Qingjie; Sarna, Sushil K.

    2014-01-01

    Background Irritable bowel syndrome (IBS) is a heterogeneous disorder with abdomen pain as one of the primary symptoms. The etiology of IBS remains unknown. Epidemiological studies found that a subset of these patients have a history of adverse early-life events. We tested the hypothesis that chronic prenatal stress (CPS) epigenetically enhances brain-derived neurotrophic factor (BDNF) in spinal cord to aggravate colon sensitivity to colorectal distension (CRD) differentially in male and female offspring. Methods We used heterotypic intermittent chronic stress (HeICS) protocols in pregnant dams from E11 until delivery. Results CPS induced significant visceral hypersensitivity (VHS) to CRD in male and female offspring. A second exposure to HeICS in adult offspring exacerbated VHS greater in female offspring that persisted longer than in male offspring. CPS upregulated BDNF expression in the lumbar-sacral dorsal horn that correlated with the exacerbation of VHS in female, but not in male offspring. The upregulation of BDNF was due to a significant increase in RNA Pol II binding, histone H3 acetylation and significant decrease in histone deacetylase 1 association with the core promoter of BDNF in female offspring. Other chronic prenatal and neonatal stress protocols were less effective than HeICS. Conclusion & Inferences The development of visceral hypersensitivity, which contributes to the symptom of intermittent abdominal pain, is a two-step process, chronic in utero stress followed by chronic stress in adult-life. This two-step process induces aggravated and persistent colon hypersensitivity in female than in male offspring. Our preclinical model explains several clinical features in IBS patients. PMID:24588943

  3. Association study of a brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and personality trait and intelligence in healthy young females.

    Science.gov (United States)

    Tsai, Shih-Jen; Hong, Chen-Jee; Yu, Younger W-Y; Chen, Tai-Jui

    2004-01-01

    Brain-derived neurotrophic factor (BDNF), a member of the nerve-growth-factor family, plays an important role in neuronal survival and development, and it can modulate serotonergic activity. Further, BDNF has been implicated in the expression of personality traits and in cognitive function. We tested the associations between functional BDNF Val66Met genetic variants, and personality trait and intelligence in a cohort of 114 healthy young Chinese females. Subjects with the Val/Val genotype had a significantly higher mean performance IQ than Val/Met carriers, especially for the Object Assembly subtest. No significant association was demonstrated for the BDNF polymorphism and any of the Tridimensional Personality Questionnaire personality-factor scores, including harm avoidance. These results suggest that genetic variants of the BDNF gene may play a role in specific cognitive functions, but not in overall intelligence. In contrast to a recent report, however, this polymorphism does not appear to be associated with the neuroticism-related personality trait.

  4. Effects of chronic ethanol administration on expression of BDNF and trkB mRNAs in rat hippocampus after experimental brain injury.

    Science.gov (United States)

    Zhang, L; Dhillon, H S; Barron, S; Hicks1, R R; Prasad, R M; Seroogy, K B

    2000-06-23

    Previous evidence indicates that both chronic alcohol treatment and traumatic brain injury modulate expression of certain neurotrophins and neurotrophin receptors in cortical tissue. However, the combined effects of chronic alcohol and brain trauma on expression of neurotrophins and their receptors have not been investigated. In the present study, we examined the effects of 6 weeks of chronic ethanol administration on lateral fluid percussion (FP) brain injury-induced alterations in expression of mRNAs for the neurotrophin brain-derived neurotrophic factor (BDNF) and its high affinity receptor, trkB, in rat hippocampus. In both the control- (pair-fed isocaloric sucrose) diet and the chronic ethanol-diet groups, unilateral FP brain injury induced a bilateral increase in levels of both BDNF and trkB mRNAs in the dentate gyrus granule cell layer, and of BDNF mRNA in hippocampal region CA3. However, no significant differences in expression were found between the control-diet and ethanol-diet groups, in either the sham-injured or FP-injured animals. These findings suggest that 6 weeks of chronic ethanol administration does not alter the plasticity of hippocampal BDNF/trkB expression in response to experimental brain injury.

  5. [Brain-derived neurotrophic factor gene (BDNF) polymorphism among Moscow citizens].

    Science.gov (United States)

    Kokaeva, Z G; Kochetkova, T O; Afonchikova, E V; Kondratyeva, N S; Klimov, E A

    2013-12-01

    Recent studies showed that brain-derived neurotrophic factor (BDNF) can participate in pathogenesis of various CNS disorders, being connected with proliferation, differentiation, and survival of neurons. In present study, analysis of occurrence rate was performed for three single nucleotide polymorphisms (SNPs) located in BDNF gene (rs6267 (A/G) allele A-0.265; rs2049046 (A/T) allele A-0.407; rs11030107 (A/G) allele A-0.872) in randomized selection of Moscow citizens. Linkage disequilibrium of rs6165 and rs2049046 loci was shown. Differences in allele frequencies in studied selection and populations of other re- gions were discovered.

  6. [Expression of BDNF neurotrophin in the hippocampus and neocortex of rats during the development of post-stress anxiety and its correction by hypoxic postconditioning].

    Science.gov (United States)

    Zen'ko, M Yu; Rybnikova, Ye A; Glushchenko, T S

    2014-01-01

    Using quantitative immunohistochemistry, changes in the expression of the BDNF (Brain-Derived Neurotrophic Factor) were studied in the hippocampus and neocortex of 24 male Wistar rats during the development of post-stress-related anxiety state in the experimental model of posttraumatic stress disorder, and its correction by hypoxic postconditioning (PC). For the induction of anxiety state, combined severe psychoemotional stress was applied (immobilization, forced swimming, ether stress followed 7 days later by repeated immobilization - restress). Correction of the anxiety state was achieved by application of hypoxic PC, which included three sessions of mild hypobaric hypoxia (360 mm Hg, 2 h, daily). The formation of the anxiety pathology was accompanied by a significant reduction in the expression of immunoreactive BDNF in dorsal (CA1) and ventral (dentate gyrus) hippocampus and neocortex, while hypoxic PC resulted in partial (hippocampus) or complete (neocortex) restoration of BDNF expression. The results indicate that the neurotrophic factors, and BDNF in particular, seem to play an important role in the pathogenesis of the anxiety-depressive disorders as well as in mechanisms of proadaptive and neuroprotective effects of hypoxic PC.

  7. Anatomical evidence for transsynaptic influences of estrogen on brain-derived neurotrophic factor expression.

    Science.gov (United States)

    Blurton-Jones, M; Kuan, P N; Tuszynski, M H

    2004-01-12

    Several studies have demonstrated that estrogen modulates brain-derived neurotrophic factor (BDNF) mRNA and protein within the adult hippocampus and cortex. However, mechanisms underlying this regulation are unknown. Although an estrogen response element (ERE)-like sequence has been identified within the BDNF gene, such a classical mechanism of estrogen-induced transcriptional activation requires the colocalized expression of estrogen receptors within cells that produce BDNF. Developmental studies have demonstrated such a relationship, but to date no studies have examined colocalization of estrogen receptors and BDNF within the adult brain. By utilizing double-label immunohistochemistry for BDNF, estrogen receptor-alpha (ER-alpha), and estrogen receptor-beta (ER-beta), we found only sparse colocalization between ER-alpha and BDNF in the hypothalamus, amygdala, prelimbic cortex, and ventral hippocampus. Furthermore, ER-beta and BDNF do not colocalize in any brain region. Given the recent finding that cortical ER-beta is almost exclusively localized to parvalbumin-immunoreactive GABAergic neurons, we performed BDNF/parvalbumin double labeling and discovered that axons from cortical ER-beta-expressing inhibitory neurons terminate on BDNF-immunoreactive pyramidal cells. Collectively, these findings support a potential transsynaptic relationship between estrogen state and cortical BDNF: By directly modulating GABAergic interneurons, estrogen may indirectly influence the activity and expression of BDNF-producing cortical neurons.

  8. Changes in spatial memory and BDNF expression to simultaneous dietary restriction and forced exercise.

    Science.gov (United States)

    Khabour, Omar F; Alzoubi, Karem H; Alomari, Mahmoud A; Alzubi, Mohammad A

    2013-01-01

    Previous literature suggests that learning and memory formation can be influenced by diet and exercise. In the current study, we investigated the combined effects of forced swimming exercise (FSE) and every other day fasting (EODF) on spatial memory formation and on the levels of brain-derived neurotrophic factor (BDNF) in the hippocampus of Wistar male rats. The radial arm water maze (RAWM) paradigm was used to assess changes in learning and memory formation, whereas ELISA assay was used to measure BDNF protein levels. The FSE and/or EODF were simultaneously instituted for 6 weeks. Results show that FSE improved learning, short-term as well as long-term memory formation, and significantly increased BDNF protein in the hippocampus (peffect on either spatial learning and memory formation or the levels of hippocamapal BDNF protein (p>0.05). In addition, EODF did not modulate beneficial effect of swimming exercise on cognitive function (p>0.05). Thus exercise enhanced, while EODF did not affect spatial learning and memory formation.

  9. Activity-Dependent Bidirectional Regulation of GAD Expression in a Homeostatic Fashion Is Mediated by BDNF-Dependent and Independent Pathways.

    Science.gov (United States)

    Hanno-Iijima, Yoko; Tanaka, Masami; Iijima, Takatoshi

    2015-01-01

    Homeostatic synaptic plasticity, or synaptic scaling, is a mechanism that tunes neuronal transmission to compensate for prolonged, excessive changes in neuronal activity. Both excitatory and inhibitory neurons undergo homeostatic changes based on synaptic transmission strength, which could effectively contribute to a fine-tuning of circuit activity. However, gene regulation that underlies homeostatic synaptic plasticity in GABAergic (GABA, gamma aminobutyric) neurons is still poorly understood. The present study demonstrated activity-dependent dynamic scaling in which NMDA-R (N-methyl-D-aspartic acid receptor) activity regulated the expression of GABA synthetic enzymes: glutamic acid decarboxylase 65 and 67 (GAD65 and GAD67). Results revealed that activity-regulated BDNF (brain-derived neurotrophic factor) release is necessary, but not sufficient, for activity-dependent up-scaling of these GAD isoforms. Bidirectional forms of activity-dependent GAD expression require both BDNF-dependent and BDNF-independent pathways, both triggered by NMDA-R activity. Additional results indicated that these two GAD genes differ in their responsiveness to chronic changes in neuronal activity, which could be partially caused by differential dependence on BDNF. In parallel to activity-dependent bidirectional scaling in GAD expression, the present study further observed that a chronic change in neuronal activity leads to an alteration in neurotransmitter release from GABAergic neurons in a homeostatic, bidirectional fashion. Therefore, the differential expression of GAD65 and 67 during prolonged changes in neuronal activity may be implicated in some aspects of bidirectional homeostatic plasticity within mature GABAergic presynapses.

  10. The influence of infant-caregiver experiences on amygdala Bdnf, OXTr, and NPY expression in developing and adult male and female rats.

    Science.gov (United States)

    Hill, Kathryn T; Warren, Megan; Roth, Tania L

    2014-10-01

    Previous work with various animal models has demonstrated that alterations in the caregiving environment produce long-term changes in anxiety-related and social behaviors, as well as amygdala gene expression. We previously introduced a rodent model in which the timing and duration of exposure to maltreatment or nurturing care outside the home cage can be controlled to assess neurobiological outcomes. Here we sought to determine whether our brief experimental conditions produce changes in gene expression within the developing and adult amygdala. Using a candidate gene approach, we examined fold mRNA changes for the Brain-derived neurotrophic factor (Bdnf), Oxytocin receptor (OXTr), and Neuropeptide Y (NPY) genes, which are all highly expressed in the amygdala and play important roles in anxiety-related and social behaviors. In adults, significant group differences were detected for only Bdnf, with higher levels of Bdnf mRNA for females that had been exposed to maltreatment and males exposed to nurturing care outside the home cage relative to littermate controls. For pups, significant group differences were detected for only OXTr, with lower levels of OXTr mRNA in females exposed to maltreatment. Finally, for adolescents, maltreated-females showed significant changes in Bdnf (decreased), OXTr (decreased), and NPY (increased) mRNA relative to controls. These data illustrate the ability of brief, but repeated exposure to different caregiving environments during the first postnatal week to have long-term effects on gene expression within the developing and adult amygdala, especially for females.

  11. A functional brain-derived neurotrophic factor (BDNF) gene variant increases the risk of moderate-to-severe allergic rhinitis

    NARCIS (Netherlands)

    Jin, Peng; Andiappan, Anand Kumar; Quek, Jia Min; Lee, Bernett; Au, Bijin; Sio, Yang Yie; Irwanto, Astrid; Schurmann, Claudia; Grabe, Hans Joergen; Suri, Bani Kaur; Matta, Sri Anusha; Westra, Harm-Jan; Franke, Lude; Esko, Tonu; Sun, Liangdan; Zhang, Xuejun; Liu, Hong; Zhang, Furen; Larbi, Anis; Xu, Xin; Poidinger, Michael; Liu, Jianjun; Chew, Fook Tim; Rotzschke, Olaf; Shi, Li; Wang, De Yun

    2015-01-01

    Background: Brain-derived neurotrophic factor (BDNF) is a secretory protein that has been implicated in the pathogenesis of allergic rhinitis (AR), atopic asthma, and eczema, but it is currently unknown whether BDNF polymorphisms influence susceptibility to moderate-to-severe AR. Objective: We sough

  12. Evidence of associations between brain-derived neurotrophic factor (BDNF serum levels and gene polymorphisms with tinnitus

    Directory of Open Access Journals (Sweden)

    Aysun Coskunoglu

    2017-01-01

    Full Text Available Background: Brain-derived neurotrophic factor (BDNF gene polymorphisms are associated with abnormalities in regulation of BDNF secretion. Studies also linked BDNF polymorphisms with changes in brainstem auditory-evoked response test results. Furthermore, BDNF levels are reduced in tinnitus, psychiatric disorders, depression, dysthymic disorder that may be associated with stress, conversion disorder, and suicide attempts due to crises of life. For this purpose, we investigated whether there is any role of BDNF changes in the pathophysiology of tinnitus. Materials and Methods: In this study, we examined the possible effects of BDNF variants in individuals diagnosed with tinnitus for more than 3 months. Fifty-two tinnitus subjects between the ages of 18 and 55, and 42 years healthy control subjects in the same age group, who were free of any otorhinolaryngology and systemic disease, were selected for examination. The intensity of tinnitus and depression was measured using the tinnitus handicap inventory, and the differential diagnosis of psychiatric diagnoses made using the Structured Clinical Interview for Fourth Edition of Mental Disorders. BDNF gene polymorphism was analyzed in the genomic deoxyribonucleic acid (DNA samples extracted from the venous blood, and the serum levels of BDNF were measured. One-way analysis of variance and Chi-squared tests were applied. Results: Serum BDNF level was found lower in the tinnitus patients than controls, and it appeared that there is no correlation between BDNF gene polymorphism and tinnitus. Conclusions: This study suggests neurotrophic factors such as BDNF may have a role in tinnitus etiology. Future studies with larger sample size may be required to further confirm our results.

  13. Delayed GM-CSF treatment stimulates axonal regeneration and functional recovery in paraplegic rats via an increased BDNF expression by endogenous macrophages.

    Science.gov (United States)

    Bouhy, Delphine; Malgrange, Brigitte; Multon, Sylvie; Poirrier, Anne-Lise; Scholtes, Félix; Schoenen, Jean; Franzen, Rachelle

    2006-06-01

    Macrophages (monocytes/microglia) could play a critical role in central nervous system repair. We have previously found a synchronism between the regression of spontaneous axonal regeneration and the deactivation of macrophages 3-4 wk after a compression-injury of rat spinal cord. To explore whether reactivation of endogenous macrophages might be beneficial for spinal cord repair, we have studied the effects of granulocyte-macrophage colony stimulating factor (GM-CSF) in the same paraplegia model and in cell cultures. There was a significant, though transient, improvement of locomotor recovery after a single delayed intraperitoneal injection of 2 microg GM-CSF, which also increased significantly the expression of Cr3 and brain-derived neurotrophic factor (BDNF) by macrophages at the lesion site. At longer survival delays, axonal regeneration was significantly enhanced in GM-CSF-treated rats. In vitro, BV2 microglial cells expressed higher levels of BDNF in the presence of GM-CSF and neurons cocultured with microglial cells activated by GM-CSF generated more neurites, an effect blocked by a BDNF antibody. These experiments suggest that GM-CSF could be an interesting treatment option for spinal cord injury and that its beneficial effects might be mediated by BDNF.

  14. Estrogen and brain-derived neurotrophic factor (BDNF) in hippocampus: complexity of steroid hormone-growth factor interactions in the adult CNS.

    OpenAIRE

    SCHARFMAN, HELEN E.; MacLusky, Neil J.

    2006-01-01

    In the CNS, there are widespread and diverse interactions between growth factors and estrogen. Here we examine the interactions of estrogen and brain-derived neurotrophic factor (BDNF), two molecules that have historically been studied separately, despite the fact that they seem to share common targets, effects, and mechanisms of action. The demonstration of an estrogen-sensitive response element on the BDNF gene provided an impetus to explore a direct relationship between estrogen and BDNF, ...

  15. Brain-derived neurotrophic factor (BDNF) and TrkB in the piglet brainstem after post-natal nicotine and intermittent hypercapnic hypoxia.

    Science.gov (United States)

    Tang, Samantha; Machaalani, Rita; Waters, Karen A

    2008-09-26

    Brain-derived neurotrophic factor (BDNF) and its receptor TrkB play a significant role in the regulation of cell growth, survival and death during central nervous system development. The expression of BDNF and TrkB is affected by noxious insults. Two insults during the early post-natal period that are of interest to our laboratory are exposure to nicotine and to intermittent hypercapnic hypoxia (IHH). Piglet models were used to mimic the conditions associated with the risk factors for the sudden infant death syndrome (SIDS) including post-natal cigarette smoke exposure (nicotine model) and prone sleeping where the infant is subjected to re-breathing of expired gases (IHH model). We aimed to determine the effects of nicotine and IHH, alone or in combination, on pro- and rhBDNF and TrkB expression in the developing piglet brainstem. Four piglet groups were studied, with equal gender ratios in each: control (n=14), nicotine (n=14), IHH (n=10) and nic+IHH (n=14). Applying immunohistochemistry, and studying six nuclei of the caudal medulla, we found that compared to controls, TrkB was the only protein significantly decreased after nicotine and nic+IHH exposure regardless of gender. For pro-BDNF and rhBDNF however, observed changes were more evident in males than females exposed to nicotine and nic+IHH. The implications of these findings are that a prior nicotine exposure makes the developing brainstem susceptible to greater changes in the neurotrophic effects of BDNF and its receptor TrkB in the face of a hypoxic insult, and that the effects are greater in males than females.

  16. Brain-Derived Neurotrophic Factor (BDNF protein levels in anxiety disorders: systematic review and meta-regression analysis

    Directory of Open Access Journals (Sweden)

    Sharain eSuliman

    2013-07-01

    Full Text Available Background: Brain-Derived Neurotrophic Factor (BDNF is a neurotrophin that is involved in the synaptic plasticity and survival of neurons. BDNF is believed to be involved in the pathogenesis of several neuropsychiatric disorders. As findings of BDNF levels in the anxiety disorders have been inconsistent, we undertook to conduct a systematic review and meta-analysis of studies that assessed BDNF protein levels in anxiety disorders. Methods: We conducted the review using electronic databases and searched reference lists of relevant articles for any further studies. Studies that measured BDNF protein levels in any anxiety disorder and compared these to a control group were included. Effect sizes of the differences in BDNF levels between anxiety disorder and control groups were calculated. Results: Eight studies with a total of 1179 participants were included. Initial findings suggested that BDNF levels were lower in individuals with any anxiety disorder compared to those without (Standard Mean Difference [SMD]=-0.94 [-1.75, -0.12], p≤0.05. This, however, differed with regards to source of BDNF protein (plasma: SMD=-1.31 [-1.69, -0.92], p≤0.01; serum: SMD=-1.06 [-2.27, 0.16], p≥0.01 and type of anxiety disorder (PTSD: SMD=-0.05 [-1.66, 1.75], p≥0.01; OCD: SMD=-2.33 [-4.21, -0.45], p≤0.01. Conclusion: Although BDNF levels appear to be reduced in individuals with an anxiety disorder, this is not consistent across the various anxiety disorders and may largely be explained by the significantly lowered BDNF levels found in OCD. Results further appear to be mediated by differences in sampling methods. Findings are, however, limited by the lack of research in this area, and given the potential for BDNF as a biomarker of anxiety disorders it would be useful to clarify the relationship further.

  17. Immunolocalization of pro- and mature-brain derived neurotrophic factor (BDNF) and receptor TrkB in the human brainstem and hippocampus.

    Science.gov (United States)

    Tang, Samantha; Machaalani, Rita; Waters, Karen A

    2010-10-01

    Brain-derived neurotrophic factor (BDNF) and its receptor TrkB are essential in promoting normal development of the central nervous system. Specific functions that are affected in knockout models include respiratory control, coordination of movement and balance, and feeding activities. The expression of these markers has not yet been studied in the human infant brain. This study provides a detailed account of the distribution and localization of both pro- and mature-recombinant human (rh) forms of BDNF, and of TrkB in the human infant brainstem and hippocampus, and qualitatively compares this expression to that seen in the human adult. Using commercially available antibodies, we applied immunohistochemistry on formalin fixed and paraffin embedded human brain tissue [n=8 for infant, n=6 for adult], and qualitatively analyzed the expression of proBDNF, rhBDNF and TrkB. Amongst the brainstem regions studied, the greatest expression of the markers was in the mesencephalic trigeminal of the pons, and in the medulla, the inferior olive and arcuate nucleus. The lowest expression was in the substantia nigra of the midbrain and pontine locus coeruleus. Compared to adults, all the studied markers had a higher expression in the infant brainstem nuclei of the hypoglossal, vestibular, dorsal motor nucleus of the vagus, prepositus, cuneate, and dorsal raphe. In the hippocampus, only TrkB showed a higher expression in infants compared to adults. We conclude that BDNF and TrkB play important roles in controlling respiration, movement, balance and feeding in the brainstem and that the TrkB receptor is the most age-sensitive component of this system, especially in the hippocampus.

  18. Exercise improves object recognition memory and induces BDNF expression and cell proliferation in cognitively enriched rats.

    Science.gov (United States)

    Bechara, R G; Kelly, Á M

    2013-05-15

    Exercise and environmental enrichment are behavioural interventions that have been shown to improve learning and increase neurogenesis in rodents, possibly via neurotrophin-mediated mechanisms. However, many enrichment protocols incorporate exercise, which can itself be viewed as a source of cognitive stimulation in animals housed in standard laboratory conditions. In this experiment we investigate the effect of each intervention separately and in combination on object recognition memory, and analyse associated changes in the dentate gyrus: specifically, in BDNF expression and cell division. We show that both exercise and enrichment improve object recognition memory, but that BDNF mRNA expression and cell proliferation in the dentate gyrus of the hippocampus increase only in exercised rats. These results are in general agreement with recent studies suggesting that the exercise component is the major neurogenic and neurotrophic stimulus in environmental enrichment protocols. We add to the expanding literature several novel aspects including the finding that enrichment in the absence of exercise can improve object recognition memory, probably via mechanisms that are independent of BDNF upregulation and neurogenesis in the dentate gyrus.

  19. Directed evolution of brain-derived neurotrophic factor for improved folding and expression in Saccharomyces cerevisiae.

    Science.gov (United States)

    Burns, Michael L; Malott, Thomas M; Metcalf, Kevin J; Hackel, Benjamin J; Chan, Jonah R; Shusta, Eric V

    2014-09-01

    Brain-derived neurotrophic factor (BDNF) plays an important role in nervous system function and has therapeutic potential. Microbial production of BDNF has resulted in a low-fidelity protein product, often in the form of large, insoluble aggregates incapable of binding to cognate TrkB or p75 receptors. In this study, employing Saccharomyces cerevisiae display and secretion systems, it was found that BDNF was poorly expressed and partially inactive on the yeast surface and that BDNF was secreted at low levels in the form of disulfide-bonded aggregates. Thus, for the purpose of increasing the compatibility of yeast as an expression host for BDNF, directed-evolution approaches were employed to improve BDNF folding and expression levels. Yeast surface display was combined with two rounds of directed evolution employing random mutagenesis and shuffling to identify BDNF mutants that had 5-fold improvements in expression, 4-fold increases in specific TrkB binding activity, and restored p75 binding activity, both as displayed proteins and as secreted proteins. Secreted BDNF mutants were found largely in the form of soluble homodimers that could stimulate TrkB phosphorylation in transfected PC12 cells. Site-directed mutagenesis studies indicated that a particularly important mutational class involved the introduction of cysteines proximal to the native cysteines that participate in the BDNF cysteine knot architecture. Taken together, these findings show that yeast is now a viable alternative for both the production and the engineering of BDNF.

  20. No association of the Val66Met polymorphism of brain-derived neurotrophic factor (BDNF) to multiple sclerosis.

    Science.gov (United States)

    Blanco, Y; Gómez-Choco, M; Arostegui, J L; Casanova, B; Martínez-Rodríguez, J E; Boscá, I; Munteis, E; Yagüe, J; Graus, F; Saiz, A

    2006-04-03

    Brain-derived neurotrophic factor (BDNF), a neurotrophin produced by neurons and immune cells, promotes neuronal survival and repair during development and after CNS injury. The BDNF-Val66Met polymorphism is functional and induces abnormal intracellular trafficking and decreased BDNF release. Therefore, we investigated the impact of the BDNF-Val66Met polymorphism on the susceptibility and clinical course in a case-control study of 224 multiple sclerosis (MS) Spanish patients and 177 healthy controls. We found no evidence for association to susceptibility or severity of the disease in our population. Moreover, we did not observe, in a subgroup of 12 MS patients, that the methionine substitution at position 66 in the prodomain had negative impact in the capacity to produce BDNF by peripheral blood mononuclear cells (PBMC).

  1. The Effects of Acute Exercise on Memory and Brain-Derived Neurotrophic Factor (BDNF).

    Science.gov (United States)

    Etnier, Jennifer L; Wideman, Laurie; Labban, Jeffrey D; Piepmeier, Aaron T; Pendleton, Daniel M; Dvorak, Kelly K; Becofsky, Katie

    2016-08-01

    Acute exercise benefits cognition, and some evidence suggests that brain-derived neurotrophic factor (BDNF) plays a role in this effect. The purpose of this study was to explore the dose-response relationship between exercise intensity, memory, and BDNF. Young adults completed 3 exercise sessions at different intensities relative to ventilator threshold (Vt) (VO2max, Vt - 20%, Vt + 20%). For each session, participants exercised for approximately 30 min. Following exercise, they performed the Rey Auditory Verbal Learning Test (RAVLT) to assess short-term memory, learning, and long-term memory recall. Twenty-four hours later, they completed the RAVLT recognition trial, which provided another measure of long-term memory. Blood was drawn before exercise, immediately postexercise, and after the 30-min recall test. Results indicated that long-term memory as assessed after the 24-hr delay differed as a function of exercise intensity with the largest benefits observed following maximal intensity exercise. BDNF data showed a significant increase in response to exercise; however, there were no differences relative to exercise intensity and there were no significant associations between BDNF and memory. Future research is warranted so that we can better understand how to use exercise to benefit cognitive performance.

  2. 天麻素对老年痴呆树鼩海马BDNF表达的影响%Effects of Gastrodin on BDNF Expression in AD Tree Shrew

    Institute of Scientific and Technical Information of China (English)

    何保丽; 角建林; 李波; 李进涛; 王丽梅

    2013-01-01

    Objective To investigate the effect of gastrodin on brain-derived neurotrophic factor (BDNF) expression in Alzheimer's disease ( AD) tree shrew. Methods AD tree shrew model was established by intracerebroventricular injection with amyloid-βpeptide (Aβ) . Since the eighth day after injection, the tree shrews were treated with gastrodin for thirty days. The expression of BDNF in tree threw hippocampus was detected by reverse transcription polymerase chain reaction (RT-PCR) . Results The expression of BDNF mRNA in the treatment group was higher than that in the model group ( <0.05) . Conclusion Gastrodin can increase some degree of the expression of BDNF.%目的:探讨天麻素对老年痴呆树鼩脑内海马BDNF表达的影响.方法用β-淀粉样蛋白(Aβ)侧脑室注射建立树鼩老年痴呆模型.从模型制作后第8天开始,治疗组树鼩连续30 d灌胃给予天麻素.通过RT-PCR检测海马脑源性神经营养因子(BDNF) mRNA的表达.结果海马BDNF mRNA在天马素治疗组的表达高于模型组(<0.05).结论天麻素能在一定程度上上调树鼩海马BDNF的表达.

  3. Sex-specific association of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and plasma BDNF with attention-deficit/hyperactivity disorder in a drug-naïve Han Chinese sample.

    Science.gov (United States)

    Li, Haimei; Liu, Lu; Tang, Yilang; Ji, Ning; Yang, Li; Qian, Qiujin; Wang, Yufeng

    2014-07-30

    A functional polymorphism of the brain derived neurotrophic factor gene (BDNF) (Val66Met) has been suggested to be involved in the pathogenesis of attention-deficit/hyperactivity disorder (ADHD). It also has an impact on peripheral BDNF levels in psychiatric disorders. This study examined the association of Val66Met with plasma BDNF level of ADHD in Han Chinese children (170 medication - naïve ADHD patients and 155 unaffected controls, aged 6-16 years). The Val allele was showed a higher frequency in females with ADHD (n=84) than controls (P=0.029) from the case-control association study. The analysis of covariance (ANCOVA) indicated that the mean plasma BDNF levels of ADHD patients were significantly higher than that of controls (P=0.001). We performed both total sample and sex stratified analyses to investigate the effect of Val66Met genotype on the plasma BDNF levels, but only a trend of association was found in females with ADHD (n=84), with a tendency of lower plasma BDNF level in Val allele carriers than Met/Met genotype carriers (P=0.071). Our results suggested a sex-specific association between BDNF and ADHD. Furthermore, there was a possible sex-specific relationship between the BDNF Val66Met genotype and plasma BDNF levels. However, further studies are required to elucidate the role of BDNF in ADHD.

  4. The brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism affects memory performance in older adults

    OpenAIRE

    Azeredo,Lucas A.; Tatiana De Nardi; Levandowski, Mateus L.; Tractenberg,Saulo G.; Julia Kommers-Molina; Andrea Wieck; Tatiana Q. Irigaray; Irênio G. da Silva Filho; Rodrigo Grassi-Oliveira

    2017-01-01

    Objective: Memory impairment is an important contributor to the reduction in quality of life experienced by older adults, and genetic risk factors seem to contribute to variance in age-related cognitive decline. Brain-derived neurotrophic factor (BDNF) is an important nerve growth factor linked with development and neural plasticity. The Val66Met polymorphism in the BDNF gene has been associated with impaired episodic memory in adults, but whether this functional variant plays a role in cogni...

  5. The impact of childhood abuse and recent stress on serum brain-derived neurotrophic factor and the moderating role of BDNF Val(66)Met

    NARCIS (Netherlands)

    Elzinga, Bernet M.; Molendijk, Marc L.; Voshaar, Richard C. Oude; Bus, Boudewijn A. A.; Prickaerts, Jos; Spinhoven, Philip; Penninx, Brenda J. W. H.

    2011-01-01

    Recent findings show lowered brain-derived neurotrophic factor (BDNF) levels in major depressive disorder (MDD). Exposure to stressful life events may (partly) underlie these BDNF reductions, but little is known about the effects of early or recent life stress on BDNF levels. Moreover, the effects o

  6. The impact of childhood abuse and recent stress on serum brain-derived neurotrophic factor and the moderating role of BDNF Val66Met

    NARCIS (Netherlands)

    Elzinga, B.M.; Molendijk, M.L.; Oude Voshaar, R.C.; Bus, B.A.A.; Prickaerts, J.; Spinhoven, P.; Penninx, B.J.

    2011-01-01

    RATIONALE: Recent findings show lowered brain-derived neurotrophic factor (BDNF) levels in major depressive disorder (MDD). Exposure to stressful life events may (partly) underlie these BDNF reductions, but little is known about the effects of early or recent life stress on BDNF levels. Moreover, th

  7. Effect of NGF, BDNF, bFGF, aFGF and cell density on NPY expression in cultured rat dorsal root ganglion neurones.

    Science.gov (United States)

    Kerekes, N; Landry, M; Lundmark, K; Hökfelt, T

    2000-07-01

    The effect of neurotrophic factors on neuropeptide Y (NPY) expression was studied in adult rat dispersed dorsal root ganglion (DRG) cultures. Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), acidic fibroblast growth factor (aFGF) or basic FGF was included in the culture medium during incubation for 72 h. In untreated cultures, around 18% of all neurones (visualized by antibodies to PGP 9.5) expressed NPY-like immunoreactivity (LI). In contrast, in vivo uninjured neurones do not contain detectable levels of NPY-LI. In the immunohistochemical analysis aFGF increased the percentage of NPY-immunoreactive (-IR) neurones 1.8-fold, while NGF, BDNF or bFGF had no significant effect on NPY expression. When the effect of these growth factors was monitored with non-radioactive in situ hybridization, both aFGF and bFGF caused a significant increase (2.25- and 1.8-fold, respectively), whereas, again, NGF and BDNF had no effect. The results also showed an effect of cell density on NPY expression, whereby fewer neurones expressed NPY in high than in low density cultures. This difference was seen in untreated as well as growth factor-treated cultures. The present results support the hypothesis that DRG neurones in culture are in an axotomized state, since they express NPY to about the same extent as axotomized DRG neurones in vivo. Surprisingly, two growth factors of the FGF family enhance NPY expression in DRG neurones, which is in apparent contrast to a published in vivo study [Ji, R.-R., Zhang, Q., Pettersson, R.F., Hökfelt, T., 1996. aFGF, bFGF and NGF differentially regulate neuropeptide expression in dorsal root ganglia after axotomy and induce autotomy. Reg. Pept. 66, 179-189.]. Finally, NPY expression was also influenced by cell density.

  8. Serum brain-derived neurotrophic factor (BDNF) levels in schizophrenia: A systematic review

    Science.gov (United States)

    Cui, Huiru; Jin, Yi; Wang, Jijun; Weng, Xuchu; Li, Chunbo

    2012-01-01

    Background There is increasing interest in the role of brain-derived neurotrophic factor (BDNF) in the onset and course of schizophrenia, but there are conflicting reports about serum levels of BDNF in patients with schizophrenia. Aim Conduct a meta-analysis combining studies from China and other countries that have evaluated the relationship of serum BDNF levels to schizophrenia. Method We used Cochrane methodology and RevMan 5.1 software to identify and pool the results of studies. Electronic searches of western and Chinese registries and follow-up assessment of references located 268 potential articles. Twenty-five articles (20 in English and 5 in Chinese) published before December 2011 that used case-control methods, included patients with schizophrenia who had no concurrent disorders, and used ELISA technology to assess serum BDNF were included in the analysis. The main outcome was the pooled standardized mean difference (SMD) between cases and controls. The quality of the studies was independently assessed by two raters using the GRADE system. The heterogeneity, sensitivity and potential publication bias of the studies was evaluated using RevMan. Results The pooled sample included 1663 patients with schizophrenia and 1355 controls. Fifteen of the included studies were rated as ‘poor quality’ and 10 were rated as ‘very poor quality’. The results of the studies were quite heterogenous (I2=95%) but subgroup analyses found that the heterogeneity was not related to country of origin, sample size, age, gender, prior use of antipsychotic medication, or study quality. The pooled SMD (computed using a random-effect model because of study heterogeneity) was -0.74 (95% CI, -0.99∼-0.50; Z=5.99, pbias. Conclusion Despite the robust statistical findings of lower serum BDNF in patients with schizophrenia than in controls, given the low quality of the available studies and the substantial heterogeneity between studies, the evidence of lower serum BDNF in patients

  9. Brain-derived neurotrophic factor (BDNF as a potential mechanism of the effects of acute exercise on cognitive performance

    Directory of Open Access Journals (Sweden)

    Aaron T. Piepmeier

    2015-03-01

    Full Text Available The literature shows that improvements in cognitive performance may be observed following an acute bout of exercise. However, evidence in support of the biological mechanisms of this effect is still limited. Findings from both rodent and human studies suggest brain-derived neurotrophic factor (BDNF as a potential mechanism of the effect of acute exercise on memory. The molecular properties of BDNF allow this protein to be assessed in the periphery (pBDNF (i.e., blood serum, blood plasma, making measurements of acute exercise-induced changes in BDNF concentration relatively accessible. Studies exploring the acute exercise–pBDNF–cognitive performance relationship have had mixed findings, but this may be more reflective of methodological differences between studies than it is a statement about the role of BDNF. For example, significant associations have been observed between acute exercise-induced changes in pBDNF concentration and cognitive performance in studies assessing memory, and non-significant associations have been found in studies assessing non-memory cognitive domains. Three suggestions are made for future research aimed at understanding the role of BDNF as a biological mechanism of this relationship: 1 Assessments of cognitive performance may benefit from a focus on various types of memory (e.g., relational, spatial, long-term; 2 More fine-grained measurements of pBDNF will allow for the assessment of concentrations of specific isoforms of the BDNF protein (i.e., immature, mature; 3 Statistical techniques designed to test the mediating role of pBDNF in the acute exercise-cognitive performance relationship should be utilized in order to make causal inferences.

  10. BDNF isoforms: a round trip ticket between neurogenesis and serotonin?

    Science.gov (United States)

    Foltran, Rocío Beatriz; Diaz, Silvina Laura

    2016-07-01

    The brain-derived neurotrophic factor, BDNF, was discovered more than 30 years ago and, like other members of the neurotrophin family, this neuropeptide is synthetized as a proneurotrophin, the pro-BDNF, which is further cleaved to yield mature BDNF. The myriad of actions of these two BDNF isoforms in the central nervous system is constantly increasing and requires the development of sophisticated tools and animal models to refine our understanding. This review is focused on BDNF isoforms, their participation in the process of neurogenesis taking place in the hippocampus of adult mammals, and the modulation of their expression by serotonergic agents. Interestingly, around this triumvirate of BDNF, serotonin, and neurogenesis, a series of recent research has emerged with apparently counterintuitive results. This calls for an exhaustive analysis of the data published so far and encourages thorough work in the quest for new hypotheses in the field. BDNF is synthetized as a pre-proneurotrophin. After removal of the pre-region, proBDNF can be cleaved by intracellular or extracellular proteases. Mature BDNF can bind TrkB receptors, promoting their homodimerization and intracellular phosphorylation. Phosphorylated-TrkB can activate three different signaling pathways. Whereas G-protein-coupled receptors can transactivate TrkB receptors, truncated forms can inhibit mBDNF signaling. Pro-BDNF binds p75(NTR) by its mature domain, whereas the pro-region binds co-receptors. © 2016 International Society for Neurochemistry.

  11. Construction and expression of recombinant adenovirus vector encoding BDNF%重组大鼠脑源性神经营养因子腺病毒的构建及体外表达分析

    Institute of Scientific and Technical Information of China (English)

    郎洪刚; 曹文斌; 牛道立; 何芬

    2011-01-01

    Objective To construct adenovirus vector encoding rat brain derived neurotrophic factor (BDNF) gene and identify the expression in vitro.Methods The specific BDNF sequence was cloned into the plasmid of pAdTrack-CMV to construct the BDNF expression plasmid pAd-BDNF.The recombinant plasmids were identified hy DNA sequencing and restriction digestion.The homologous recomhination between the recombinant vector and the adenovirus hone vector pAdeasy-1 in the Ecoli BJ5183 resulted to the formation of recombinant adenovirus vector Ad-BDNF.The infecting recomhinant virus particles Ad-BDNF was produced after the recombinant adenovirus vector had been transfected to the human embry kidney 293 cells.The recombinant adenovirus vector infected the hela cell, the expression of BDNF was detected by RT-PCR, Western blot and immunocytochemistry.Results The sequence results of pAd-BDNF were consistent with expectancy.After homologous recombination and packaging with 293 cells , the recombinant Ad-BDNF adenovirus was obtained.RT-PCR, Western blot and immunocytochemistry suggested that the BDNF was expressed.Conclusions The Ad-BDNF was constructed successfully.It is confirmed that the interest proteins were expressed in the infected cells , which lays the basis for its application in the treatment of the neurodamaged diseases.%目的 构建含有大鼠脑源性神经营养因子(BDNF)基因的重组腺病毒(AD)载体,并分析其体外表达情况.方法 将采用RT-PCR技术获取的大鼠BDNF的cDNA基因定向克隆入穿梭质粒pAdTrack-CMV中.通过与腺病毒骨架载体pAdeasy-1在细菌内同源重组形成重组腺病毒质粒pAd-BDNF,转染人胚肾293细胞后包装成有感染能力的重组腺病毒颗粒(Ad-BDNF).重组病毒感染体外培养的Hela细胞后,用RT-PCR、Western blot及免疫细胞化学检测细胞BDNF基因及蛋白表达情况.结果 pAd-BDNF测序结果和预期一致,同源重组并经293细胞包装后形成重组腺病毒Ad-BDNF,重组病毒

  12. The expression of brain derived neurotrophic factor mRNA in rats after fluid percussion brain injury%液压冲击脑损伤大鼠海马BDNF mRNA表达实验研究

    Institute of Scientific and Technical Information of China (English)

    陈于波; 黄代新; 吴梅筠; 张林; 李荣华; 吴家文

    2001-01-01

    目的:研究脑损伤后脑源性神经营养因子(BDNF)mRNA表达及其时序性变化,进一步研究脑损伤的分子机制.方法:用免疫组织化学及原位杂交方法,观察液压冲击脑损伤大鼠海马BDNF mRNA受伤后不同时间(5、15、30分钟和1、3、6、12小时及1、3、7日) 的表达情况,以正常大鼠及手术大鼠作为对照.结果:正常及手术对照组大鼠脑组织海马表达少量的BDNF;脑损伤后1小时海马齿状回CA2及CA3细胞表达增强,3~6小时达高峰,12小时开始下降,24小时后降至对照水平.1、3、6和12小时与正常及手术对照组比较均有显著性差异.结论:液压冲击脑损伤可诱导BDNF基因的表达,BDNF mRNA表达存在时间差异,提示机体对脑损伤存在自身保护机制.

  13. Effects of rAAV-mediated rhBDNF gene transfection on BDNF gene expression in the retina of a rabbit model of acute high intraocular pressure%rAAV介导hBDNF基因转染对急性高眼压兔眼视网膜BDNF表达的影响

    Institute of Scientific and Technical Information of China (English)

    王建明; 孙乃学; 惠娜; 范雅稚; 冯海晓; 赵世平

    2009-01-01

    Objective To observe the changes in the expression of brain derived neurotrophic factor (BDNF) gene in the retina of rabbits with acute high intraocular pressure (IOP) after injection of recombinant adeno-associated virus (rAAV) vector containing human BDNF gene (rAAV-hBDNF), and investigate the neuroprotective mechanism of rAAV-hBDNF. Methods The unilateral eyes of 24 white rabbits were randomly chosen as the model group with high IOP induced by saline perfusion into the anterior chamber, and the contralateral eyes served as the control group without treatment. In another 24 white rabbits, 10 μl rAAV-BDNF was injected into the vitreous body of one of the eyes 3 days before induction of high IOP. On days 1,3,7, and 14 after perfusion, the bilateral eyes of 6 rabbits were excised for immunohistochemistry for the expression of endogenous BDNF gene in the retina. Results The number of BDNF-positive cells in the retina decreased after induction of high IOP, and injection of rAAV-hBDNF resulted in a significant increase in BDNF-positive cells as compared with the positive cell number in the high IOP model and control groups (P<0.05, P<0.01). Conclusion rAAV-mediated BDNF gene transfection can increase endogenous BDNF expression in the retina of rabbits with acute high IOP. Intravitreous injection is an effective pathway for rAAV-hBDNF gene transfection into the retina.%目的 通过观察视网膜内源性脑源性神经营养因:F(BDNF)表达的变化,探讨玻璃体注射携带人脑源性神经营养因子(hBDNF)的重组腺伴随病毒(rAAV-BDNF)对急性高眼压兔眼神经损害的保护机制.方法 24只健康日本大耳白兔任选一眼作为造模眼(为模型组,共24眼),用生理盐水前房灌注法造成急性高眼压模型,对侧眼不作任何处理作为正常对照组(24眼).另24只健康日本大耳白兔任选一眼作为造模眼(为BDNF组,共24眼),BDNF组在造模前3d玻璃体内注射10μl rAAV-BDNF.于造模后第1、3、7、14d

  14. Effect of dexmedetomidine on hippocampal neuron development and BDNF-TrkB signal expression in neonatal rats

    Science.gov (United States)

    Lv, Jie; Ou, Wei; Zou, Xiao-Hua; Yao, Yin; Wu, Jin-Li

    2016-01-01

    The study aimed to explore the effect of dexmedetomidine (DEX) on hippocampal neuron development process and on molecular expression of brain-derived neurotrophic factor (BDNF)-tyrosine receptor kinase B (TrkB) signaling pathway in neonatal rats. The hippocampal neuron cells were isolated from newborn neonatal rats and cultured in vitro. One control group and three treated groups with 1, 10, and 100 μmol/L DEX were used for the study. Cell activity and apoptosis were detected by the MTT and terminal deoxynucleotidyl transferase-mediated biotinylated uridine triphosphate (UTP) nick end labeling assays. The synaptophysin (SYN) and postsynaptic density 95 (PSD95) were detected by quantitative polymerase chain reaction. There was no difference in the viability of neuron cells among the different dose groups of DEX and the control group during days 2–10 (P>0.05). Compared to the control group, there was no significant difference (P>0.05) in the expressions of SYN and PSD95 in the groups treated with 1 and 10 μmol/L DEX, whereas significant difference in the expression was observed in the group treated with 100 μmol/L DEX (PBDNF was significantly upregulated (PTrkB expression among the four groups. The expression of p-N-methyl-D-aspartate receptor increased with an increase in the concentration of DEX; however, only the high dose revealed a significant upregulation compared with the control group. The neuroprotective effect of DEX may be achieved by upregulating the expression of BDNF and phosphorylation level of N-methyl-D-aspartate receptor. PMID:28003751

  15. The role of brain-derived neurotrophic factor (BDNF in comorbid depression: possible linkage with steroid hormones, cytokines, and nutrition

    Directory of Open Access Journals (Sweden)

    Tadahiro eNumakawa

    2014-09-01

    Full Text Available Increasing evidence demonstrates a connection between growth factor function (including brain-derived neurotrophic factor, BDNF, glucocorticoid levels (one of the steroid hormones, and the pathophysiology of depressive disorders. Because both BDNF and glucocorticoids regulate synaptic function in the central nervous system, their functional interaction is of major concern. Interestingly, alterations in levels of estrogen, another steroid hormone, may play a role in depressive-like behavior in postpartum females with fluctuations of BDNF-related molecules in the brain. BDNF and cytokines, which are protein regulators of inflammation, stimulate multiple intracellular signaling cascades involved in neuropsychiatric illness. Pro-inflammatory cytokines may increase vulnerability to depressive symptoms, such as the increased risk observed in patients with cancer and/or autoimmune diseases. In this review, we discuss the possible relationship between inflammation and depression, in addition to the crosstalk among cytokines, BDNF and steroids. Further, since nutritional status has been shown to affect critical pathways involved in depression through both BDNF function and the monoamine system, we also review current evidence surrounding diet and supplementation (e.g., flavonoids on BDNF-mediated brain functions.

  16. Expression of brain-derived neurotrophic factor mRNA in rat hippocampus after treatment with antipsychotic drugs.

    Science.gov (United States)

    Bai, Ou; Chlan-Fourney, Jennifer; Bowen, Rudy; Keegan, David; Li, Xin-Min

    2003-01-01

    Typical and atypical antipsychotic drugs, though both effective, act on different neurotransmitter receptors and are dissimilar in some clinical effects and side effects. The typical antipsychotic drug haloperidol has been shown to cause a decrease in the expression of brain-derived neurotrophic factor (BDNF), which plays an important role in neuronal cell survival, differentiation, and neuronal connectivity. However, it is still unknown whether atypical antipsychotic drugs similarly regulate BDNF expression. We examined the effects of chronic (28 days) administration of typical and atypical antipsychotic drugs on BDNF mRNA expression in the rat hippocampus using in situ hybridization. Quantitative analysis revealed that the typical antipsychotic drug haloperidol (1 mg/kg) down-regulated BDNF mRNA expression in both CA1 (P BDNF mRNA expression in CA1, CA3, and dentate gyrus regions of the rat hippocampus compared with their respective controls (P BDNF mRNA expression in rat hippocampus.

  17. Saikosaponin A Alleviates Symptoms of Attention Deficit Hyperactivity Disorder through Downregulation of DAT and Enhancing BDNF Expression in Spontaneous Hypertensive Rats

    Science.gov (United States)

    Jichao, Sun; Xianguo, Ren; Dongqi, Yin; Rongyi, Zhou; Shuang, Lei; Yue, You; Yuchen, Song; Jingnan, Ying

    2017-01-01

    The disturbed dopamine availability and brain-derived neurotrophic factor (BDNF) expression are due in part to be associated with attention deficit hyperactivity disorder (ADHD). In this study, we investigated the therapeutical effect of saikosaponin a (SSa) isolated from Bupleurum Chinese DC, against spontaneously hypertensive rat (SHR) model of ADHD. Methylphenidate and SSa were orally administered for 3 weeks. Activity was assessed by open-field test and Morris water maze test. Dopamine (DA) and BDNF were determined in specific brain regions. The mRNA or protein expression of tyrosine hydroxylase (TH), dopamine transporter (DAT), and vesicles monoamine transporter (VMAT) was also studied. Both MPH and SSa reduced hyperactivity and improved the spatial learning memory deficit in SHRs. An increased DA concentration in the prefrontal cortex (PFC) and striatum was also observed after treating with the SSa. The increased DA concentration may partially be attributed to the decreased mRNA and protein expression of DAT in PFC while SSa exhibited no significant effects on the mRNA expression of TH and VMAT in PFC of SHRs. In addition, BDNF expression in SHRs was also increased after treating with SSa or MPH. The obtained result suggested that SSa may be a potential drug for treating ADHD.

  18. Developmental traumatic brain injury decreased brain derived neurotrophic factor expression late after injury.

    Science.gov (United States)

    Schober, Michelle Elena; Block, Benjamin; Requena, Daniela F; Hale, Merica A; Lane, Robert H

    2012-06-01

    Pediatric traumatic brain injury (TBI) is a major cause of acquired cognitive dysfunction in children. Hippocampal Brain Derived Neurotrophic Factor (BDNF) is important for normal cognition. Little is known about the effects of TBI on BDNF levels in the developing hippocampus. We used controlled cortical impact (CCI) in the 17 day old rat pup to test the hypothesis that CCI would first increase rat hippocampal BDNF mRNA/protein levels relative to SHAM and Naïve rats by post injury day (PID) 2 and then decrease BDNF mRNA/protein by PID14. Relative to SHAM, CCI did not change BDNF mRNA/protein levels in the injured hippocampus in the first 2 days after injury but did decrease BDNF protein at PID14. Surprisingly, BDNF mRNA decreased at PID 1, 3, 7 and 14, and BDNF protein decreased at PID 2, in SHAM and CCI hippocampi relative to Naïve. In conclusion, TBI decreased BDNF protein in the injured rat pup hippocampus 14 days after injury. BDNF mRNA levels decreased in both CCI and SHAM hippocampi relative to Naïve, suggesting that certain aspects of the experimental paradigm (such as craniotomy, anesthesia, and/or maternal separation) may decrease the expression of BDNF in the developing hippocampus. While BDNF is important for normal cognition, no inferences can be made regarding the cognitive impact of any of these factors. Such findings, however, suggest that meticulous attention to the experimental paradigm, and possible inclusion of a Naïve group, is warranted in studies of BDNF expression in the developing brain after TBI.

  19. Influence of brain-derived neurotrophic factor (BDNF) on serotonin neurotransmission in the hippocampus of adult rodents.

    Science.gov (United States)

    Benmansour, Saloua; Deltheil, Thierry; Piotrowski, Jonathan; Nicolas, Lorelei; Reperant, Christelle; Gardier, Alain M; Frazer, Alan; David, Denis J

    2008-06-10

    Whereas SSRIs produce rapid blockade of the serotonin transporter (SERT) in vitro and in vivo, the onset of an observable clinical effect takes longer to occur and a variety of pharmacological effects caused by antidepressants have been speculated to be involved either in initiating antidepressant effects and/or enhancing their effects on serotonergic transmission so as to cause clinical improvement. Among such secondary factors is increased activity of brain-derived neurotrophic factor (BDNF), which requires the Tropomyosine-related kinase B receptor (TrkB) for its effects. To begin an analysis of the influence of BDNF on serotonergic activity, we studied the acute effects of BDNF on SERT activity. A single BDNF injection (either intracerebroventricularly or directly into the CA3 region of hippocampus) decreased the signal amplitude and clearance rate produced by exogenously applied 5-HT compared to what was measured in control rats, shown using in vivo chronoamperometry. It also reduced the ability of a locally applied SSRI to block the clearance of 5-HT. In awake freely moving mice, acute intrahippocampal injection of BDNF decreased extracellular levels of 5-HT in the hippocampus, as measured using microdialysis. In addition, perfusion with BDNF decreased KCl-evoked elevations of 5-HT. These effects of BDNF were blocked by the non-selective antagonist of TrkB receptors, K252a. Overall, it may be inferred that in the hippocampus, through TrkB activation, a single injection of BDNF enhances SERT function. Such acute effects of BDNF would be expected to counter early effects of SSRIs, which might, in part, account for some delay in therapeutic effect.

  20. Neuropeptide Trefoil Factor 3 Reverses Depressive-Like Behaviors by Activation of BDNF-ERK-CREB Signaling in Olfactory Bulbectomized Rats

    Directory of Open Access Journals (Sweden)

    Jiali Li

    2015-11-01

    Full Text Available The trefoil factors (TFFs are a family of three polypeptides, among which TFF1 and TFF3 are widely distributed in the central nervous system. Our previous study indicated that TFF3 was a potential rapid-onset antidepressant as it reversed the depressive-like behaviors induced by acute or chronic mild stress. In order to further identify the antidepressant-like effect of TFF3, we applied an olfactory bulbectomy (OB, a classic animal model of depression, in the present study. To elucidate the mechanism underlying the antidepressant-like activity of TFF3, we tested the role of brain-derived neurotrophic factor (BDNF-extracellular signal-related kinase (ERK-cyclic adenosine monophosphate response element binding protein (CREB signaling in the hippocampus in the process. Chronic systemic administration of TFF3 (0.1 mg/kg, i.p. for seven days not only produced a significant antidepressant-like efficacy in the OB paradigm, but also restored the expression of BDNF, pERK, and pCREB in the hippocampal CA3. Inhibition of BDNF or extracellular signal-related kinase (ERK signaling in CA3 blocked the antidepressant-like activity of TFF3 in OB rats. Our findings further confirmed the therapeutic effect of TFF3 against depression and suggested that the normalization of the BDNF-ERK-CREB pathway was involved in the behavioral response of TFF3 for the treatment of depression.

  1. Neuropeptide Trefoil Factor 3 Reverses Depressive-Like Behaviors by Activation of BDNF-ERK-CREB Signaling in Olfactory Bulbectomized Rats.

    Science.gov (United States)

    Li, Jiali; Luo, Yixiao; Zhang, Ruoxi; Shi, Haishui; Zhu, Weili; Shi, Jie

    2015-11-30

    The trefoil factors (TFFs) are a family of three polypeptides, among which TFF1 and TFF3 are widely distributed in the central nervous system. Our previous study indicated that TFF3 was a potential rapid-onset antidepressant as it reversed the depressive-like behaviors induced by acute or chronic mild stress. In order to further identify the antidepressant-like effect of TFF3, we applied an olfactory bulbectomy (OB), a classic animal model of depression, in the present study. To elucidate the mechanism underlying the antidepressant-like activity of TFF3, we tested the role of brain-derived neurotrophic factor (BDNF)-extracellular signal-related kinase (ERK)-cyclic adenosine monophosphate response element binding protein (CREB) signaling in the hippocampus in the process. Chronic systemic administration of TFF3 (0.1 mg/kg, i.p.) for seven days not only produced a significant antidepressant-like efficacy in the OB paradigm, but also restored the expression of BDNF, pERK, and pCREB in the hippocampal CA3. Inhibition of BDNF or extracellular signal-related kinase (ERK) signaling in CA3 blocked the antidepressant-like activity of TFF3 in OB rats. Our findings further confirmed the therapeutic effect of TFF3 against depression and suggested that the normalization of the BDNF-ERK-CREB pathway was involved in the behavioral response of TFF3 for the treatment of depression.

  2. Cross-sex hormone treatment in male-to-female transsexual persons reduces serum brain-derived neurotrophic factor (BDNF).

    Science.gov (United States)

    Fuss, Johannes; Hellweg, Rainer; Van Caenegem, Eva; Briken, Peer; Stalla, Günter K; T'Sjoen, Guy; Auer, Matthias K

    2015-01-01

    Serum levels of brain-derived neurotrophic factor (BDNF) are reduced in male-to-female transsexual persons (MtF) compared to male controls. It was hypothesized before that this might reflect either an involvement of BDNF in a biomechanism of transsexualism or to be the result of persistent social stress due to the condition. Here, we demonstrate that 12 month of cross-sex hormone treatment reduces serum BDNF levels in male-to-female transsexual persons independent of anthropometric measures. Participants were acquired through the European Network for the Investigation of Gender Incongruence (ENIGI). Reduced serum BDNF in MtF thus seems to be a result of hormonal treatment rather than a consequence or risk factor of transsexualism.

  3. From Molecular to Nanotechnology Strategies for Delivery of Neurotrophins: Emphasis on Brain-Derived Neurotrophic Factor (BDNF

    Directory of Open Access Journals (Sweden)

    Claire Géral

    2013-02-01

    Full Text Available Neurodegenerative diseases represent a major public health problem, but beneficial clinical treatment with neurotrophic factors has not been established yet. The therapeutic use of neurotrophins has been restrained by their instability and rapid degradation in biological medium. A variety of strategies has been proposed for the administration of these leading therapeutic candidates, which are essential for the development, survival and function of human neurons. In this review, we describe the existing approaches for delivery of brain-derived neurotrophic factor (BDNF, which is the most abundant neurotrophin in the mammalian central nervous system (CNS. Biomimetic peptides of BDNF have emerged as a promising therapy against neurodegenerative disorders. Polymer-based carriers have provided sustained neurotrophin delivery, whereas lipid-based particles have contributed also to potentiation of the BDNF action. Nanotechnology offers new possibilities for the design of vehicles for neuroprotection and neuroregeneration. Recent developments in nanoscale carriers for encapsulation and transport of BDNF are highlighted.

  4. From molecular to nanotechnology strategies for delivery of neurotrophins: emphasis on brain-derived neurotrophic factor (BDNF).

    Science.gov (United States)

    Géral, Claire; Angelova, Angelina; Lesieur, Sylviane

    2013-02-08

    Neurodegenerative diseases represent a major public health problem, but beneficial clinical treatment with neurotrophic factors has not been established yet. The therapeutic use of neurotrophins has been restrained by their instability and rapid degradation in biological medium. A variety of strategies has been proposed for the administration of these leading therapeutic candidates, which are essential for the development, survival and function of human neurons. In this review, we describe the existing approaches for delivery of brain-derived neurotrophic factor (BDNF), which is the most abundant neurotrophin in the mammalian central nervous system (CNS). Biomimetic peptides of BDNF have emerged as a promising therapy against neurodegenerative disorders. Polymer-based carriers have provided sustained neurotrophin delivery, whereas lipid-based particles have contributed also to potentiation of the BDNF action. Nanotechnology offers new possibilities for the design of vehicles for neuroprotection and neuroregeneration. Recent developments in nanoscale carriers for encapsulation and transport of BDNF are highlighted.

  5. Reduced hippocampal brain-derived neurotrophic factor (BDNF) in neonatal rats after prenatal exposure to propylthiouracil (PTU).

    Science.gov (United States)

    Chakraborty, Goutam; Magagna-Poveda, Alejandra; Parratt, Carolyn; Umans, Jason G; MacLusky, Neil J; Scharfman, Helen E

    2012-03-01

    Thyroid hormone is critical for central nervous system development. Fetal hypothyroidism leads to reduced cognitive performance in offspring as well as other effects on neural development in both humans and experimental animals. The nature of these impairments suggests that thyroid hormone may exert its effects via dysregulation of the neurotrophin brain-derived neurotrophic factor (BDNF), which is critical to normal development of the central nervous system and has been implicated in neurodevelopmental disorders. The only evidence of BDNF dysregulation in early development, however, comes from experimental models in which severe prenatal hypothyroidism occurred. By contrast, milder prenatal hypothyroidism has been shown to alter BDNF levels and BDNF-dependent functions only much later in life. We hypothesized that mild experimental prenatal hypothyroidism might lead to dysregulation of BDNF in the early postnatal period. BDNF levels were measured by ELISA at 3 or 7 d after birth in different regions of the brains of rats exposed to propylthiouracil (PTU) in the drinking water. The dose of PTU that was used induced mild maternal thyroid hormone insufficiency. Pups, but not the parents, exhibited alterations in tissue BDNF levels. Hippocampal BDNF levels were reduced at both d 3 and 7, but no significant reductions were observed in either the cerebellum or brain stem. Unexpectedly, more males than females were born to PTU-treated dams, suggesting an effect of PTU on sex determination. These results support the hypothesis that reduced hippocampal BDNF levels during early development may contribute to the adverse neurodevelopmental effects of mild thyroid hormone insufficiency during pregnancy.

  6. Brain-derived neurotrophic factor (BDNF) and neurocognitive deficits in people with schizophrenia: a meta-analysis.

    Science.gov (United States)

    Ahmed, Anthony O; Mantini, Andrew M; Fridberg, Daniel J; Buckley, Peter F

    2015-03-30

    Studies suggest that the BDNF Val66Met (rs6265) polymorphism is associated with the incidence of schizophrenia and neurocognitive functioning. These associations appear to be however somewhat mixed. We conducted two separate meta-analyses to investigate (1) the association between the Val66Met polymorphism and neurocognition in people with schizophrenia and (2) the association between peripheral expression of BDNF and neurocognitive phenotypes. For the first aim, we identified 12 studies and 67 comparisons of Met allele carriers and Val homozygotes. These comparisons included 1890 people with schizophrenia (men=1465, women=553), of whom 972 were Met allele carriers and 918 were Val homozygotes. For the second aim, we identified five studies and 25 correlations of peripheral BDNF and neurocognitive scores. The meta-analysis for the second aim included 414 people with schizophrenia (men=292, women=170). First, we found non-significant difference between the genotype groups on most neurocognitive domains. Second, correlations between peripheral BDNF and neurocognitive phenotypes were minimal but we obtained significant effects for the reasoning and problem-solving domains; thus, higher levels of BDNF expression corresponded to better performance on reasoning/problem-solving tasks. The meta-analyses did not robustly establish an association between BDNF Val66Met polymorphism and neurocognition in schizophrenia.

  7. Effects of multiparity on recognition memory, monoaminergic neurotransmitters, and brain-derived neurotrophic factor (BDNF).

    Science.gov (United States)

    Macbeth, Abbe H; Scharfman, Helen E; Maclusky, Neil J; Gautreaux, Claris; Luine, Victoria N

    2008-06-01

    Recognition memory and anxiety were examined in nulliparous (NP: 0 litters) and multiparous (MP: 5-6 litters) middle-aged female rats (12 months old) to assess possible enduring effects of multiparity at least 3 months after the last litter was weaned. MP females performed significantly better than NP females on the non-spatial memory task, object recognition, and the spatial memory task, object placement. Anxiety as measured on the elevated plus maze did not differ between groups. Monoaminergic activity and levels were measured in prefrontal cortex, CA1 hippocampus, CA3 hippocampus, and olfactory bulb (OB). NP and MP females differed in monoamine concentrations in the OB only, with MP females having significantly greater concentrations of dopamine and metabolite DOPAC, norepinephrine and metabolite MHPG, and the serotonin metabolite 5-HIAA, as compared to NP females. These results indicate a long-term change in OB neurochemistry as a result of multiparity. Brain-derived neurotrophic factor (BDNF) was also measured in hippocampus (CA1, CA3, dentate gyrus) and septum. MP females had higher BDNF levels in both CA1 and septum; as these regions are implicated in memory performance, elevated BDNF may underlie the observed memory task differences. Thus, MP females (experiencing multiple bouts of pregnancy, birth, and pup rearing during the first year of life) displayed enhanced memory task performance but equal anxiety responses, as compared to NP females. These results are consistent with previous studies showing long-term changes in behavioral function in MP, as compared to NP, rats and suggest that alterations in monoamines and a neurotrophin, BDNF, may contribute to the observed behavioral changes.

  8. Positive association between the brain-derived neurotrophic factor (BDNF) gene and bipolar disorder in the Han Chinese population.

    Science.gov (United States)

    Xu, Jie; Liu, Yun; Wang, Peng; Li, Sheng; Wang, Yabing; Li, Jun; Zhou, Daizhan; Chen, Zhuo; Zhao, Teng; Wang, Ting; Xu, He; Yang, Yifeng; Feng, Guoyin; He, Lin; Yu, Lan

    2010-01-05

    Brain-derived neurotrophic factor (BDNF) is the most widely distributed neurotrophin in the central nervous system (CNS), and services many biological functions such as neural survival, differentiation, and plasticity. Previous studies have suggested that the Val66Met (also known as rs6265 or G196A) variant of BDNF is associated with bipolar disorder (BPD), but the results have been inconclusive. We therefore genotyped the Val66Met polymorphism in a Han Chinese population sample (498 cases and 501 control subjects). We found that the BDNF genotype is associated with BPD in this population (chi(2) = 9.4666, df = 2, P = 0.00884). Furthermore, our data suggested that the Met allele rather than the Val allele increased the risk for BPD in our Han population (OR = 1.44; 95% CI = 1.070-1.950; P = 0.016). Further studies are necessary to elucidate the involvement of the BDNF gene in the pathophysiology of BPD.

  9. Imipramine induces brain-derived neurotrophic factor mRNA expression in cultured astrocytes.

    Science.gov (United States)

    Takano, Katsura; Yamasaki, Hiroshi; Kawabe, Kenji; Moriyama, Mitsuaki; Nakamura, Yoichi

    2012-01-01

    Depression is one of the most prevalent and livelihood-threatening forms of mental illnesses and the neural circuitry underlying depression remains incompletely understood. Recent studies suggest that the neuronal plasticity involved with brain-derived neurotrophic factor (BDNF) plays an important role in the recovery from depression. Some antidepressants are reported to induce BDNF expression in vivo; however, the mechanisms have been considered solely in neurons and not fully elucidated. In the present study, we evaluated the effects of imipramine, a classic tricyclic antidepressant drug, on BDNF expression in cultured rat brain astrocytes. Imipramine dose-dependently increased BDNF mRNA expression in astrocytes. The imipramine-induced BDNF increase was suppressed with inhibitors for protein kinase A (PKA) or MEK/ERK. Moreover, imipramine exposure activated transcription factor cAMP response element binding protein (CREB) in a dose-dependent manner. These results suggested that imipramine induced BDNF expression through CREB activation via PKA and/or ERK pathways. Imipramine treatment in depression might exert antidepressant action through BDNF production from astrocytes, and glial BDNF expression might be a target of developing novel antidepressants.

  10. Alterations of BDNF and trkB mRNA expression in the 6-hydroxydopamine-induced model of preclinical stages of Parkinson's disease: an influence of chronic pramipexole in rats.

    Directory of Open Access Journals (Sweden)

    Klemencja Berghauzen-Maciejewska

    Full Text Available Our recent study has indicated that a moderate lesion of the mesostriatal and mesolimbic pathways in rats, modelling preclinical stages of Parkinson's disease, induces a depressive-like behaviour which is reversed by chronic treatment with pramipexole. The purpose of the present study was to examine the role of brain derived neurotrophic factor (BDNF signalling in the aforementioned model of depression. Therefore, we investigated the influence of 6-hydoxydopamine (6-OHDA administration into the ventral region of the caudate-putamen on mRNA levels of BDNF and tropomyosin-related kinase B (trkB receptor. The BDNF and trkB mRNA levels were determined in the nigrostriatal and limbic structures by in situ hybridization 2 weeks after the operation. Pramipexole (1 mg/kg sc twice a day and imipramine (10 mg/kg ip once a day were injected for 2 weeks. The lesion lowered the BDNF and trkB mRNA levels in the hippocampus [CA1, CA3 and dentate gyrus (DG] and amygdala (basolateral/lateral as well as the BDNF mRNA content in the habenula (medial/lateral. The lesion did not influence BDNF and trkB expression in the caudate-putamen, substantia nigra, nucleus accumbens (shell and core and ventral tegmental area (VTA. Chronic imipramine reversed the lesion-induced decreases in BDNF mRNA in the DG. Chronic pramipexole increased BDNF mRNA, but decreased trkB mRNA in the VTA in lesioned rats. Furthermore, it reduced BDNF and trkB mRNA expression in the shell and core of the nucleus accumbens, BDNF mRNA in the amygdala and trkB mRNA in the caudate-putamen in these animals. The present study indicates that both the 6-OHDA-induced dopaminergic lesion and chronic pramipexole influence BDNF signalling in limbic structures, which may be related to their pro-depressive and antidepressant activity in rats, respectively.

  11. Alterations of BDNF and trkB mRNA expression in the 6-hydroxydopamine-induced model of preclinical stages of Parkinson's disease: an influence of chronic pramipexole in rats.

    Science.gov (United States)

    Berghauzen-Maciejewska, Klemencja; Wardas, Jadwiga; Kosmowska, Barbara; Głowacka, Urszula; Kuter, Katarzyna; Ossowska, Krystyna

    2015-01-01

    Our recent study has indicated that a moderate lesion of the mesostriatal and mesolimbic pathways in rats, modelling preclinical stages of Parkinson's disease, induces a depressive-like behaviour which is reversed by chronic treatment with pramipexole. The purpose of the present study was to examine the role of brain derived neurotrophic factor (BDNF) signalling in the aforementioned model of depression. Therefore, we investigated the influence of 6-hydoxydopamine (6-OHDA) administration into the ventral region of the caudate-putamen on mRNA levels of BDNF and tropomyosin-related kinase B (trkB) receptor. The BDNF and trkB mRNA levels were determined in the nigrostriatal and limbic structures by in situ hybridization 2 weeks after the operation. Pramipexole (1 mg/kg sc twice a day) and imipramine (10 mg/kg ip once a day) were injected for 2 weeks. The lesion lowered the BDNF and trkB mRNA levels in the hippocampus [CA1, CA3 and dentate gyrus (DG)] and amygdala (basolateral/lateral) as well as the BDNF mRNA content in the habenula (medial/lateral). The lesion did not influence BDNF and trkB expression in the caudate-putamen, substantia nigra, nucleus accumbens (shell and core) and ventral tegmental area (VTA). Chronic imipramine reversed the lesion-induced decreases in BDNF mRNA in the DG. Chronic pramipexole increased BDNF mRNA, but decreased trkB mRNA in the VTA in lesioned rats. Furthermore, it reduced BDNF and trkB mRNA expression in the shell and core of the nucleus accumbens, BDNF mRNA in the amygdala and trkB mRNA in the caudate-putamen in these animals. The present study indicates that both the 6-OHDA-induced dopaminergic lesion and chronic pramipexole influence BDNF signalling in limbic structures, which may be related to their pro-depressive and antidepressant activity in rats, respectively.

  12. 基因转染的虹膜色素上皮细胞移植后RCS鼠视网膜BDNF表达观察%Retinal BDNF expressions in RCS rats after transplantation of gene transfected iris pigment epithelium

    Institute of Scientific and Technical Information of China (English)

    张英瑜; 高朋芬; 杨丽霞

    2011-01-01

    目的 探讨脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)基因转染的虹膜色素上皮细胞(AAV-BDNF-IPE)移植入皇家外科学院(royal college of surgeons,RCS)大鼠视网膜下腔后,不同时期视网膜组织BDNF表达变化.方法 通过外路途径将BDNF基因转染的虹膜色素上皮细胞移植到RCS大鼠视网膜下腔,术后3、5、7、9、11周分别取RCS大鼠手术眼及对照组动物眼视网膜组织,用酶联免疫吸附法(Elisa)检测视网膜组织中BDNF的表达水平,比较分析这些数据.结果 对照组RCS大鼠出生后3周龄时视网膜组织中BDNF仍保持较高水平,其后迅速降低,其中3周龄组与其它周龄组比较,P<0.01;手术组RCS大鼠术时、术后3、5、7、9、11周各组间两两比较,BDNF表达无显著差异(P>0.05);出生后6周龄直到14周龄的不同时期,AAV-BDNF-IPE移植手术组RCS大鼠视网膜BDNF表达水平均明显高于对照组(其中6周龄组P<0.05,其它各周龄组P<0.01).结论 BDNF基因转染的虹膜色素上皮细胞在RCS大鼠视网膜下腔移植后,视网膜组织中BDNF可以持续稳定高水平表达,这为临床开发新的神经营养因子给药方式提供了实验依据.%Objective To investigate the retinal brain derived neurotrophic factor( BDNF) expressions in different phases of royal college of surgeons( RCS) rats after BDNF transfected iris pigment epithelium( AAV-BDNF-IPE) being transplanted into the subretinal space of RCS rat. Methods AAV-BDNF-IPEs were transplanted into the subretinal space of RCS rats. BDNF expressions in retinal tissue of intact RCS rats and surgery RCS rats were detected by enzyme linked immunosorbent assay ( Elisa) at 3 ,5 ,7 ,9and 11 weeks after surgery. Results BDNF expressions in retinal tissue of intact RCS rats were still high at postnatal 3w and were sharply decreased into low level later; retinal BDNF expression of intact RCS rats at postnatal 3w were much higher than those at other

  13. Brain derived neurotrophic factor gene (BDNF) and personality traits: the modifying effect of season of birth and sex.

    Science.gov (United States)

    Kazantseva, A; Gaysina, D; Kutlumbetova, Yu; Kanzafarova, R; Malykh, S; Lobaskova, M; Khusnutdinova, E

    2015-01-02

    Personality traits are complex phenotypes influenced by interactions of multiple genetic variants of small effect and environmental factors. It has been suggested that the brain derived neurotrophic factor gene (BDNF) is involved in personality traits. Season of birth (SOB) has also been shown to affect personality traits due to its influences on brain development during prenatal and early postnatal periods. The present study aimed to investigate the effects of BDNF on personality traits; and the modifying effects of SOB and sex on associations between BDNF and personality traits. A sample of 1018 young adults (68% women; age range 17-25years) of Caucasian origin from the Russian Federation was assessed on personality traits (Novelty Seeking, Harm Avoidance, Reward Dependence, Persistence, Self-directedness, Cooperativeness, Self-transcendence) with the Temperament and Character Inventory-125 (TCI-125). Associations between personality traits and 12 BDNF SNPs were tested using linear regression models. The present study demonstrated the effect of rs11030102 on Persistence in females only (PFDR=0.043; r(2)=1.3%). There were significant interaction effects between Val66Met (rs6265) and SOB (PFDR=0.048, r(2)=1.4%), and between rs2030323 and SOB (PFDR=0.042, r(2)=1.3%), on Harm Avoidance. Our findings provide evidence for the modifying effect of SOB on the association between BDNF and Harm Avoidance, and for the modifying effect of sex on the association between BDNF and Persistence.

  14. Brain Derived Neurotrophic Factor (BDNF) levels as a possible predictor of psychopathology in healthy twins at high and low risk for affective disorder

    DEFF Research Database (Denmark)

    Vinberg, Maj; Miskowiak, Kamilla; Kessing, Lars Vedel

    2014-01-01

    Brain Derived Neurotrophic Factor (BDNF) is a potential biomarker of affective disorder. However, longitudinal studies evaluating a potential predictive role of BDNF on subsequent psychopathology are lacking. The aim of this study was to investigate whether BDNF alone or in interaction...... with the BDNF Val66Met polymorphism predict onset of affective disorder in healthy individuals at heritable risk for affective disorder. In a high-risk study, we assessed whole blood levels of BDNF in 234 healthy monozygotic and dizygotic twins with or without a co-twin history of affective disorder (high...... developed psychiatric disorder. Cox regression analysis revealed that BDNF levels at baseline were not associated with onset of illness in this explorative study. Further, two-way interactions between BDNF levels and the Val66Met polymorphism or between familial risk and the Val66Met polymorphism did...

  15. EXPRESSING HUMAN MATURED BRAIN-DERIVED NEUROTROPHIC FACTOR GENE IN E. Coli AND DETERMINING ITS BIOACTIVITY

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective Expressing the human matured brain-derived neurotrophic factor (mBDNF) gene in E.Coli and determining its bioactivity. Methods The resulting gene of mBDNF was subcloned into the EcoRI-BamHI site of the expression vector plasmid pBV220. The ligation products were used to transform the competent E. Coli DH5α. The proteins of mBDNF were experessed by temperature inducing. The expression products were dealed with solubilizing inclusion bodies and refolding protein. It was introduced into the embryonic chicken DRG to test whether the expressed mBDNF is a biologically active protein. Results The recombinant plasmid pBV/mBDNF was successfully constructed. By temperature inducing,under the control of the bacteriophage λ PL promoter, the experessed mBDNF protein was a 14Kd non-fusion protein,which existed in E. Coli as inclusion bodies. The size of expressed mBDNF is identical to the prediction. Bioactivity of the products was proved that it could support the cell survival and neurite growth in the primary cultures of embryonic 8-day-old chicken DRG neurons as compared to control.Conclusion The mBDNF gene can be expressed bioactively in E. Coli.

  16. FTY720/Fingolimod Reduces Synucleinopathy and Improves Gut Motility in A53T Mice: CONTRIBUTIONS OF PRO-BRAIN-DERIVED NEUROTROPHIC FACTOR (PRO-BDNF) AND MATURE BDNF.

    Science.gov (United States)

    Vidal-Martínez, Guadalupe; Vargas-Medrano, Javier; Gil-Tommee, Carolina; Medina, David; Garza, Nathan T; Yang, Barbara; Segura-Ulate, Ismael; Dominguez, Samantha J; Perez, Ruth G

    2016-09-23

    Patients with Parkinson's disease (PD) often have aggregated α-synuclein (aSyn) in enteric nervous system (ENS) neurons, which may be associated with the development of constipation. This occurs well before the onset of classic PD motor symptoms. We previously found that aging A53T transgenic (Tg) mice closely model PD-like ENS aSyn pathology, making them appropriate for testing potential PD therapies. Here we show that Tg mice overexpressing mutant human aSyn develop ENS pathology by 4 months. We then evaluated the responses of Tg mice and their WT littermates to the Food and Drug Administration-approved drug FTY720 (fingolimod, Gilenya) or vehicle control solution from 5 months of age. Long term oral FTY720 in Tg mice reduced ENS aSyn aggregation and constipation, enhanced gut motility, and increased levels of brain-derived neurotrophic factor (BDNF) but produced no significant change in WT littermates. A role for BDNF was directly assessed in a cohort of young A53T mice given vehicle, FTY720, the Trk-B receptor inhibitor ANA-12, or FTY720 + ANA-12 from 1 to 4 months of age. ANA-12-treated Tg mice developed more gut aSyn aggregation as well as constipation, whereas FTY720-treated Tg mice had reduced aSyn aggregation and less constipation, occurring in part by increasing both pro-BDNF and mature BDNF levels. The data from young and old Tg mice revealed FTY720-associated neuroprotection and reduced aSyn pathology, suggesting that FTY720 may also benefit PD patients and others with synucleinopathy. Another finding was a loss of tyrosine hydroxylase immunoreactivity in gut neurons with aggregated aSyn, comparable with our prior findings in the CNS.

  17. Expression of brain derived-neurotrophic factor and granulocyte-colony stimulating factor in the urothelium: relation with voiding function

    OpenAIRE

    Yuk, Seung Mo; Shin, Ju Hyun; Song, Ki Hak; Na, Yong Gil; Lim, Jae Sung; Sul, Chong Koo

    2015-01-01

    Background We designed this experiment to elucidate the relationship between the expression of brain derived-neurotrophic factor (BDNF), the expression of granulocyte-colony stimulating factor (G-CSF), and the development of overactive bladder (OAB). In our previous study, the urothelium was observed to be more than a simple mechanosensory receptor and was found to be a potential therapeutic target for OAB. Moreover, neuregulin-1 and BDNF were found to be potential new biomarkers of OAB. Here...

  18. Chronic ethanol ingestion, type 2 diabetes mellitus, and brain-derived neurotrophic factor (BDNF) in rats.

    Science.gov (United States)

    Jung, Kyu-In; Ju, Anes; Lee, Hee-Mi; Lee, Seong-Su; Song, Chan-Hee; Won, Wang-Youn; Jeong, Jae-Seung; Hong, Oak-Kee; Kim, Jae-Hwa; Kim, Dai-Jin

    2011-01-07

    Chronic alcohol consumption contributes to the development of type 2 diabetes mellitus (T2DM) while decreasing the level of brain-derived neurotrophic factor (BDNF). BDNF may be an important regulator of glucose metabolism, so it may be associated with an increased risk for T2DM in alcoholism. We evaluated the association of chronic heavy alcohol exposure, T2DM and BDNF level. Ten week-old type 2 diabetic OLETF rats and non-diabetic LETO rats of similar weight were used. The rats were randomized by weight into four treatment groups: (1) OLETF-Ethanol (O-E, n=13), (2) OLETF-Control (O-C, n=15), (3) LETO-Ethanol (L-E, n=11), and (4) LETO-Control (L-C, n=14). The ethanol groups were fed an isocaloric liquid diet containing ethanol while the control groups were fed with the same diet containing maltose-dextran over a 6-week period using a pair-feeding control model in order to regulate different caloric ingestion. After 6 weeks of feeding, an Intraperitoneal Glucose Tolerance Test (IP-GTT) was performed and BDNF levels were analyzed. Prior to IP-GTT, the mean glucose levels in the O-E, O-C, L-E, and L-C groups were 90.38±12.84, 102.13±5.04, 95.18±6.43, and 102.36±4.43mg/dL, respectively. Thirty minutes after intraperitoneal injection, the mean glucose levels were 262.62±63.77, 229.07±51.30, 163.45±26.63, and 156.64±34.42mg/dL, respectively; the increased amount of the mean glucose level in the O-E group was significantly higher than that in the O-C group (palcohol ingestion may aggravate T2DM and may possibly lower BDNF level.

  19. Changes in brain-derived neurotrophic factor (BDNF) during abstinence could be associated with relapse in cocaine-dependent patients.

    Science.gov (United States)

    Corominas-Roso, Margarida; Roncero, Carlos; Daigre, Constanza; Grau-Lopez, Lara; Ros-Cucurull, Elena; Rodríguez-Cintas, Laia; Sanchez-Mora, Cristina; Lopez, Maria Victoria; Ribases, Marta; Casas, Miguel

    2015-02-28

    Brain-derived neurotrophic factor (BDNF) is involved in cocaine craving in humans and drug seeking in rodents. Based on this, the aim of this study was to explore the possible role of serum BDNF in cocaine relapse in abstinent addicts. Forty cocaine dependent subjects (DSM-IV criteria) were included in an inpatient 2 weeks abstinence program. Organic and psychiatric co-morbidities were excluded. Two serum samples were collected for each subject at baseline and at after 14 abstinence days. After discharge, all cocaine addicts underwent a 22 weeks follow-up, after which they were classified into early relapsers (ER) (resumed during the first 14 days after discharge,) or late relapsers (LR) (resumed beyond 14 days after discharge). The only clinical differences between groups were the number of consumption days during the last month before detoxification. Serum BDNF levels increased significantly across the 12 days of abstinence in the LR group (p=0.02), whereas in the ER group BDNF remained unchanged. In the ER group, the change of serum BDNF during abstinence negatively correlated with the improvement in depressive symptoms (p=0.02). These results suggest that BDNF has a role in relapse to cocaine consumption in abstinent addicts, although the underlying neurobiological mechanisms remain to be clarified.

  20. Immunohistochemical, ultrastructural and functional analysis of axonal regeneration through peripheral nerve grafts containing Schwann cells expressing BDNF, CNTF or NT3.

    Directory of Open Access Journals (Sweden)

    Maria João Godinho

    Full Text Available We used morphological, immunohistochemical and functional assessments to determine the impact of genetically-modified peripheral nerve (PN grafts on axonal regeneration after injury. Grafts were assembled from acellular nerve sheaths repopulated ex vivo with Schwann cells (SCs modified to express brain-derived neurotrophic factor (BDNF, a secretable form of ciliary neurotrophic factor (CNTF, or neurotrophin-3 (NT3. Grafts were used to repair unilateral 1 cm defects in rat peroneal nerves and 10 weeks later outcomes were compared to normal nerves and various controls: autografts, acellular grafts and grafts with unmodified SCs. The number of regenerated βIII-Tubulin positive axons was similar in all grafts with the exception of CNTF, which contained the fewest immunostained axons. There were significantly lower fiber counts in acellular, untransduced SC and NT3 groups using a PanNF antibody, suggesting a paucity of large caliber axons. In addition, NT3 grafts contained the greatest number of sensory fibres, identified with either IB4 or CGRP markers. Examination of semi- and ultra-thin sections revealed heterogeneous graft morphologies, particularly in BDNF and NT3 grafts in which the fascicular organization was pronounced. Unmyelinated axons were loosely organized in numerous Remak bundles in NT3 grafts, while the BDNF graft group displayed the lowest ratio of umyelinated to myelinated axons. Gait analysis revealed that stance width was increased in rats with CNTF and NT3 grafts, and step length involving the injured left hindlimb was significantly greater in NT3 grafted rats, suggesting enhanced sensory sensitivity in these animals. In summary, the selective expression of BDNF, CNTF or NT3 by genetically modified SCs had differential effects on PN graft morphology, the number and type of regenerating axons, myelination, and locomotor function.

  1. Expression and purification of BDNF-TAT fusion protein in E.coli and its distribution in brain%BDNF-TAT融合蛋白在大肠杆菌中的表达纯化及脑中分布

    Institute of Scientific and Technical Information of China (English)

    罗道飞; 李文适; 陈姗; 季爱民

    2011-01-01

    目的 在大肠杆菌中表达并纯化BDNF-TAT融合蛋白,研究其靶向性及在脑中的分布.方法 重组质粒PET-30(a)-BDNF-TAT转染至大肠杆菌BL21(DE3)pLysS中,IPTG诱导其表达后用SP-Sepharose阳离子交换柱纯化,纯化后蛋白用0.4 mol/L精氨酸倍比稀释法复性.KM种小鼠采用随机数字表法分为给药组[尾静脉注射复性后BDNF-TAT融合蛋白4 μg(适量生理盐水溶解)]、阴性对照组(尾静脉注射等体积生理盐水)和空白对照组(不进行任何处理),每组各3只.3 h后提取小鼠脑组织全蛋白,Western blotting检测脑组织中BDNF-TAT表达,SABC免疫组化染色观察BDNF-TAT在脑组织中的分布.结果 获得纯度约90%活性的BDNF-TAT融合蛋白.给药组BDNF-TAT蛋白的相对表达最为1.897±0.286,阴性对照组BDNF-TAT蛋白的相对表达量为0.615±0.234,空白对照组BDNF-TAT蛋白的相对表达量为0.335±0.154,比较差异有统计学意义(F=39.019,P=0.0000).免疫组化染色结果显示给药组BDNF-TAT主要分布于小鼠脑组织海马CA1、CA3和DG区,而阴性对照组和空白对照组巾没有明显阳性染色.结论 BDNF-TAT融合蛋白在大肠杆菌中以包涵体形式大量表达,并能通过外周给药靶向至小鼠脑组织.%Objective To explore the expression and purification of BDNF-TAT fusion protein in E.coli, and study its brain-targeting and distribution in brain. Methods Plasmid PET-30(a) -BDNF-TAT was transfected into the E.coli BL21 (DE3)pLysS;the expression of PET-30(a)-BDNF-TAT was induced by isopropyl-beta-d-thiogalactopyranoside (IPTG);this BDNF-TAT fusion protein was purified by SP-Sepharose cation exchange column and then renatured by 0.4 mol/L arginine. According to the random number table method, KM mice were divided into 3 groups: BDNF-TAT treatment group (giving 4 μg BDNF-TAT through intravenous injection, n=3), negative control group (giving same volume of saline through intravenous injection, n=3) and blank control group

  2. Spinal Plasticity and Behavior: BDNF-Induced Neuromodulation in Uninjured and Injured Spinal Cord

    Directory of Open Access Journals (Sweden)

    Sandra M. Garraway

    2016-01-01

    Full Text Available Brain-derived neurotrophic factor (BDNF is a member of the neurotrophic factor family of signaling molecules. Since its discovery over three decades ago, BDNF has been identified as an important regulator of neuronal development, synaptic transmission, and cellular and synaptic plasticity and has been shown to function in the formation and maintenance of certain forms of memory. Neural plasticity that underlies learning and memory in the hippocampus shares distinct characteristics with spinal cord nociceptive plasticity. Research examining the role BDNF plays in spinal nociception and pain overwhelmingly suggests that BDNF promotes pronociceptive effects. BDNF induces synaptic facilitation and engages central sensitization-like mechanisms. Also, peripheral injury-induced neuropathic pain is often accompanied with increased spinal expression of BDNF. Research has extended to examine how spinal cord injury (SCI influences BDNF plasticity and the effects BDNF has on sensory and motor functions after SCI. Functional recovery and adaptive plasticity after SCI are typically associated with upregulation of BDNF. Although neuropathic pain is a common consequence of SCI, the relation between BDNF and pain after SCI remains elusive. This article reviews recent literature and discusses the diverse actions of BDNF. We also highlight similarities and differences in BDNF-induced nociceptive plasticity in naïve and SCI conditions.

  3. Corticosterone regulates expression of BDNF and trkB but not NT-3 and trkC mRNA in the rat hippocampus.

    Science.gov (United States)

    Schaaf, M J; Hoetelmans, R W; de Kloet, E R; Vreugdenhil, E

    1997-05-15

    Corticosterone has profound effects on growth, differentiation, and synaptic transmission of hippocampal neurons by activation of mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs). In the present study we tested if neurotrophins can be implicated in these effects. For this purpose we injected 30, 300, and 1,000 microg corticosterone s.c. (per kg body weight) in adrenalectomized rats and measured the mRNA levels of brain-derived neurotrophic factor (BDNF), tyrosine receptor kinase (trk)B, neurotrophin (NT)-3, and trkC in hippocampal cell fields at 6 hr after steroid administration by in situ hybridization. NT-3 and trkC mRNA did not show significant changes in any hippocampal region after the various doses of corticosterone. BDNF mRNA decreased after corticosterone administration dose dependently, resulting in a maximal suppression of 35, 20, and 50% in dentate gyrus, CA3, and CA1, respectively. Interestingly, trkB responded to corticosterone in an inverted U-shaped fashion in CA3 and dentate gyrus: the low dose of corticosterone increased trkB mRNA expression in both regions by approximately 30%, while the effect of the two higher doses was not different from the vehicle injected controls. In conclusion, we found differential effects of low and high doses of corticosterone on BDNF and trkB expression in hippocampus, which suggests involvement of a coordinated MR- and GR-mediated action.

  4. Time-dependent biphasic modulation of human BDNF by antidepressants in neuroblastoma cells

    Directory of Open Access Journals (Sweden)

    Musazzi Laura

    2008-07-01

    Full Text Available Abstract Background Recent rodent studies reported that antidepressant treatments affect the expression of brain-derived neurotrophic factor (BDNF mRNA in a way that is dependent on treatment duration, by selective modulation of different BDNF transcripts. However, no data are available for the human BDNF gene. We studied the effect of different antidepressants on BDNF mRNA expression in human neuroblastoma SH-SY5Y cells. Results Cultured cells were treated with the antidepressants fluoxetine, reboxetine and desipramine for different time lengths (6, 24, 48 hours. Expression of total BDNF mRNA was analyzed by reverse transcription PCR and levels of different BDNF transcripts were detected by hemi-nested PCR with specific primers. Short-term treatment (6 hours with reboxetine or desipramine reduced total BDNF, whereas long-term treatment (48 hours significantly increased total BDNF mRNA levels. These changes were accounted for by differential regulation of BDNF IV and VIa/b transcripts. Fluoxetine showed no significant effects. Conclusion This is the first study showing biphasic changes in the expression of total and specific BDNF transcripts in human cells following antidepressant treatments. These findings suggest that biphasic induction of BDNF by antidepressants could be a feature common to rodents and humans and encourage the use of SH-SY5Y cells as a tool for investigation of drug effects on human genes.

  5. THE ROLE OF BDNF IN THE DEVELOPMENT OF FEAR LEARNING

    Science.gov (United States)

    Dincheva, Iva; Lynch, Niccola B.; Lee, Francis S.

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) is a growth factor that is dynamically expressed in the brain across postnatal development, regulating neuronal differentiation and synaptic plasticity. The neurotrophic hypothesis of psychiatric mood disorders postulates that in the adult brain, decreased BDNF levels leads to altered neural plasticity, contributing to disease. Although BDNF has been established as a key factor regulating the critical period plasticity in the developing visual system, it has recently been shown to also play a role in fear circuitry maturation, which has implications for the emergence of fear-related mood disorders. This review provides a detailed overview of developmental changes in expression of BDNF isoforms, as well as their receptors across postnatal life. In addition, recent developmental studies utilizing a genetic BDNF single nucleotide polymorphism (Val66Met) knock-in mouse highlight the impact of BDNF on fear learning during a sensitive period spanning the transition into adolescent time frame. We hypothesize that BDNF in the developing brain regulates fear circuit plasticity during a sensitive period in early adolescence, and alterations in BDNF expression (genetic or environmental) have a persistent impact on fear behavior and fear-related disorders. PMID:27699937

  6. Molecular mechanisms underlying the regulation of brain-derived neurotrophic factor (BDNF) translation in dendrites

    OpenAIRE

    Pinheiro, Vera Lúcia Margarido

    2010-01-01

    Dissertação de mestrado em Biologia Celular e Molecular apresentada ao Departamento de Ciências da Vida da Faculdade de Ciências e Tecnologia da Universidade de Coimbra A especificidade espacial e temporal subjacente à diversidade de processos de plasticidade sináptica que ocorrem no sistema nervoso central está profundamente relacionada com a disponibilidade da proteína brain-derived neurotrophic factor (BDNF) em domínios sub-celulares distintos, especialmente na área pós-sinápti...

  7. Molecular mechanisms underlying the regulation of brain-derived neurotrophic factor (BDNF) translation in dendrites

    OpenAIRE

    Pinheiro, Vera Lúcia Margarido

    2010-01-01

    Dissertação de mestrado em Biologia Celular e Molecular apresentada ao Departamento de Ciências da Vida da Faculdade de Ciências e Tecnologia da Universidade de Coimbra A especificidade espacial e temporal subjacente à diversidade de processos de plasticidade sináptica que ocorrem no sistema nervoso central está profundamente relacionada com a disponibilidade da proteína brain-derived neurotrophic factor (BDNF) em domínios sub-celulares distintos, especialmente na área pós-sinápti...

  8. Baclofen prevents the elevated plus maze behavior and BDNF expression during naloxone precipitated morphine withdrawal in male and female mice.

    Science.gov (United States)

    Pedrón, Valeria T; Varani, André P; Balerio, Graciela N

    2016-05-01

    In previous studies we have shown that baclofen, a selective GABAB receptor agonist, prevents the somatic expression and reestablishes the dopamine and μ-opioid receptors levels, modified during naloxone-precipitated morphine withdrawal syndrome in male and female mice. There are no previous reports regarding sex differences in the elevated plus maze (EPM) and the expression of BDNF in morphine-withdrawn mice. The present study analyses the behavioral and biochemical variations during morphine withdrawal in mice of both sexes, and whether these variations are prevented with baclofen. Swiss-Webster albino prepubertal mice received morphine (2 mg/kg, i.p.) twice daily, for 9 consecutive days. On the 10th day, one group of morphine-treated mice received naloxone (opioid receptor antagonist; 6 mg/kg, i.p.) 1 h after the last dose of morphine to precipitate withdrawal. A second group received baclofen (2 mg/kg, i.p.) before naloxone administration. The EPM behavior was measured during 15 min after naloxone injection. The expression of BDNF-positive cells was determined by immunohistochemistry. Withdrawn male mice showed a higher percentage of time spent and number of entries to the open arms compared to withdrawn female mice. Baclofen prevented this behavior in both sexes. BDNF expression decreased in the AcbC, BNST, CeC, and CA3 of the hippocampus while increased in the BLA of morphine withdrawn male. Baclofen pretreatment prevented the BDNF expression observed in morphine withdrawn male mice in all the brain areas studied except in the CeC. Baclofen prevention of the EPM behavior associated to morphine withdrawal could be partially related to changes in BDNF expression.

  9. Ultra-sensitive detection of brain-derived neurotrophic factor (BDNF) in the brain of freely moving mice using an interdigitated microelectrode (IME) biosensor.

    Science.gov (United States)

    Yoo, Yong Kyoung; Lee, Jaekwang; Kim, Jinsik; Kim, Gangeun; Kim, Sunpil; Kim, Jeongyeon; Chun, Heejung; Lee, Jeong Hoon; Lee, C Justin; Hwang, Kyo Seon

    2016-09-19

    Brain-derived neurotrophic factor (BDNF) plays a critical role in cognitive processes including learning and memory. However, it has been difficult to detect BDNF in the brains of behaving animals because of its extremely low concentration, i.e., at the sub-nanogram/mL level. Here, we developed an interdigitated microelectrode (IME) biosensor coated with an anti-BDNF an anti-BDNF antibody in a polydimethylsiloxane (PDMS)-based microfluidic channel chip. This sensor could detect BDNF from microliter volumes of liquid samples even at femtogram/mL concentrations with high selectivity over other growth factors. Using this biosensor, we examined whether BDNF is detectable from periodical collection of cerebrospinal fluid microdialysate, sampled every 10 min from the hippocampus of mice during the context-dependent fear-conditioning test. We found that the IME biosensor could detect a significant increase in BDNF levels after the memory task. This increase in BDNF levels was prevented by gene silencing of BDNF, indicating that the IME biosensor reliably detected BDNF in vivo. We propose that the IME biosensor provides a general-purpose probe for ultrasensitive detection of biomolecules with low abundance in the brains of behaving animals.

  10. The brain-derived neurotrophic factor (BDNF gene Val66Met polymorphism affects memory performance in older adults

    Directory of Open Access Journals (Sweden)

    Lucas A. de Azeredo

    Full Text Available Objective: Memory impairment is an important contributor to the reduction in quality of life experienced by older adults, and genetic risk factors seem to contribute to variance in age-related cognitive decline. Brain-derived neurotrophic factor (BDNF is an important nerve growth factor linked with development and neural plasticity. The Val66Met polymorphism in the BDNF gene has been associated with impaired episodic memory in adults, but whether this functional variant plays a role in cognitive aging remains unclear. The purpose of this study was to investigate the effects of the BDNF Val66Met polymorphism on memory performance in a sample of elderly adults. Methods: Eighty-seven subjects aged > 55 years were recruited using a community-based convenience sampling strategy in Porto Alegre, Brazil. The logical memory subset of the Wechsler Memory Scale-Revised was used to assess immediate verbal recall (IVR, delayed verbal recall (DVR, and memory retention rate. Results: BDNF Met allele carriers had lower DVR scores (p = 0.004 and a decline in memory retention (p = 0.017 when compared to Val/Val homozygotes. However, we found no significant differences in IVR between the two groups (p = 0.088. Conclusion: These results support the hypothesis of the BDNF Val66Met polymorphism as a risk factor associated with cognitive impairment, corroborating previous findings in young and older adults.

  11. The brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism affects memory performance in older adults.

    Science.gov (United States)

    Azeredo, Lucas A de; De Nardi, Tatiana; Levandowski, Mateus L; Tractenberg, Saulo G; Kommers-Molina, Julia; Wieck, Andrea; Irigaray, Tatiana Q; Silva, Irênio G da; Grassi-Oliveira, Rodrigo

    2017-01-01

    Memory impairment is an important contributor to the reduction in quality of life experienced by older adults, and genetic risk factors seem to contribute to variance in age-related cognitive decline. Brain-derived neurotrophic factor (BDNF) is an important nerve growth factor linked with development and neural plasticity. The Val66Met polymorphism in the BDNF gene has been associated with impaired episodic memory in adults, but whether this functional variant plays a role in cognitive aging remains unclear. The purpose of this study was to investigate the effects of the BDNF Val66Met polymorphism on memory performance in a sample of elderly adults. Eighty-seven subjects aged > 55 years were recruited using a community-based convenience sampling strategy in Porto Alegre, Brazil. The logical memory subset of the Wechsler Memory Scale-Revised was used to assess immediate verbal recall (IVR), delayed verbal recall (DVR), and memory retention rate. BDNF Met allele carriers had lower DVR scores (p = 0.004) and a decline in memory retention (p = 0.017) when compared to Val/Val homozygotes. However, we found no significant differences in IVR between the two groups (p = 0.088). These results support the hypothesis of the BDNF Val66Met polymorphism as a risk factor associated with cognitive impairment, corroborating previous findings in young and older adults.

  12. Acute exercise modulates BDNF and pro-BDNF protein content in immune cells.

    Science.gov (United States)

    Brunelli, Andrea; Dimauro, Ivan; Sgrò, Paolo; Emerenziani, Gian Pietro; Magi, Fiorenza; Baldari, Carlo; Guidetti, Laura; Di Luigi, Luigi; Parisi, Paolo; Caporossi, Daniela

    2012-10-01

    Although several studies have shown that immune cells stimulated by in vitro stress are capable to produce neurotrophins, there is still no evidence whether physiological stress, such as exercise, can modulate the in vivo levels of brain-derived neurotrophic factor (BDNF) in peripheral blood mononuclear cells (PBMCs). This work investigated whether acute exercise modulates the expression of BDNF, pro-BDNF, and p75(NTR) in the PBMCs of 10 healthy young men who performed a cycling incremental test to exhaustion (MAX) or exercised at individual anaerobic threshold (IAT). The PBMC expression of stress response proteins and the level of circulating BDNF, vascular endothelial growth growth factor, platelet-derived growth factor subunit B, basic fibroblast growth factor pro-inflammatory, and anti-inflammatory cytokines were analyzed as well. A major finding is that both sessions of acute exercise regulated the content of BDNF isoforms within PBMCs in a manner related to the physiological stress exerted. Although the pro-BDNF increased after both MAX and IAT protocols, BDNF showed a kinetics dependent on exercise type: MAX induced a 54% protein increase immediately after exercise, followed by a significant drop 60 min after its conclusion (38% lower than the baseline). Differently, in the IAT, BDNF increased significantly up to 75% from the baseline throughout the recovery phase. All physiological parameters, as well as the p75(NTR) receptor and the stress-inducible proteins, were also differently regulated by the two exercise conditions. These data supported the hypothesis that PBMCs might produce and secrete BDNF isoforms, as well as modulate the proteins p75(NTR) , Bcl-xL, hsp90, hsp27, and αB-crystallin, as part of the physiological stress response induced by acute exercise, offering a novel example of bidirectional interaction between nervous and immune systems.

  13. Opposite effects of acute ethanol exposure on GAP-43 and BDNF expression in the hippocampus versus the cerebellum of juvenile rats.

    Science.gov (United States)

    Kulkarny, V V; Wiest, N E; Marquez, C P; Nixon, S C; Valenzuela, C F; Perrone-Bizzozero, N I

    2011-08-01

    The adolescent brain is particularly vulnerable to the effects of alcohol, with intoxications at this developmental age often producing long-lasting effects. The present study addresses the effects of a single acute ethanol exposure on growth-associated protein-43 (GAP-43) and brain-derived neurotrophic factor (BDNF) gene expression in neurons in the cerebellum and hippocampus of adolescent rats. Male postnatal day 23 (P23) Sprague-Dawley rats were exposed to ethanol vapors for 2h and after a recovery period of 2h, the cerebellum and hippocampus were harvested and samples were taken for blood alcohol concentration (BAC) determinations. We found that this exposure resulted in a mean BAC of 174 mg/dL, which resembles levels in human adolescents after binge drinking. Analyses of total RNA and protein by quantitative reverse transcription PCR and western blotting, respectively, revealed that this single ethanol exposure significantly decreased the levels of GAP-43 mRNA and protein in the cerebellum but increased the levels of mRNA and protein in the hippocampus. BDNF mRNA and protein levels were also increased in the hippocampus but not in the cerebellum of these animals. In situ hybridizations revealed that GAP-43 and BDNF mRNA levels were primarily increased by alcohol exposure in hippocampal dentate granule cells and CA3 neurons. Overall, the reported alterations in the expression of the plasticity-associated genes GAP-43 and BDNF in juvenile rats are consistent with the known deleterious effects of binge drinking on motor coordination and cognitive function.

  14. Expression of brain-crived neurotrophic factor (BDNF) in hippocampus in rats after chronic morphine treatment%吗啡依赖大鼠海马内脑源性神经营养因子的表达

    Institute of Scientific and Technical Information of China (English)

    黄静; 方琴; 王季石; 李淑芳

    2009-01-01

    目的 研究脑源性神经营养因子(BDNF)在大鼠吗啡精神依赖中所起的作用.方法 大鼠连续6 d腹腔注射吗啡10 mg/kg,诱导吗啡条件性位置偏爱(CPP)形成.免疫组化法测定大鼠海马内BDNF的表达.结果经6 d吗啡训练后,吗啡组在伴药侧的停留时间较对照组显著增加(P<0.01).吗啡组大鼠海马内BDNF的阳性细胞数、平均光密度值分别为(99.18±15.85)、(188.29±22.42),均显著高于对照组(36.01±9.53)、(73.28±13.36)(P<0.01,P<0.01).结论 BDNF在慢性吗啡处理大鼠海马内的表达上调,证实BDNF参与了慢性吗啡依赖生物学过程,推测BDNF可能在精神依赖中起重要作用.

  15. Estrogen and brain-derived neurotrophic factor (BDNF) in hippocampus: complexity of steroid hormone-growth factor interactions in the adult CNS.

    Science.gov (United States)

    Scharfman, Helen E; MacLusky, Neil J

    2006-12-01

    In the CNS, there are widespread and diverse interactions between growth factors and estrogen. Here we examine the interactions of estrogen and brain-derived neurotrophic factor (BDNF), two molecules that have historically been studied separately, despite the fact that they seem to share common targets, effects, and mechanisms of action. The demonstration of an estrogen-sensitive response element on the BDNF gene provided an impetus to explore a direct relationship between estrogen and BDNF, and predicted that the effects of estrogen, at least in part, might be due to the induction of BDNF. This hypothesis is discussed with respect to the hippocampus, where substantial evidence has accumulated in favor of it, but alternate hypotheses are also raised. It is suggested that some of the interactions between estrogen and BDNF, as well as the controversies and implications associated with their respective actions, may be best appreciated in light of the ability of BDNF to induce neuropeptide Y (NPY) synthesis in hippocampal neurons. Taken together, this tri-molecular cascade, estrogen-BDNF-NPY, may be important in understanding the hormonal regulation of hippocampal function. It may also be relevant to other regions of the CNS where estrogen is known to exert profound effects, such as amygdala and hypothalamus; and may provide greater insight into neurological disorders and psychiatric illness, including Alzheimer's disease, depression and epilepsy.

  16. Alterations in BDNF (brain derived neurotrophic factor) and GDNF (glial cell line-derived neurotrophic factor) serum levels in bipolar disorder: The role of lithium.

    Science.gov (United States)

    Tunca, Zeliha; Ozerdem, Aysegul; Ceylan, Deniz; Yalçın, Yaprak; Can, Güneş; Resmi, Halil; Akan, Pınar; Ergör, Gül; Aydemir, Omer; Cengisiz, Cengiz; Kerim, Doyuran

    2014-09-01

    Brain-derived neurotrophic factor (BDNF) has been consistently reported to be decreased in mania or depression in bipolar disorders. Evidence suggests that Glial cell line-derived neurotrophic factor (GDNF) has a role in the pathogenesis of mood disorders. Whether GDNF and BDNF act in the same way across different episodes in bipolar disorders is unclear. BDNF and GDNF serum levels were measured simultaneously by enzyme-linked immunosorbent assay (ELISA) method in 96 patients diagnosed with bipolar disorder according to DSM-IV (37 euthymic, 33 manic, 26 depressed) in comparison to 61 healthy volunteers. SCID- I and SCID-non patient version were used for clinical evaluation of the patients and healthy volunteers respectively. Correlations between the two trophic factor levels, and medication dose, duration and serum levels of lithium or valproate were studied across different episodes of illness. Patients had significantly lower BDNF levels during mania and depression compared to euthymic patients and healthy controls. GDNF levels were not distinctive. However GDNF/BDNF ratio was higher in manic state compared to euthymia and healthy controls. Significant negative correlation was observed between BDNF and GDNF levels in euthymic patients. While BDNF levels correlated positively, GDNF levels correlated negatively with lithium levels. Regression analysis confirmed that lithium levels predicted only GDNF levels positively in mania, and negatively in euthymia. Small sample size in different episodes and drug-free patients was the limitation of thestudy. Current data suggests that lithium exerts its therapeutic action by an inverse effect on BDNF and GDNF levels, possibly by up-regulating BDNF and down-regulating GDNF to achieve euthymia. Copyright © 2014 Elsevier B.V. All rights reserved.

  17. Brain-derived neurotrophic factor expression predicts adverse pathological & clinical outcomes in human breast cancer

    Directory of Open Access Journals (Sweden)

    Mokbel Kefah

    2011-07-01

    Full Text Available Abstract Introduction Brain-derived neurotrophic factor (BDNF has established physiological roles in the development and function of the vertebrate nervous system. BDNF has also been implicated in several human malignancies, including breast cancer (BC. However, the precise biological role of BDNF and its utility as a novel biomarker have yet to be determined. The objective of this study was to determine the mRNA and protein expression of BDNF in a cohort of women with BC. Expression levels were compared with normal background tissues and evaluated against established pathological parameters and clinical outcome over a 10 year follow-up period. Methods BC tissues (n = 127 and normal tissues (n = 33 underwent RNA extraction and reverse transcription, BDNF transcript levels were determined using real-time quantitative PCR. BDNF protein expression in mammary tissues was assessed with standard immuno-histochemical methodology. Expression levels were analyzed against tumour size, grade, nodal involvement, TNM stage, Nottingham Prognostic Index (NPI and clinical outcome over a 10 year follow-up period. Results Immuno-histochemical staining revealed substantially greater BDNF expression within neoplastic cells, compared to normal mammary epithelial cells. Significantly higher mRNA transcript levels were found in the BC specimens compared to background tissues (p = 0.007. The expression of BDNF mRNA was demonstrated to increase with increasing NPI; NPI-1 vs. NPI-2 (p = 0.009. Increased BDNF transcript levels were found to be significantly associated with nodal positivity (p = 0.047. Compared to patients who remained disease free, higher BDNF expression was significantly associated with local recurrence (LR (p = 0.0014, death from BC (p = 0.018 and poor prognosis overall (p = 0.013. After a median follow up of 10 years, higher BDNF expression levels were significantly associated with reduced overall survival (OS (106 vs. 136 months, p = 0.006. BDNF

  18. Early enriched environment induces an increased conversion of proBDNF to BDNF in the adult rat's hippocampus.

    Science.gov (United States)

    Cao, Wenyu; Duan, Juan; Wang, Xueqin; Zhong, Xiaolin; Hu, Zhaolan; Huang, Fulian; Wang, Hongtao; Zhang, Juan; Li, Fang; Zhang, Jianyi; Luo, Xuegang; Li, Chang-Qi

    2014-05-15

    An enriched environment has been shown to influence brain plasticity and function by involving the action of brain-derived neurotrophic factor (BDNF). BDNF, which is synthesized as a precursor molecule (proBDNF) that undergoes proteolytic cleavage, plays an important role in synaptic plasticity and contributes to several brain functions such as memory, learning, and behavior. The neurotrophins and proneurotrophins often play opposite roles in the brain, suggesting that proteolytic cleavage of proneurotrophins controls the action of neurotrophins. However, few studies have focused on the expression and cleavage of proBDNF after exposure to an enriched environment. Our study aimed to explore the effects of an early-enriched environment on the conversion of proBDNF to BDNF in the adult rats' hippocampus. We found that there was no difference in the expression of proBDNF in the hippocampus between the SE (standard environment) and EE (enriched environment) rats, but a significantly increased BDNF protein level was found in the EE rats. Thus, a remarkably enhanced ratio of BDNF to proBDNF (BDNF/proBDNF) was observed in the EE rats. In addition, the EE resulted in a remarkably up-regulated matrix metalloproteinase-9 (MMP-9) in the hippocampus, which played a key role in converting proBDNF to BDNF in the extracellular space. Furthermore, the expression of synapse-related proteins (NR1 and NR2A) was analyzed, and the results indicated that EE could significantly increase the expression of NR1 and NR2A in the hippocampus. In addition, the behavioral results showed that EE reduced anxiety-like behavior in the elevated-plus maze test and reduced immobility time in the forced swimming test. Moreover, the EE resulted in an increased preference for sucrose compared to the SE. These results suggested that the EE up-regulated MMP-9 levels within the hippocampus, which might facilitate the conversion of proBDNF to BDNF, thereby contributing to the long lasting alterations of

  19. Phencyclidine (PCP)-induced disruption in cognitive performance is gender-specific and associated with a reduction in brain-derived neurotrophic factor (BDNF) in specific regions of the female rat brain.

    Science.gov (United States)

    Snigdha, Shikha; Neill, Joanna C; McLean, Samantha L; Shemar, Gaurav K; Cruise, Leonie; Shahid, Mohammed; Henry, Brian

    2011-03-01

    Phencyclidine (PCP), used to mimic certain aspects of schizophrenia, induces sexually dimorphic, cognitive deficits in rats. In this study, the effects of sub-chronic PCP on expression of brain-derived neurotrophic factor (BDNF), a neurotrophic factor implicated in the pathogenesis of schizophrenia, have been evaluated in male and female rats. Male and female hooded-Lister rats received vehicle or PCP (n=8 per group; 2 mg/kg i.p. twice daily for 7 days) and were tested in the attentional set shifting task prior to being sacrificed (6 weeks post-treatment). Levels of BDNF mRNA were measured in specific brain regions using in situ hybridisation. Male rats were less sensitive to PCP-induced deficits in the extra-dimensional shift stage of the attentional set shifting task compared to female rats. Quantitative analysis of brain regions demonstrated reduced BDNF levels in the medial prefrontal cortex (pPCP-treated rats compared with controls. In contrast, BDNF was significantly reduced only in the orbital cortex and central amygdaloid region of male rats (pPCP administration has a long-lasting down-regulatory effect on BDNF mRNA expression in the female rat brain which may underlie some of the behavioural deficits observed post PCP administration.

  20. Effects of brain-derived neurotrophic factor on synapsin expression in rat spinal cord anterior horn neurons cultured in vitro

    Institute of Scientific and Technical Information of China (English)

    Zhifei Wang; Daguang Liao; Changqi Li

    2010-01-01

    Brain-derived neurotrophic factor(BDNF)promotes synaptic formation and functional maturation by upregulating synapsin expression in cortical and hippocampal neurons.However,it remains controversial whether BDNF affects synapsin expression in spinal cord anterior horn neurons.Wistar rat spinal cord anterior hom neurons were cultured in serum-supplemented medium containing BDNF,BDNF antibody,and Hank's solution for 3 days,and then synapsin I and synaptophysin protein and mRNA expression was detected.Under serum-supplemented conditions,the number of surviving neurons in the spinal cord anterior horn was similar among BDNF,anti-BDNF,and control groups(P > 0.05).Synapsin I and synaptophysin protein and mRNA expressions were increased in BDNF-treated neurons,but decreased in BDNF antibody-treated neurons(P< 0.01).These results indicated that BDNF significantly promotes synapsin I and synaptophysin expression in in vitro-cultured rat spinal cord anterior horn neurons.

  1. Brain-derived neurotrophic factor (BDNF) induces sustained intracellular Ca2+ elevation through the up-regulation of surface transient receptor potential 3 (TRPC3) channels in rodent microglia.

    Science.gov (United States)

    Mizoguchi, Yoshito; Kato, Takahiro A; Seki, Yoshihiro; Ohgidani, Masahiro; Sagata, Noriaki; Horikawa, Hideki; Yamauchi, Yusuke; Sato-Kasai, Mina; Hayakawa, Kohei; Inoue, Ryuji; Kanba, Shigenobu; Monji, Akira

    2014-06-27

    Microglia are immune cells that release factors, including proinflammatory cytokines, nitric oxide (NO), and neurotrophins, following activation after disturbance in the brain. Elevation of intracellular Ca(2+) concentration ([Ca(2+)]i) is important for microglial functions such as the release of cytokines and NO from activated microglia. There is increasing evidence suggesting that pathophysiology of neuropsychiatric disorders is related to the inflammatory responses mediated by microglia. Brain-derived neurotrophic factor (BDNF) is a neurotrophin well known for its roles in the activation of microglia as well as in pathophysiology and/or treatment of neuropsychiatric disorders. In this study, we sought to examine the underlying mechanism of BDNF-induced sustained increase in [Ca(2+)]i in rodent microglial cells. We observed that canonical transient receptor potential 3 (TRPC3) channels contribute to the maintenance of BDNF-induced sustained intracellular Ca(2+) elevation. Immunocytochemical technique and flow cytometry also revealed that BDNF rapidly up-regulated the surface expression of TRPC3 channels in rodent microglial cells. In addition, pretreatment with BDNF suppressed the production of NO induced by tumor necrosis factor α (TNFα), which was prevented by co-adiministration of a selective TRPC3 inhibitor. These suggest that BDNF induces sustained intracellular Ca(2+) elevation through the up-regulation of surface TRPC3 channels and TRPC3 channels could be important for the BDNF-induced suppression of the NO production in activated microglia. We show that TRPC3 channels could also play important roles in microglial functions, which might be important for the regulation of inflammatory responses and may also be involved in the pathophysiology and/or the treatment of neuropsychiatric disorders.

  2. A Case-Control Study and Meta-Analysis Reveal BDNF Val66Met Is a Possible Risk Factor for PTSD

    Directory of Open Access Journals (Sweden)

    Dagmar Bruenig

    2016-01-01

    Full Text Available Posttraumatic stress disorder (PTSD is a debilitating condition that develops in some people after exposure to a traumatic event. Brain-derived neurotrophic factor (BDNF is highly expressed in the mammalian brain and is thought to be involved in learning and memory processes. A nonsynonymous polymorphism in the BDNF gene, rs6265 (Val66Met, has been hypothesised to be associated with PTSD. Association studies examining the Val66Met polymorphism and PTSD have been inconclusive, likely due to the variability in type of trauma exposure analysed. Vietnam veterans (n=257 screened for PTSD and controlled for trauma exposure were genotyped for BDNF Val66Met. The association was not significant so we incorporated our data into a meta-analysis to obtain greater statistical power. A comprehensive search of more than 1237 articles revealed eight additional studies suitable for meta-analysis (n=3625. A random-effects meta-analysis observed a potential protective factor of the Val/Val genotype. After removing two studies with violation of Hardy-Weinberg equilibrium, findings for the Val/Val genotype reached significance. Subgroup analyses confirmed a trend for this finding. Limitations of some studies that inform this meta-analysis include poorly screened controls and a lack of examination of population stratification. Effectively designed studies should inform this line of research in the future.

  3. Regulation of brain-derived neurotrophic factor (BDNF) in the chronic unpredictable stress rat model and the effects of chronic antidepressant treatment

    DEFF Research Database (Denmark)

    Larsen, Marianne H; Mikkelsen, Jens D; Hay-Schmidt, Anders

    2010-01-01

    mRNA expression in both the dentate gyrus of the dorsal hippocampus and the CA3 region of the ventral hippocampus indicating that there is no simple link between depression-like behaviors per se and brain BDNF levels in rats. However, a significant increase in BDNF mRNA levels in the dentate gyrus...

  4. Long-term treadmill exercise improves spatial memory of male APPswe/PS1dE9 mice by regulation of BDNF expression and microglia activation.

    Science.gov (United States)

    Xiong, J Y; Li, S C; Sun, Y X; Zhang, X S; Dong, Z Z; Zhong, P; Sun, X R

    2015-11-01

    Increasing evidence suggests that physical activity could delay or attenuate the symptoms of Alzheimer's disease (AD). But the underlying mechanisms are still not fully understood. To investigate the effect of long-term treadmill exercise on the spatial memory of AD mice and the possible role of β-amyloid, brain-derived neurotrophic factor (BDNF) and microglia in the effect, male APPswe/PS1dE9 AD mice aged 4 months were subjected to treadmill exercise for 5 months with 6 sessions per week and gradually increased load. A Morris water maze was used to evaluate the spatial memory. Expression levels of β-amyloid, BDNF and Iba-1 (a microglia marker) in brain tissue were detected by immunohistochemistry. Sedentary AD mice and wildtype C57BL/6J mice served as controls. The results showed that 5-month treadmill exercise significantly decreased the escape latencies (P memory of the AD mice in the water maze test. Meanwhile, treadmill exercise significantly increased the number of BDNF-positive cells and decreased the ratios of activated microglia in both the cerebral cortex and the hippocampus. However, treadmill exercise did not significantly alleviate the accumulation of β-amyloid in either the cerebral cortex or the hippocampus of the AD mice (P > 0.05). The study suggested that long-term treadmill exercise could improve the spatial memory of the male APPswe/PS1dE9 AD mice. The increase in BDNF-positive cells and decrease in activated microglia might underpin the beneficial effect.

  5. Ethanol-BDNF interactions: still more questions than answers.

    Science.gov (United States)

    Davis, Margaret I

    2008-04-01

    Brain-derived neurotrophic factor (BDNF) has emerged as a regulator of development, plasticity and, recently, addiction. Decreased neurotrophic activity may be involved in ethanol-induced neurodegeneration in the adult brain and in the etiology of alcohol-related neurodevelopmental disorders. This can occur through decreased expression of BDNF or through inability of the receptor to transduce signals in the presence of ethanol. In contrast, recent studies implicate region-specific up-regulation of BDNF and associated signaling pathways in anxiety, addiction and homeostasis after ethanol exposure. Anxiety and depression are precipitating factors for substance abuse and these disorders also involve region-specific changes in BDNF in both pathogenesis and response to pharmacotherapy. Polymorphisms in the genes coding for BDNF and its receptor TrkB are linked to affective, substance abuse and appetitive disorders and therefore may play a role in the development of alcoholism. This review summarizes historical and pre-clinical data on BDNF and TrkB as it relates to ethanol toxicity and addiction. Many unresolved questions about region-specific changes in BDNF expression and the precise role of BDNF in neuropsychiatric disorders and addiction remain to be elucidated. Resolution of these questions will require significant integration of the literature on addiction and comorbid psychiatric disorders that contribute to the development of alcoholism.

  6. N-palmitoyl serotonin alleviates scopolamine-induced memory impairment via regulation of cholinergic and antioxidant systems, and expression of BDNF and p-CREB in mice.

    Science.gov (United States)

    Min, A Young; Doo, Choon Nan; Son, Eun Jung; Sung, Nak Yun; Lee, Kun Jong; Sok, Dai-Eun; Kim, Mee Ree

    2015-12-05

    N-Palmitoyl-5-hydroxytryptamines (Pal-5HT), a cannabinoid, has recently been reported to express anti-allergic and anti-inflammatory actions in RBL-2H3 cells, and ameliorate glutamate-induced cytotoxicity in HT-22 cells. In this study, we examined the effect of Pal-5HT on deficits of learning and memory induced by scopolamine in mice. Memory performance was evaluated using Morris water maze test and passive avoidance test. Activities of acetylcholinesterase (AChE) and choline acetyltransferase (ChAT), level of oxidative stress markers, and expression of brain-derived neurotrophic factor (BDNF), phosphorylation of cAMP response element-binding protein (p-CREB) were determined. Loss of neuronal cells in hippocampus was evaluated by histological examinations. Pal-5HT significantly improved the amnesia in the behavioral assessment. Pal-5HT regulated cholinergic function by inhibiting scopolamine-induced elevation of AChE activity and decline of ChAT activity. Pal-5HT suppressed oxidative stress by increasing activities of glutathione peroxidase (GPx), glutathione reductase (GR) or NAD(P)H quinine oxidoreductase-1 (NQO-1) and lowering MDA level. Additionally, it prevented against scopolamine-induced expression of iNOS and COX-2. Moreover, Pal-5HT suppressed the death of neuronal cells in CA1 and CA3 regions, while it restored expression of p-CREB and BDNF in hippocampus. Taken together, Pal-5HT is suggested to ameliorate deficits of memory and learning through regulation of cholinergic function, activation of antioxidant systems as well as restoration of BDNF and p-CREB expression. From these, Pal-5HT may be a potential candidate to prevent against neurodegeneration related to the memory deficit.

  7. BDNF pro-peptide actions facilitate hippocampal LTD and are altered by the common BDNF polymorphism Val66Met.

    Science.gov (United States)

    Mizui, Toshiyuki; Ishikawa, Yasuyuki; Kumanogoh, Haruko; Lume, Maria; Matsumoto, Tomoya; Hara, Tomoko; Yamawaki, Shigeto; Takahashi, Masami; Shiosaka, Sadao; Itami, Chiaki; Uegaki, Koichi; Saarma, Mart; Kojima, Masami

    2015-06-09

    Most growth factors are initially synthesized as precursor proteins and subsequently processed into their mature form by proteolytic cleavage, resulting in simultaneous removal of a pro-peptide. However, compared with that of mature form, the biological role of the pro-peptide is poorly understood. Here, we investigated the biological role of the pro-peptide of brain-derived neurotrophic factor (BDNF) and first showed that the pro-peptide is expressed and secreted in hippocampal tissues and cultures, respectively. Interestingly, we found that the BDNF pro-peptide directly facilitates hippocampal long-term depression (LTD), requiring the activation of GluN2B-containing NMDA receptors and the pan-neurotrophin receptor p75(NTR). The BDNF pro-peptide also enhances NMDA-induced α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor endocytosis, a mechanism crucial for LTD expression. Thus, the BDNF pro-peptide is involved in synaptic plasticity that regulates a mechanism responsible for promoting LTD. The well-known BDNF polymorphism valine for methionine at amino acid position 66 (Val66Met) affects human memory function. Here, the BDNF pro-peptide with Met mutation completely inhibits hippocampal LTD. These findings demonstrate functional roles for the BDNF pro-peptide and a naturally occurring human BDNF polymorphism in hippocampal synaptic depression.

  8. Blood BDNF concentrations reflect brain-tissue BDNF levels across species

    DEFF Research Database (Denmark)

    Klein, Anders B; Williamson, Rebecca; Santini, Martin A

    2011-01-01

    Brain-derived neurotrophic factor (BDNF) is involved in synaptic plasticity, neuronal differentiation and survival of neurons. Observations of decreased serum BDNF levels in patients with neuropsychiatric disorders have highlighted the potential of BDNF as a biomarker, but so far there have been...... positive correlation between frontal cortex and hippocampal BDNF levels in mice (r2=0.81, p=0.0139). Our data support the view that measures of blood and plasma BDNF levels reflect brain-tissue BDNF levels....

  9. Roles of brain-derived neurotrophic factor/tropomyosin-related kinase B (BDNF/TrkB) signalling in Alzheimer's disease.

    Science.gov (United States)

    Zhang, Fang; Kang, Zhilong; Li, Wen; Xiao, Zhicheng; Zhou, Xinfu

    2012-07-01

    Alzheimer's disease (AD) is one of the most common causes of dementia in the elderly. It is characterized by extracellular deposition of the neurotoxic peptide, amyloid-beta (Aβ) peptide fibrils, and is accompanied by extensive loss of neurons in the brains of affected individuals. However, the pathogenesis of AD is not fully understood. The aim of this review is to discuss the possible role of brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) signalling in the development of AD, focusing on BDNF/TrkB signalling in the production of Aβ, tau hyperphosphorylation and cognition decline, and exploring new possibilities for AD intervention.

  10. BDNF pro-peptide regulates dendritic spines via caspase-3

    OpenAIRE

    Guo, J.; Ji, Y.; Y. Ding; Jiang, W.; Sun, Y.; B. Lu; Nagappan, G

    2016-01-01

    The precursor of brain-derived neurotrophic factor (BDNF) (proBDNF) is enzymatically cleaved, by either intracellular (furin/PC1) or extracellular proteases (tPA/plasmin/MMP), to generate mature BDNF (mBDNF) and its pro-peptide (BDNF pro-peptide). Little is known about the function of BDNF pro-peptide. We have developed an antibody that specifically detects cleaved BDNF pro-peptide, but not proBDNF or mBDNF. Neuronal depolarization elicited a marked increase in extracellular BDNF pro-peptide,...

  11. Neuropeptide S and BDNF gene expression in the amygdala are influenced by social decision-making under stress

    Directory of Open Access Journals (Sweden)

    Justin P. Smith

    2014-04-01

    Full Text Available In a newly developed conceptual model of stressful social decision making, the Stress-Alternatives Model (SAM; used for the 1st time in mice elicits two types of response: escape or remain submissively. Daily (4d aggressive social interaction in a neutral arena between a C57BL6/N test mouse and a larger, novel aggressive CD1 mouse, begin after an audible tone (conditioned stimulus; CS. Although escape holes (only large enough for smaller test animals are available, and the aggressor is unremittingly antagonistic, only half of the mice tested utilize the possibility of escape. During training, for mice that choose to leave the arena and social interaction, latency to escape dramatically decreases over time; this is also true for control C57BL6/N mice which experienced no aggression. Therefore, the open field of the SAM apparatus is intrinsically anxiogenic. It also means that submission to the aggressor is chosen despite this anxiety and the high intensity of the aggressive attacks and defeat. While both groups that received aggression displayed stress responsiveness, corticosterone levels were significantly higher in animals that chose submissive coexistence. Although both escaping and non-escaping groups of animals experienced aggression and defeat, submissive animals also exhibited classic fear conditioning, freezing in response to the CS alone, while escaping animals did not. In the basolateral amygdala, gene expression of BDNF was diminished, but NPS expression was significantly elevated, but only in submissive animals. This increase in submission-evoked NPS mRNA expression was greatest in the central amygdala, which coincided with decreased BDNF expression. Reduced expression of BDNF is only in submissive animals that also exhibit elevated NPS expression, despite elevated corticosterone in all socially interacting animals. The results suggest an interwoven relationship, linked by social context, between amygdalar BDNF, NPS and plasma

  12. Amyloid-Beta Induced Changes in Vesicular Transport of BDNF in Hippocampal Neurons

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    Bianca Seifert

    2016-01-01

    Full Text Available The neurotrophin brain derived neurotrophic factor (BDNF is an important growth factor in the CNS. Deficits in transport of this secretory protein could underlie neurodegenerative diseases. Investigation of disease-related changes in BDNF transport might provide insights into the cellular mechanism underlying, for example, Alzheimer’s disease (AD. To analyze the role of BDNF transport in AD, live cell imaging of fluorescently labeled BDNF was performed in hippocampal neurons of different AD model systems. BDNF and APP colocalized with low incidence in vesicular structures. Anterograde as well as retrograde transport of BDNF vesicles was reduced and these effects were mediated by factors released from hippocampal neurons into the extracellular medium. Transport of BDNF was altered at a very early time point after onset of human APP expression or after acute amyloid-beta(1-42 treatment, while the activity-dependent release of BDNF remained unaffected. Taken together, extracellular cleavage products of APP induced rapid changes in anterograde and retrograde transport of BDNF-containing vesicles while release of BDNF was unaffected by transgenic expression of mutated APP. These early transport deficits might lead to permanently impaired brain functions in the adult brain.

  13. Increase in serum brain-derived neurotrophic factor in met allele carriers of the BDNF Val66Met polymorphism is specific to males.

    NARCIS (Netherlands)

    Bus, B.A.A.; Arias Vasquez, A.; Franke, B.; Prickaerts, J.; Graaf, J. de; Oude Voshaar, R.C.

    2012-01-01

    BACKGROUND: Association studies of the Val66Met polymorphism and serum brain-derived neurotrophic factor (BDNF) levels have yielded conflicting results. Recently, sex-specific differences in BDNF levels were demonstrated. As these might explain the reported inconsistencies, we tested sex interaction

  14. Short-term striatal gene expression responses to brain-derived neurotrophic factor are dependent on MEK and ERK activation.

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    Ozgun Gokce

    Full Text Available BACKGROUND: Brain-derived neurotrophic factor (BDNF is believed to be an important regulator of striatal neuron survival, differentiation, and plasticity. Moreover, reduction of BDNF delivery to the striatum has been implicated in the pathophysiology of Huntington's disease. Nevertheless, many essential aspects of BDNF responses in striatal neurons remain to be elucidated. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we assessed the relative contributions of multipartite intracellular signaling pathways to the short-term induction of striatal gene expression by BDNF. To identify genes regulated by BDNF in these GABAergic cells, we first used DNA microarrays to quantify their transcriptomic responses following 3 h of BDNF exposure. The signal transduction pathways underlying gene induction were subsequently dissected using pharmacological agents and quantitative real-time PCR. Gene expression responses to BDNF were abolished by inhibitors of TrkB (K252a and calcium (chelator BAPTA-AM and transient receptor potential cation channel [TRPC] antagonist SKF-96365. Interestingly, inhibitors of mitogen-activated protein kinase kinases 1 and 2 (MEK1/2 and extracellular signal-regulated kinase ERK also blocked the BDNF-mediated induction of all tested BDNF-responsive genes. In contrast, inhibitors of nitric oxide synthase (NOS, phosphotidylinositol-3-kinase (PI3K, and CAMK exhibited less prevalent, gene-specific effects on BDNF-induced RNA expression. At the nuclear level, the activation of both Elk-1 and CREB showed MEK dependence. Importantly, MEK-dependent activation of transcription was shown to be required for BDNF-induced striatal neurite outgrowth, providing evidence for its contribution to striatal neuron plasticity. CONCLUSIONS: These results show that the MEK/ERK pathway is a major mediator of neuronal plasticity and other important BDNF-dependent striatal functions that are fulfilled through the positive regulation of gene expression.

  15. The expression and putative role of brain-derived neurotrophic factor and its receptor in bovine sperm.

    Science.gov (United States)

    Li, C; Li, C; Zhu, X; Wang, C; Liu, Zhuo; Li, W; Lu, Chen; Zhou, Xu

    2012-02-01

    The neurotrophin family of proteins promote the survival and differentiation of nerve cells and are thought to play an important role in development of reproductive tissues. The objective of the present study was to detect the presence of Brain-derived neurotrophic factor (BDNF) and its receptor TrkB in bovine sperm, and explore the potential role of BDNF in sperm function. We demonstrated that both the neorotrophin BDNF and the tyrosine kinase receptor protein TrkB were expressed in ejaculated bovine sperm. Furthermore, BDNF per se was secreted by sperm. Insulin and leptin secretion by bovine sperm were increased (P BDNF, whereas insulin was decreased by K252a. Therefore, we inferred that BDNF could be a regulator of sperm secretion of insulin and leptin through the TrkB receptor. Sperm viability and mitochondrial activity were both decreased (P BDNF/TrkB signaling pathway was blocked with K252a. Furthermore, BDNF promoted apoptosis of bovine sperm through TrkB binding (P BDNF secreted by bovine sperm was important in regulation of insulin and leptin secretion in ejaculated bovine sperm. Furthermore, BDNF may affect sperm mitochondrial activity and apoptosis, as well as their viability.

  16. Upregulated gene expression of local brain-derived neurotrophic factor and nerve growth factor after intracisternal administration of marrow stromal cells in rats with traumatic brain injury

    Institute of Scientific and Technical Information of China (English)

    胡德志; 周良辅; 朱剑虹; 毛颖; 吴雪海

    2005-01-01

    Objective: To examine the effects of rat marrow stromal cells (rMSCs) on gene expression of local brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) after injection of rMSCs into Cistern Magnum of adult rats subjected to traumatic brain injury(TBI).Results: Group cell transplantation had higher BDNF and NGF gene expressions than Group saline control during a period of less than 3 weeks (P<0.05).Conclusions: rMSCs transplantation via Cistern Magnum in rats subjected to traumatic brain injury can enhance expressions of local brain NGF and BDNF to a certain extent.

  17. Abnormal hippocampal BDNF and miR-16 expression is associated with depression-like behaviors induced by stress during early life.

    Directory of Open Access Journals (Sweden)

    Mei Bai

    Full Text Available Some environmental stressors lead to the onset of depression via inhibiting hippocampal BDNF expression, but other environmental stressors-induced depression exhibits no change in BDNF expression. The underlying mechanisms behind the divergence remain unknown. In this study, depression-like behaviors were induced in rats by maternal deprivation (MD and chronic unpredictable stress (CUPS. Depression-like behaviors were tested by open field test, forced swimming test, and sucrose consumption test. BDNF and miR-16 expressions in the hippocampus were examined by real-time PCR. MD and CUPS rats crawled less distance, exhibited decreased vertical activity, and produced more fecal pellets than control rats in the open field test. However, MD rats crawled less distance and produced significantly less fecal pellets than CUPS rats. In the forced swimming and sucrose consumption tests, CUPS and MD rats exhibited longer floating time and consumed less sucrose than control rats, but MD rats exhibited shorter floating time and consumed less sucrose than CUPS rats. MD but not CUPS rats showed lower BDNF mRNA and higher miR-16 expression than control rats. In MD rats, BDNF mRNA expression negatively correlated with the expression of miR-16. BDNF expression positively correlated with the total distance rats crawled and vertical activity in the open field test while miR-16 expression negatively correlated the two behaviors. BDNF positively correlated with sucrose preference rate while miR-16 negatively correlated with sucrose preference rate of the sucrose consumption test. Our study suggests that MD and CUPS induced different depression-like behaviors in rats. Depression induced by MD but not CUPS was significantly associated with upregulation of miR-16 and possibly subsequent downregulation of BDNF in hippocampus.

  18. Effect of vitamin E on cerebral cortical oxidative stress and brain-derived neurotrophic factor gene expression induced by hypoxia and exercise in rats.

    Science.gov (United States)

    Sakr, H F; Abbas, A M; El Samanoudy, A Z

    2015-04-01

    Brain-derived neurotrophic factor (BDNF) is involved in the proliferation of neurons, and its expression increases significantly with exercise. We aimed to investigate the effects of chronic exercise (swimming) and sustained hypoxia on cortical BDNF expression in both the presence and absence of vitamin E. Sixty four male Sprague-Dawley rats were divided into two equal groups; a normoxic group and a hypoxic group. Both groups were equally subdivided into four subgroups: sedentary, sedentary with vitamin E, chronic exercise either with or without vitamin E supplementation. Arterial PO(2), and the levels of cortical malondialdehyde (MDA), antioxidants (reduced glutathione GSH, superoxide dismutase (SOD), catalase (CAT) and vitamin E) and BDNF gene expression were investigated. Hypoxia significantly increased MDA production and BDNF gene expression and decreased the antioxidants compared to control rats. Chronic exercise in hypoxic and normoxic rats increased MDA level and BDNF gene expression and decreased the antioxidants. Providing vitamin E supplementation to the hypoxic and normoxic rats significantly reduced MDA and BDNF gene expression and increased antioxidants. We conclude that sustained hypoxia and chronic exercise increased BDNF gene expression and induced oxidative stress. Moreover, vitamin E attenuated the oxidative stress and decreased BDNF gene expression in sustained hypoxia and chronic exercise which confirms the oxidative stress-induced stimulation of BDNF gene expression.

  19. Alterations in brain-derived neurotrophic factor (BDNF) and its precursor proBDNF in the brain regions of a learned helplessness rat model and the antidepressant effects of a TrkB agonist and antagonist.

    Science.gov (United States)

    Shirayama, Yukihiko; Yang, Chun; Zhang, Ji-chun; Ren, Qian; Yao, Wei; Hashimoto, Kenji

    2015-12-01

    Role of brain-derived neurotrophic factor (BDNF)-TrkB signaling in a learned helplessness (LH) model of depression was investigated. LH rats showed a reduction of BDNF in the medial prefrontal cortex (mPFC), CA3, and dentate gyrus (DG) of the hippocampus, whereas LH rats showed an increase in BDNF in the nucleus accumbens (NAc). Furthermore, levels of proBDNF, a BDNF precursor, were higher in the mPFC, but lower in the NAc, of LH rats. A single bilateral infusion of a TrkB agonist 7,8-DHF, but not a TrkB antagonist ANA-12, into the infralimbic (IL) of mPFC, DG, and CA3, but not the prelimbic (PrL) of mPFC, exerted antidepressant effects in LH rats. In contrast, a single bilateral infusion of ANA-12, but not 7,8-DHF, into the core and shell of NAc exerted antidepressant-like effects in LH rats, with more potent effects observed for the NAc core than for NAc shell. Interestingly, a single administration of 7,8-DHF (10mg/kg, i.p.) significantly improved a decreased phosphorylation of TrkB in the mPFC, CA3, and DG of LH rats. Additionally, ANA-12 (0.5mg/kg, i.p.) significantly improved an increased phosphorylation of TrkB in the NAc of LH rats. In conclusion, these results suggest that LH causes depression-like behavior by altering BDNF in the brain regions, and that proBDNF-BDNF processing and transport may be altered in the mPFC-NAc circuit of LH rats. Therefore, TrkB agonists might exert antidepressant effects by stimulating TrkB in the IL, CA3, and DG, while TrkB antagonists might exert antidepressant effects by blocking TrkB in the NAc.

  20. BDNF Val 66 Met and 5-HTTLPR genotype moderate the impact of early psychosocial adversity on plasma brain-derived neurotrophic factor and depressive symptoms: a prospective study.

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    Buchmann, Arlette F; Hellweg, Rainer; Rietschel, Marcella; Treutlein, Jens; Witt, Stephanie H; Zimmermann, Ulrich S; Schmidt, Martin H; Esser, Günter; Banaschewski, Tobias; Laucht, Manfred; Deuschle, Michael

    2013-08-01

    Recent studies have emphasized an important role for neurotrophins, such as brain-derived neurotrophic factor (BDNF), in regulating the plasticity of neural circuits involved in the pathophysiology of stress-related diseases. The aim of the present study was to examine the interplay of the BDNF Val⁶⁶Met and the serotonin transporter promoter (5-HTTLPR) polymorphisms in moderating the impact of early-life adversity on BDNF plasma concentration and depressive symptoms. Participants were taken from an epidemiological cohort study following the long-term outcome of early risk factors from birth into young adulthood. In 259 individuals (119 males, 140 females), genotyped for the BDNF Val⁶⁶Met and the 5-HTTLPR polymorphisms, plasma BDNF was assessed at the age of 19 years. In addition, participants completed the Beck Depression Inventory (BDI). Early adversity was determined according to a family adversity index assessed at 3 months of age. Results indicated that individuals homozygous for both the BDNF Val and the 5-HTTLPR L allele showed significantly reduced BDNF levels following exposure to high adversity. In contrast, BDNF levels appeared to be unaffected by early psychosocial adversity in carriers of the BDNF Met or the 5-HTTLPR S allele. While the former group appeared to be most susceptible to depressive symptoms, the impact of early adversity was less pronounced in the latter group. This is the first preliminary evidence indicating that early-life adverse experiences may have lasting sequelae for plasma BDNF levels in humans, highlighting that the susceptibility to this effect is moderated by BDNF Val⁶⁶Met and 5-HTTLPR genotype.

  1. Local administration of AAV-BDNF to subventricular zone induces functional recovery in stroke rats.

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    Seong-Jin Yu

    Full Text Available Migration of new neuroprogenitor cells (NPCs from the subventricular zone (SVZ plays an important role in neurorepair after injury. Previous studies have shown that brain derived neurotrophic factor (BDNF enhances the migration of NPCs from SVZ explants in neonatal mice in vitro. The purpose of this study was to identify the role of BDNF in SVZ cells using AAV-BDNF in an animal model of stroke. BDNF protein production after AAV-BDNF infection was verified in primary neuronal culture. AAV-BDNF or AAV-RFP was injected into the left SVZ region of adult rats at 14 days prior to right middle cerebral artery occlusion (MCAo. SVZ tissues were collected from the brain and placed in Metrigel cultures 1 day after MCAo. Treatment with AAV-BDNF significantly increased the migration of SVZ cells in the stroke brain in vitro. In another set of animals, AAV-GFP was co-injected with AAV-BDNF or AAV-RFP to label cells in left SVZ prior to right MCAo. Local administration of AAV-BDNF significantly enhanced recovery of locomotor function and migration of GFP-positive cells from the SVZ toward the lesioned hemisphere in stroke rats. Our data suggest that focal administration of AAV-BDNF to the SVZ increases behavioral recovery post stroke, possibly through the enhancement of migration of cells from SVZ in stroke animals. Regional manipulation of BDNF expression through AAV may be a novel approach for neurorepair in stroke brains.

  2. Local administration of AAV-BDNF to subventricular zone induces functional recovery in stroke rats.

    Science.gov (United States)

    Yu, Seong-Jin; Tseng, Kuan-Yin; Shen, Hui; Harvey, Brandon K; Airavaara, Mikko; Wang, Yun

    2013-01-01

    Migration of new neuroprogenitor cells (NPCs) from the subventricular zone (SVZ) plays an important role in neurorepair after injury. Previous studies have shown that brain derived neurotrophic factor (BDNF) enhances the migration of NPCs from SVZ explants in neonatal mice in vitro. The purpose of this study was to identify the role of BDNF in SVZ cells using AAV-BDNF in an animal model of stroke. BDNF protein production after AAV-BDNF infection was verified in primary neuronal culture. AAV-BDNF or AAV-RFP was injected into the left SVZ region of adult rats at 14 days prior to right middle cerebral artery occlusion (MCAo). SVZ tissues were collected from the brain and placed in Metrigel cultures 1 day after MCAo. Treatment with AAV-BDNF significantly increased the migration of SVZ cells in the stroke brain in vitro. In another set of animals, AAV-GFP was co-injected with AAV-BDNF or AAV-RFP to label cells in left SVZ prior to right MCAo. Local administration of AAV-BDNF significantly enhanced recovery of locomotor function and migration of GFP-positive cells from the SVZ toward the lesioned hemisphere in stroke rats. Our data suggest that focal administration of AAV-BDNF to the SVZ increases behavioral recovery post stroke, possibly through the enhancement of migration of cells from SVZ in stroke animals. Regional manipulation of BDNF expression through AAV may be a novel approach for neurorepair in stroke brains.

  3. Circulating brain derived neurotrophic factor (BDNF) and frequency of BDNF positive T cells in peripheral blood in human ischemic stroke: Effect on outcome.

    Science.gov (United States)

    Chan, Adeline; Yan, Jun; Csurhes, Peter; Greer, Judith; McCombe, Pamela

    2015-09-15

    The aim of this study was to measure the levels of circulating BDNF and the frequency of BDNF-producing T cells after acute ischaemic stroke. Serum BDNF levels were measured by ELISA. Flow cytometry was used to enumerate peripheral blood leukocytes that were labelled with antibodies against markers of T cells, T regulatory cells (Tregs), and intracellular BDNF. There was a slight increase in serum BDNF levels after stroke. There was no overall difference between stroke patients and controls in the frequency of CD4(+) and CD8(+) BDNF(+) cells, although a subgroup of stroke patients showed high frequencies of these cells. However, there was an increase in the percentage of BDNF(+) Treg cells in the CD4(+) population in stroke patients compared to controls. Patients with high percentages of CD4(+) BDNF(+) Treg cells had a better outcome at 6months than those with lower levels. These groups did not differ in age, gender or initial stroke severity. Enhancement of BDNF production after stroke could be a useful means of improving neuroprotection and recovery after stroke.

  4. BDNF promotes differentiation and maturation of adult-born neurons through GABAergic transmission.

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    Waterhouse, Emily G; An, Juan Ji; Orefice, Lauren L; Baydyuk, Maryna; Liao, Guey-Ying; Zheng, Kang; Lu, Bai; Xu, Baoji

    2012-10-10

    Brain-derived neurotrophic factor (BDNF) has been implicated in regulating adult neurogenesis in the subgranular zone (SGZ) of the dentate gyrus; however, the mechanism underlying this regulation remains unclear. In this study, we found that Bdnf mRNA localized to distal dendrites of dentate gyrus granule cells isolated from wild-type (WT) mice, but not from Bdnf(klox/klox) mice where the long 3' untranslated region (UTR) of Bdnf mRNA is truncated. KCl-induced membrane depolarization stimulated release of dendritic BDNF translated from long 3' UTR Bdnf mRNA in cultured hippocampal neurons, but not from short 3' UTR Bdnf mRNA. Bdnf(klox/klox) mice exhibited reduced expression of glutamic acid decarboxylase 65 (a GABA synthase), increased proliferation of progenitor cells, and impaired differentiation and maturation of newborn neurons in the SGZ. These deficits in adult neurogenesis were rescued with administration of phenobarbital, an enhancer of GABA(A) receptor activity. Furthermore, we observed similar neurogenesis deficits in mice where the receptor for BDNF, TrkB, was selectively abolished in parvalbumin (PV)-expressing GABAergic interneurons. Thus, our data suggest that locally synthesized BDNF in dendrites of granule cells promotes differentiation and maturation of progenitor cells in the SGZ by enhancing GABA release, at least in part, from PV-expressing GABAergic interneurons.

  5. The role of BDNF/TrkB signaling in acute amphetamine-induced locomotor activity and opioid peptide gene expression in the rat dorsal striatum

    Directory of Open Access Journals (Sweden)

    Jacqueline F McGinty

    2011-07-01

    Full Text Available Exposure to psychostimulants increases brain-derived neurotrophic factor (BDNF mRNA and protein levels in the cerebral cortex and subcortical structures. Because BDNF is co-localized with dopamine and glutamate in afferents to the striatum of rats, it may be co-released with those neurotransmitters upon stimulation. Further, there may be an interaction between the intracellular signaling cascades activated by dopamine, glutamate, and TrkB receptors in medium spiny striatal neurons. In the present study, the effect of acute amphetamine administration on TrkB phosphorylation (p-TrkB, as an indirect indicator of activation, and striatal gene expression, was evaluated. In Experiment 1, 15 minutes or 2 hours after a single saline or amphetamine (2.5 mg/kg, i.p. injection, the caudate-putamen (CPu, nucleus accumbens (NAc, and dorsomedial prefrontal cortex (dmPFC were extracted and processed for phospho (p-TrkB immunoreactivity. Immunoprecipitation analyses indicated that neither the tyrosine phosphorylation (p-Tyr or autophosphorylation sites of TrkB (706 were changed in NAc, CPu, or dmPFC 15 min after amphetamine administration. In contrast, p-Tyr and the PLCγ phosphorylation site of TrkB (816 were increased in the NAc and CPu 2 hrs after amphetamine. In Experiment 2, intra-striatal infusion of the tyrosine kinase inhibitor, K252a, increased amphetamine-induced vertical activity but not total distance traveled. In addition, K252a inhibited amphetamine -induced preprodynorphin, but not preproenkephalin, mRNA expression in the striatum. These data indicate that acute amphetamine administration induces p-TrkB activation and signaling in a time- and brain region-dependent manner and that TrkB/BDNF signaling plays an important role in amphetamine-induced behavior and striatal gene expression.

  6. Rai1 haploinsufficiency causes reduced Bdnf expression resulting in hyperphagia, obesity and altered fat distribution in mice and humans with no evidence of metabolic syndrome.

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    Burns, Brooke; Schmidt, Kristie; Williams, Stephen R; Kim, Sun; Girirajan, Santhosh; Elsea, Sarah H

    2010-10-15

    Smith-Magenis syndrome (SMS) is a genetic disorder caused by haploinsufficiency of the retinoic acid induced 1 (RAI1) gene. In addition to intellectual disabilities, behavioral abnormalities and sleep disturbances, a majority of children with SMS also have significant early-onset obesity. To study the role of RAI1 in obesity, we investigated the growth and obesity phenotype in a mouse model haploinsufficient for Rai1. Data show that Rai1(+/-) mice are hyperphagic, have an impaired satiety response and have altered abdominal and subcutaneous fat distribution, with Rai1(+/-) female mice having a higher proportion of abdominal fat when compared with wild-type female mice. Expression analyses revealed that Bdnf (brain-derived neurotrophic factor), a gene previously associated with hyperphagia and obesity, is downregulated in the Rai1(+/-) mouse hypothalamus, and reporter studies show that RAI1 directly regulates the expression of BDNF. Even though the Rai1(+/-) mice are significantly obese, serum analyses do not reveal any evidence of metabolic syndrome. Supporting these findings, a caregiver survey revealed that even though a high incidence of abdominal obesity is observed in females with SMS, they did not exhibit a higher incidence of indicators of metabolic syndrome above the general population. We conclude that Rai1 haploinsufficiency represents a single-gene model of obesity with hyperphagia, abnormal fat distribution and altered hypothalamic gene expression associated with satiety, food intake, behavior and obesity. Linking RAI1 and BDNF provides a more thorough understanding of the role of Rai1 in growth and obesity and insight into the complex pathogenicity of obesity, behavior and sex-specific differences in adiposity.

  7. Intravenous administration of adipose tissue-derived stem cells enhances nerve healing and promotes BDNF expression via the TrkB signaling in a rat stroke model

    Directory of Open Access Journals (Sweden)

    Li X

    2016-06-01

    Full Text Available Xin Li,1 Wei Zheng,2 Hongying Bai,1 Jin Wang,3 Ruili Wei,1 Hongtao Wen,3 Hanbing Ning3 1Department of Neurology, 2Department of Nursing, The Second Affiliated Hospital of Zhengzhou University, 3Department of Digestive Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China Abstract: Previous studies have shown the beneficial effects of adipose-derived stem cells (ADSCs transplantation in stroke. However, the molecular mechanism by which transplanted ADSCs promote nerve healing is not yet elucidated. In order to make clear the molecular mechanism for the neuroprotective effects of ADSCs and investigate roles of the BDNF–TrkB signaling in neuroprotection of ADSCs, we, therefore, examined the neurological function, brain water content, and the protein expression in middle cerebral artery occlusion (MCAO rats with or without ADSCs transplantation. ADSCs were transplanted intravenously into rats at 30 minutes after MCAO. K252a, an inhibitor of TrkB, was administered into rats by intraventricular and brain stereotaxic injection. Modified neurological severity score tests were performed to measure behavioral outcomes. The results showed that ADSCs significantly alleviated neurological deficits and reduced brain water content in MCAO rats. The protein expression levels of BDNF and TrkB significantly increased in the cortex of MCAO rats with ADSCs treatment. However, K252a administration reversed the ADSCs-induced elevation of BDNF, TrkB, and Bcl-2 and reduction of Bax protein in MCAO rats. ADSCs promote BDNF expression via the TrkB signaling and improve functional neurological recovery in stroke rats. Keywords: stroke, adipose tissue-derived stem cells, brain-derived neurotrophic factor, TrkB

  8. miR-204对癫痫神经元中BDNF/TrkB信号通路的影响%The Study of miR-204 Regulates BDNF/TrkB Expression in Epileptic Neurons

    Institute of Scientific and Technical Information of China (English)

    常伟; 潘立平; 吴秋静; 宋毅军

    2014-01-01

    Objective To study the effect of miR-204 on BDNF/TrkB signaling and pathogenesis on the neuron model of epilepsy. Methods Primary hippocampal neurons were cultured in vitro for 7 days, and were divided into control group, control+BDNF group, epilepsy group, epilepsy+BDNF group , control+miR204 group, epilepsy+miR204 group and ep-ilepsy+miR204+BDNF group. The epilepsy model of hippocampal neurons was established by being exposed to Mg2+free me-dia for 3 hours. The miR-204 lentivirus vector was constructed. The effect of miR-204 on BDNF/TrkB expression was detect-ed by immunohistochemistry, patch clamp and Western blot technique. Results Compared with the control group, the TrkB phosphorylation level was higher in control+BDNF group. The TrkB phosphorylation level was lower in epilepsy+BDNF group than that of control+BDNF group, but it was higher than that of epilepsy group. The TrkB phosphorylation level was higher in epilepsy+miR204+BDNF group than that of epilepsy+BDNF group and epilepsy+ miR204 group. Conclusion BDNF and miR-204 can improve the inhibitory condition of BDNF/TrkB signaling and may play an important role in alleviat-ing epilepsy disease.%目的:研究海马神经元癫痫模型中转染miR-204后对脑源性神经营养因子(BDNF)与TrkB通路调控作用的影响。方法取原代培养7 d后的细胞,分为正常组、正常+BDNF组、癫痫组、癫痫+BDNF组、正常转染miR-204组、癫痫转染miR-204组、癫痫转染miR-204+BDNF组。癫痫组用无镁液处理3 h制作癫痫模型。制备成功miR-204慢病毒表达载体。采用免疫荧光、膜片钳及免疫印迹技术鉴定及观察miR-204对BDNF/TrkB通路表达的影响。结果 TrkB蛋白的磷酸化水平:正常+BDNF组高于正常组;癫痫+BDNF组低于正常+BDNF组,高于癫痫组;癫痫+miR-204+BDNF组高于癫痫+BDNF组和癫痫+miR-204组。结论BDNF及miR-204可以改善BDNF/TrkB受抑制的状态,从而在癫痫疾病的缓解中可能发挥重要作用。

  9. Postnatal development of brain-derived neurotrophic factor (BDNF) and tyrosine protein kinase B (TrkB) receptor immunoreactivity in multiple brain stem respiratory-related nuclei of the rat.

    Science.gov (United States)

    Liu, Qiuli; Wong-Riley, Margaret T T

    2013-01-01

    Previously, we found a transient imbalance between suppressed excitation and enhanced inhibition in the respiratory network of the rat around postnatal days (P) 12-13, a critical period when the hypoxic ventilatory response is at its weakest. The mechanism underlying the imbalance is poorly understood. Brain-derived neurotrophic factor (BDNF) and its tyrosine protein kinase B (TrkB) receptors are known to potentiate glutamatergic and attenuate gamma-aminobutyric acid (GABA)ergic neurotransmission, and BDNF is essential for respiratory development. We hypothesized that the excitation-inhibition imbalance during the critical period stemmed from a reduced expression of BDNF and TrkB at that time within respiratory-related nuclei of the brain stem. An in-depth, semiquantitative immunohistochemical study was undertaken in seven respiratory-related brain stem nuclei and one nonrespiratory nucleus in P0-21 rats. The results indicate that the expressions of BDNF and TrkB: 1) in the pre-Bötzinger complex, nucleus ambiguus, commissural and ventrolateral subnuclei of solitary tract nucleus, and retrotrapezoid nucleus/parafacial respiratory group were significantly reduced at P12, but returned to P11 levels by P14; 2) in the lateral paragigantocellular nucleus and parapyramidal region were increased from P0 to P7, but were strikingly reduced at P10 and plateaued thereafter; and 3) in the nonrespiratory cuneate nucleus showed a gentle plateau throughout the first 3 postnatal weeks, with only a slight decline of BDNF expression after P11. Thus, the significant downregulation of both BDNF and TrkB in respiratory-related nuclei during the critical period may form the basis of, or at least contribute to, the inhibitory-excitatory imbalance within the respiratory network during this time.

  10. Reduced serum concentrations of brain-derived neurotrophic factor (BDNF) in transsexual Brazilian men.

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    Fontanari, Anna Martha Vaitses; Costa, Angelo Brandelli; Aguiar, Bianca; Tusset, Cíntia; Andreazza, Tahiana; Schneider, Maiko; da Rosa, Eduarda Dias; Soll, Bianca Machado Borba; Schwarz, Karine; da Silva, Dhiordan Cardoso; Borba, André Oliveira; Mueller, Andressa; Massuda, Raffael; Lobato, Maria Inês Rodrigues

    2016-09-06

    Serum BDNF levels are significantly decreased in transsexual Brazilian women when compared to cis-sexual men. Since transsexual men are also exposed to chronic social stress and have a high prevalence of associated psychopathologies, it is plausible to inquire if BDNF serum levels are altered in transsexual men as well. Therefore, our objective was to evaluate differences in BDNF serum level of transsexual men when compared to cis-sexual men and women. Our sample comprises 27 transsexual men, 31 cis-sexual women and 30 cis-sexual men recruited between 2011 and 2015. We observed that BDNF serum concentration is decreased in transsexual men comparing to cis-sexual men and women. Cross-sex hormone treatment, chronic social stress or long-term gender dysphoria (GD) could explain the variation found in BDNF serum levels.

  11. Sustained expression of brain-derived neurotrophic factor is required for maintenance of dendritic spines and normal behavior.

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    Vigers, A J; Amin, D S; Talley-Farnham, T; Gorski, J A; Xu, B; Jones, K R

    2012-06-14

    Brain-derived neurotrophic factor (BDNF) plays important roles in the development, maintenance, and plasticity of the mammalian forebrain. These functions include regulation of neuronal maturation and survival, axonal and dendritic arborization, synaptic efficacy, and modulation of complex behaviors including depression and spatial learning. Although analysis of mutant mice has helped establish essential developmental functions for BDNF, its requirement in the adult is less well documented. We have studied late-onset forebrain-specific BDNF knockout (CaMK-BDNF(KO)) mice, in which BDNF is lost primarily from the cortex and hippocampus in early adulthood, well after BDNF expression has begun in these structures. We found that although CaMK-BDNF(KO) mice grew at a normal rate and can survive more than a year, they had smaller brains than wild-type siblings. The CaMK-BDNF(KO) mice had generally normal behavior in tests for ataxia and anxiety, but displayed reduced spatial learning ability in the Morris water task and increased depression in the Porsolt swim test. These behavioral deficits were very similar to those we previously described in an early-onset forebrain-specific BDNF knockout. To identify an anatomical correlate of the abnormal behavior, we quantified dendritic spines in cortical neurons. The spine density of CaMK-BDNF(KO) mice was normal at P35, but by P84, there was a 30% reduction in spine density. The strong similarities we find between early- and late-onset BDNF knockouts suggest that BDNF signaling is required continuously in the CNS for the maintenance of some forebrain circuitry also affected by developmental BDNF depletion.

  12. Association of brain-derived neurotrophic factor (BDNF) haploinsufficiency with lower adaptive behaviour and reduced cognitive functioning in WAGR/11p13 deletion syndrome.

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    Han, Joan C; Thurm, Audrey; Golden Williams, Christine; Joseph, Lisa A; Zein, Wadih M; Brooks, Brian P; Butman, John A; Brady, Sheila M; Fuhr, Shannon R; Hicks, Melanie D; Huey, Amanda E; Hanish, Alyson E; Danley, Kristen M; Raygada, Margarita J; Rennert, Owen M; Martinowich, Keri; Sharp, Stephen J; Tsao, Jack W; Swedo, Susan E

    2013-01-01

    In animal studies, brain-derived neurotrophic factor (BDNF) is an important regulator of central nervous system development and synaptic plasticity. WAGR (Wilms tumour, Aniridia, Genitourinary anomalies, and mental Retardation) syndrome is caused by 11p13 deletions of variable size near the BDNF locus and can serve as a model for studying human BDNF haploinsufficiency (+/-). We hypothesized that BDNF+/- would be associated with more severe cognitive impairment in subjects with WAGR syndrome. Twenty-eight subjects with WAGR syndrome (6-28 years), 12 subjects with isolated aniridia due to PAX6 mutations/microdeletions (7-54 years), and 20 healthy controls (4-32 years) received neurocognitive assessments. Deletion boundaries for the subjects in the WAGR group were determined by high-resolution oligonucleotide array comparative genomic hybridization. Within the WAGR group, BDNF+/- subjects (n = 15), compared with BDNF intact (+/+) subjects (n = 13), had lower adaptive behaviour (p = .02), reduced cognitive functioning (p = .04), higher levels of reported historical (p = .02) and current (p = .02) social impairment, and higher percentage meeting cut-off score for autism (p = .047) on Autism Diagnostic Interview-Revised. These differences remained nominally significant after adjusting for visual acuity. Using diagnostic measures and clinical judgement, 3 subjects (2 BDNF+/- and 1 BDNF+/+) in the WAGR group (10.7%) were classified with autism spectrum disorder. A comparison group of visually impaired subjects with isolated aniridia had cognitive functioning comparable to that of healthy controls. In summary, among subjects with WAGR syndrome, BDNF+/- subjects had a mean Vineland Adaptive Behaviour Compose score that was 14-points lower and a mean intelligence quotient (IQ) that was 20-points lower than BDNF+/+ subjects. Our findings support the hypothesis that BDNF plays an important role in human neurocognitive development.

  13. Involvement of brain-derived neurotrophic factor (BDNF) in the functional elimination of synaptic contacts at polyinnervated neuromuscular synapses during development.

    Science.gov (United States)

    Garcia, N; Santafe, M M; Tomàs, M; Lanuza, M A; Besalduch, N; Tomàs, J

    2010-05-15

    We use immunohistochemistry to describe the localization of brain-derived neurotrophic factor (BDNF) and its receptors trkB and p75(NTR) in the neuromuscular synapses of postnatal rats (P6-P7) during the synapse elimination period. The receptor protein p75(NTR) is present in the nerve terminal, muscle cell and glial Schwann cell whereas BDNF and trkB proteins can be detected mainly in the pre- and postsynaptic elements. Exogenously applied BDNF (10 nM for 3 hr or 50 nM for 1 hr) increases ACh release from singly and dually innervated synapses. This effect may be specific for BDNF because the neurotrophin NT-4 (2-8 nM) does not modulate release at P6-P7. Blocking the receptors trkB and p75(NTR) (with K-252a and anti-p75-192-IgG, respectively) completely abolishes the potentiating effect of exogenous BDNF. In addition, exogenous BDNF transiently recruits functionally depressed silent terminals, and this effect seems to be mediated by trkB. Calcium ions, the L-type voltage-dependent calcium channels and protein kinase C are involved in BDNF-mediated nerve ending recruitment. Blocking experiments suggest that endogenous BDNF could operate through p75(NTR) receptors coupled to potentiate ACh release in all nerve terminals because the anti-p75-192-IgG reduces release. However, blocking the trkB receptor (K-252a) or neutralizing endogenous BDNF with the trkB-IgG fusion protein reveals a trkB-mediated release inhibition on almost mature strong endings in dual junctions. Taken together these results suggest that a BDNF-induced p75(NTR)-mediated ACh release potentiating mechanism and a BDNF-induced trkB-mediated release inhibitory mechanism may contribute to developmental synapse disconnection.

  14. Changes of BDNF Expression in Neurons in Traumatic Brain Injury Rats%脑损伤大鼠运动皮质BDNF的表达变化

    Institute of Scientific and Technical Information of China (English)

    赵波; 汤海玲; 但齐琴; 赵楠; 刘佳

    2012-01-01

    目的 观察刨伤性脑损伤(TBI)大鼠脑组织运动皮质脑源性神经营养因子(BDNF)表达变化并探讨其与神经行为学的关系.方法 成年SD大鼠分假手术对照组和自由落体脑外伤组(TBI组),每组13只.TBI后1、3、8、13d分别进行大鼠神经功能缺损评分(NSS).术后7d处死大鼠,取损伤处脑组织行RT-PCR检测BDNFmRNA表达;术后13d处死大鼠,取损伤处脑组织行免疫组化和原位杂交检测BDNF表达.结果 TBI后大鼠神经行为明显受损,NSS评分较假手术组增加(P<0.05),但随时间延长NSS评分有所下降(P<0.05).RT-PCR结果显示,BDNF mRNA表达水平TBI组和假手术组差异无统计学意义(P>0.05).免疫组化和原位杂交染色结果显示,BDNF蛋白和mRNA主要分布在皮质神经元,阳性细胞数量明显减少(P<0.05),而细胞内BDNF的光密度值则明显增加(P<0.05).结论 TBI后大鼠神经功能有一定恢复,其机制可能与备用神经元内BDNF的表达水平上调有关.%Objective To investigate changes of brain derived neurotrophic factor (BDNF) expression in neurons in traumatic brain injury (TBI) rats. Methods Adult SD rats were divided into sham and operated group resulted from hammer fall contusion (30 cm high. 50 g weight). Thirteen rats in each group were used. Some of animals (n = 6 in each group) were used to perform immunohistochemistry and in situ hybridization, and the other (n = 7) was used for RT-PCR. After NSS assessment was determined at I, 3, 8, 13 days, TBI rats were sacrificed, brain tissues were then harvested to measure BDNF level. Data were analyzed by using statistic method. Results A increased NSS scores (P<0. 05) was observed after TBI, which implied the significant neurobehavioral changes in rats. But a gradual decreasing NSS scores (P < 0. 05) was also observed along with time prolonged. Severe neurological severity function was seen following TBI, and it presents a gradual improvement indicated by decreasing NSS

  15. Blockade of Cannabinoid CB1 receptor attenuates the acquisition of morphine-induced conditioned place preference along with a downregulation of ERK, CREB phosphorylation, and BDNF expression in the nucleus accumbens and hippocampus.

    Science.gov (United States)

    Zhang, Jianbo; Wang, Na; Chen, Bo; Wang, Yi'nan; He, Jing; Cai, Xintong; Zhang, Hongbo; Wei, Shuguang; Li, Shengbin

    2016-09-06

    Cannabinoid CB1 receptor (CB1R) is highly expressed in the mesocorticolimbic system and associated with drug craving and relapse. Clinical trials suggest that CB1R antagonists may represent new therapies for drug addiction. However, the downstream signaling of CB1R is not fully elucidated. In the present study, we investigated the relationship between CB1R and the extracellular signal-regulated kinase (ERK), cAMP response element-binding protein (CREB), brain-derived neurotrophic factor (BDNF) signaling in the nucleus accumbens (NAc) and hippocampus in morphine-induced conditioned place preference (CPP), which is used to assess the morphine-induced reward memory. The protein level of CB1R, ERK, CREB, and BDNF were detected by western blotting. Additionally, a CB1R antagonist, AM251, was used to study whether blockade of CB1R altered the CPP and above-mentioned molecules. We found an increase of CB1R expression in the NAc and hippocampus of the mice following morphine CPP, but not those after repeated morphine in home cage without context exposure (NO-CPP). Both morphine CPP and NO-CPP induced an upregulation of ERK, CREB phosphorylation and BDNF expression. Furthermore, pretreatment with AM251 before morphine attenuated the CPP acquisition and CB1R expression as well as the activation of ERK-CREB-BDNF cascade. Collectively, these findings demonstrate that (1) Repeated morphine with context exposures but not merely the pharmacological effects of morphine increased CB1R expression both in the NAc and hippocampus. (2) CB1R antagonist mediated blockade of ERK-CREB-BDNF signaling activation in the NAc and hippocampus may be an important mechanism underlying the attenuation of morphine CPP.

  16. RACK1 affects morphine reward via BDNF.

    Science.gov (United States)

    Wan, Lihong; Xie, Yizhou; Su, Lan; Liu, Yanyou; Wang, Yuhui; Wang, Zhengrong

    2011-10-06

    Chronic morphine addiction may trigger functional changes in the mesolimbic dopamine system, which is believed to be the neurobiological substrate of opiate addiction. Brain derived neurotrophic factor (BDNF) has been implicated in addiction-related pathology in animal studies. Our previous studies have shown that RACK1 is involved in morphine reward in mice. The recent research indicates nuclear RACK1 by localizing at the promoter IV region of the BDNF gene and the subsequent chromatin modifications leads to the activation of the promoter and transcription of BDNF. The present study was designed to investigate if shRACK1 (a short hairpin RNA of RACK1) could reverse the mice's behavioral responses to morphine and BDNF expression in hippocampus and prefrontal cortex. No significant changes were observed in vehicle-infused mice which received no morphine treatment (CONC) and shRACK1-infused mice which received no morphine treatment (CONR), whereas vehicle-infused mice preceded the morphine injection (MIC) showed increased BDNF expression in hippocampus and prefrontal cortex, as compared to vehicle-infused mice which received no morphine treatment (CONC). Intracerebroventricular shRACK1 treatment reversed these, and in fact, ShRACK1-infused mice preceded the morphine injection (MIR) showed reduced BDNF expression in hippocampus and prefrontal cortex, as compared to MIC. In the conditioned place preference (CPP) test, inactivating RACK1 markedly reduces morphine-induced conditioned place preference. Non-specific changes in CPP could not account for these effects since general CPP of shRACK1- and vehicle-infused animals was not different. Combined behavioral and molecular approaches have support the possibility that the RACK1-BDNF system plays an important role in the response to morphine-induced reward.

  17. Physical therapy intervention (PTI) increases plasma brain-derived neurotrophic factor (BDNF) levels in non-frail and pre-frail elderly women.

    Science.gov (United States)

    Coelho, F M; Pereira, D S; Lustosa, L P; Silva, J P; Dias, J M D; Dias, R C D; Queiroz, B Z; Teixeira, A L; Teixeira, M M; Pereira, L S M

    2012-01-01

    Biomarkers are important factors in the identification of the frail elderly (higher risk of developing disease) and in assessing the impact of PTI. On the other hand, BDNF has been related to neuroprotection in a series of central nervous system diseases in older age. The levels of BDNF in groups of elderly women classified according to Fried phenotype (non-frail and pre-frail) were compared. We assessed the impact of a PTI on BDNF levels. A convenience sample of 48 elderly women was randomly selected. The PTI group was composed by 20 elderly women selected from this group. Plasma neurotrophic factors, such as BDNF, glial-derived neutrophic factor (GDNF), and nerve growth factor (NGF) were measured by enzyme-linked immunosorbent assay (ELISA). Timed-up-and-go (TUG) test, hand-grip and work/body weight were evaluated before and after the intervention. Plasma concentrations of BDNF were significantly higher in non-frail in comparison to pre-frail elderly women. After the PTI, higher levels of BDNF were found in elderly women (before 351±68 pg/ml and after 593±79 pg/ml; pelderly women suggest that this neurotrophic factor may be a key pathophysiological mediator in the syndrome of frailty. The fact that PTI increased BDNF levels in both groups suggests that it may be possible to modify this phenotype.

  18. Neurogenic and neurotrophic effects of BDNF peptides in mouse hippocampal primary neuronal cell cultures.

    Directory of Open Access Journals (Sweden)

    Maria del Carmen Cardenas-Aguayo

    Full Text Available The level of brain-derived neurotrophic factor (BDNF, a member of the neurotrophin family, is down regulated in Alzheimer's disease (AD, Parkinson's disease (PD, depression, stress, and anxiety; conversely the level of this neurotrophin is increased in autism spectrum disorders. Thus, modulating the level of BDNF can be a potential therapeutic approach for nervous system pathologies. In the present study, we designed five different tetra peptides (peptides B-1 to B-5 corresponding to different active regions of BDNF. These tetra peptides were found to be non-toxic, and they induced the expression of neuronal markers in mouse embryonic day 18 (E18 primary hippocampal neuronal cultures. Additionally, peptide B-5 induced the expression of BDNF and its receptor, TrkB, suggesting a positive feedback mechanism. The BDNF peptides induced only a moderate activation (phosphorylation at Tyr 706 of the TrkB receptor, which could be blocked by the Trk's inhibitor, K252a. Peptide B-3, when combined with BDNF, potentiated the survival effect of this neurotrophin on H(2O(2-treated E18 hippocampal cells. Peptides B-3 and B-5 were found to work as partial agonists and as partial antagonists competing with BDNF to activate the TrkB receptor in a dose-dependent manner. Taken together, these results suggest that the described BDNF tetra peptides are neurotrophic, can modulate BDNF signaling in a partial agonist/antagonist way, and offer a novel therapeutic approach to neural pathologies where BDNF levels are dysregulated.

  19. Histone deacetylase activity and brain-derived neurotrophic factor (BDNF levels in a pharmacological model of mania

    Directory of Open Access Journals (Sweden)

    Laura Stertz

    2014-03-01

    Full Text Available Objective: In the present study, we aimed to examine the effects of repeated D-amphetamine (AMPH exposure, a well-accepted animal model of acute mania in bipolar disorder (BD, and histone deacetylase (HDAC inhibitors on locomotor behavior and HDAC activity in the prefrontal cortex (PFC and peripheral blood mononuclear cells (PBMCs of rats. Moreover, we aimed to assess brain-derived neurotrophic factor (BDNF protein and mRNA levels in these samples. Methods: We treated adult male Wistar rats with 2 mg/kg AMPH or saline intraperitoneally for 14 days. Between the 8th and 14th days, rats also received 47.5 mg/kg lithium (Li, 200 mg/kg sodium valproate (VPT, 2 mg/kg sodium butyrate (SB, or saline. We evaluated locomotor activity in the open-field task and assessed HDAC activity in the PFC and PBMCs, and BDNF levels in the PFC and plasma. Results: AMPH significantly increased locomotor activity, which was reversed by all drugs. This hyperactivity was associated with increased HDAC activity in the PFC, which was partially reversed by Li, VPT, and SB. No differences were found in BDNF levels. Conclusion: Repeated AMPH administration increases HDAC activity in the PFC without altering BDNF levels. The partial reversal of HDAC increase by Li, VPT, and SB may account for their ability to reverse AMPH-induced hyperactivity.

  20. Chronic corticosterone decreases brain-derived neurotrophic factor (BDNF) mRNA and protein in the hippocampus, but not in the frontal cortex, of the rat.

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    Jacobsen, Jacob P R; Mørk, Arne

    2006-09-19

    This study examined the effects of chronic corticosterone (32 mg/kg/day, s.c., 21 days) on brain-derived neurotrophic factor (BDNF) mRNA and protein in the frontal cortex and hippocampus of the rat. Because evidence suggests that BDNF is an important determinant of the function of the 5-hydroxytryptamine (5-HT) system, we also quantified tissue levels of 5-HT and its major metabolite, 5-hydroxyindoleacetic acid (5-HIAA), to investigate if changes in BDNF mRNA and protein paralleled changes in the 5-HT system. Corticosterone modestly decreased BDNF protein (-16.6%) in whole hippocampus and BDNF mRNA (-19%) in the CA3 area. In contrast, BDNF mRNA and protein in the frontal cortex were unchanged. In both the frontal cortex and hippocampus, tissue levels of 5-HT and 5-HIAA were increased and decreased, respectively. Combined, these data suggests that the effects of corticosterone on the BDNF system are not linked to the effects on the 5-HT systems. However, our findings do suggest that chronic corticosterone impairs hippocampal BDNF function, a finding with potential relevance for the hippocampal atrophy reported in major depression. Additionally, as inferred from the alterations in tissue levels of 5-HT and 5-HIAA, chronic corticosterone may influence the function of the 5-HT system.

  1. Genetic Variant of BDNF (Val66Met) Polymorphism Attenuates Stroke-Induced Angiogenic Responses by Enhancing Anti-Angiogenic Mediator CD36 Expression

    OpenAIRE

    Qin, Luye; Kim, Eunhee; Ratan, Rajiv; Lee, Francis S.; Cho, Sunghee

    2011-01-01

    Brain-derived neurotrophic factor (BDNF) has been shown to be necessary and sufficient for post-stroke recovery in rodents. From these observations, we and others have hypothesized that a common single nucleotide polymorphism (SNP) in the pro-domain of bdnf that leads to a methionine (Met) substitution for valine (Val) at codon 66 (Val66Met) will affect stroke outcome. Here we investigate the effect of the BDNF genetic variant on ischemic outcome by using mice with a genetic knock-in of the h...

  2. Physical exercise and antidepressants enhance BDNF targeting in hippocampal CA3 dendrites: further evidence of a spatial code for BDNF splice variants.

    Science.gov (United States)

    Baj, Gabriele; D'Alessandro, Valentina; Musazzi, Laura; Mallei, Alessandra; Sartori, Cesar R; Sciancalepore, Marina; Tardito, Daniela; Langone, Francesco; Popoli, Maurizio; Tongiorgi, Enrico

    2012-06-01

    Brain-derived neurotrophic factor (BDNF) is encoded by multiple BDNF transcripts, whose function is unclear. We recently showed that a subset of BDNF transcripts can traffic into distal dendrites in response to electrical activity, while others are segregated into the somatoproximal domains. Physical exercise and antidepressant treatments exert their beneficial effects through upregulation of BDNF, which is required to support survival and differentiation of newborn dentate gyrus (DG) neurons. While these DG processes are required for the antidepressant effect, a role for CA1 in antidepressant action has been excluded, and the effect on CA3 neurons remains unclear. Here, we show for the first time that physical exercise and antidepressants induce local increase of BDNF in CA3. Voluntary physical exercise for 28 consecutive days, or 2-week treatment with 10 mg/kg per day fluoxetine or reboxetine, produced a global increase of BDNF mRNA and protein in the neuronal somata of the whole hippocampus and a specific increase of BDNF in dendrites of CA3 neurons. This increase was accounted for by BDNF exon 6 variant. In cultured hippocampal neurons, application of serotonin or norepinephrine (10-50 μM) induced increase in synaptic transmission and targeting of BDNF mRNA in dendrites. The increased expression of BDNF in CA3 dendrites following antidepressants or exercise further supports the neurotrophin hypothesis of antidepressants action and confirms that the differential subcellular localization of BDNF mRNA splice variants provides a spatial code for a selective expression of BDNF in specific subcellular districts. This selective expression may be exploited to design more specific antidepressants.

  3. Measuring the expression of exogenous BDNF of NSCs after infection of supernatant from recombi-nant retrovirus pLXSN-BDNF%pLXSN-BDNF体外转染神经干细胞及其外源基因的表达

    Institute of Scientific and Technical Information of China (English)

    周雪美; 原慧萍; 吴东来; 王雅; 王卓

    2009-01-01

    目的 建立体外稳定表达脑源性神经生长因子(BDNF)的神经干细胞(NSCs).方法 采用有限稀释法纯化体外培养的NSCs.用重组和空白逆转录病毒感染NSCs,分别采用荧光定量PCR法和ELISA法检测3组(pLXSN-BDNF病毒感染组、pLXSN病毒感染组、空白对照组)NSCs中外源基因的表达水平.结果 荧光定量PCR法测定pLXSN-BDNF组BDNF原始模板拷贝数为(19.57±0.65)×10~3copies/μl,与其余两组比较差异有统计学意义(P<0.05);ELISA法测定pLXSN-BDNF组NSCs细胞上清中BDNF含量最高,与其余两组比较差异有统计学意义(P<0.05).结论 用携带BDNF的重组逆转录病毒能成功地将外源基因导入NSCs中,为NSCs眼内移植研究,也为基因治疗视神经损伤的量化研究提供实验依据.%Objective To develop neural stem cells(NSCs) which can stably express exogenous brain-derived neurotrophic factor(BDNF) in vitro. Methods NSCs from the subependymal zone of embry-onic day 14.5(E14.5) rat brain were purified by limiting dilution assay and then infected with supernatant of recombinant retrovirus pLXSN-BDNF and retrovirus pLXSN. The original copy numbers of exogenous gene templates from three groups NSCs(pLXSN-BDNF viral infection group, pLXSN viral infection group, control group) were detected by fluorescent quantitative PCR(FQ-PCR). ELISA assay was used for determining the protein contents of BDNF of supernatant from three groups NSCs for six days continually after seeded in 24-well plates in the same cell density. Results NSCs were purified successfully by limiting dilution assay.The original copy numbers of exogenous BDNF gene templates from pLXSN-BDNF viral infection group by FQ-PCR were (19.57±0.65) × 10~3 copies/μl, higher than those of another two groups(P < 0.05). The protein contents of BDNF of supernatant from NSCs of pLXSN-BDNF viral infection group was highest among three groups and compared with another two groups had statistical significance (P <0

  4. Involvement of BDNF signaling transmission from basolateral amygdala to infralimbic prefrontal cortex in conditioned taste aversion extinction.

    Science.gov (United States)

    Xin, Jian; Ma, Ling; Zhang, Tian-Yi; Yu, Hui; Wang, Yue; Kong, Liang; Chen, Zhe-Yu

    2014-05-21

    Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase receptor B (TrkB), play a critical role in memory extinction. However, the detailed role of BDNF in memory extinction on the basis of neural circuit has not been fully understood. Here, we aim to investigate the role of BDNF signaling circuit in mediating conditioned taste aversion (CTA) memory extinction of the rats. We found region-specific changes in BDNF gene expression during CTA extinction. CTA extinction led to increased BDNF gene expression in the basolateral amygdala (BLA) and infralimbic prefrontal cortex (IL) but not in the central amygdaloid nucleus (CeA) and hippocampus (HIP). Moreover, blocking BDNF signaling or exogenous microinjection of BDNF into the BLA or IL could disrupt or enhance CTA extinction, which suggested that BDNF signaling in the BLA and IL is necessary and sufficient for CTA extinction. Interestingly, we found that microinjection of BDNF-neutralizing antibody into the BLA could abolish the extinction training-induced BDNF mRNA level increase in the IL, but not vice versa, demonstrating that BDNF signaling is transmitted from the BLA to IL during extinction. Finally, the accelerated extinction learning by infusion of exogenous BDNF in the BLA could also be blocked by IL infusion of BDNF-neutralizing antibody rather than vice versa, indicating that the IL, but not BLA, is the primary action site of BDNF in CTA extinction. Together, these data suggest that BLA-IL circuit regulates CTA memory extinction by identifying BDNF as a key regulator.

  5. S-adenosylmethionine Administration Attenuates Low Brain-Derived Neurotrophic Factor Expression Induced by Chronic Cerebrovascular Hypoperfusion or Beta Amyloid Treatment.

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    Li, Qian; Cui, Jing; Fang, Chen; Zhang, Xiaowen; Li, Liang

    2016-04-01

    Chronic cerebrovascular hypoperfusion is a high-risk factor for Alzheimer's disease (AD) as it is conducive to beta amyloid (Aβ) over-production. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family widely expressed in the central nervous system. The structure of the rat BDNF gene is complex, consisting of eight non-coding exons (I-VIII) and one coding exon (IX). The BDNF gene is transcribed from multiple promoters located upstream of different 5' non-coding exons to produce a heterogeneous population of BDNF mRNAs. S-adenosylmethionine (SAM) produced in the methionine cycle is the primary methyl donor and the precursor of glutathione. In this study, a cerebrovascular hypoperfusion rat model and an Aβ intrahippocampal injection rat model were used to explore the expression profiles of all BDNF transcripts in the hippocampus with chronic cerebrovascular hypoperfusion or Aβ injection as well as with SAM treatment. We found that the BDNF mRNAs and protein were down-regulated in the hippocampus undergoing chronic cerebrovascular hypoperfusion as well as Aβ treatment, and BDNF exons IV and VI played key roles. SAM improved the low BDNF expression following these insults mainly through exons IV and VI. These results suggest that SAM plays a neuroprotective role by increasing the expression of endogenous BDNF and could be a potential target for AD therapy.

  6. BDNF serum levels, but not BDNF Val66Met genotype, are correlated with personality traits in healthy subjects.

    Science.gov (United States)

    Minelli, Alessandra; Zanardini, Roberta; Bonvicini, Cristian; Sartori, Riccardo; Pedrini, Laura; Gennarelli, Massimo; Bocchio-Chiavetto, Luisella

    2011-08-01

    Consisting evidence in animal models has suggested that alterations in brain-derived neurotrophic factor (BDNF) brain expression and release are involved in the pathogenesis of mental illnesses, such as, mood, anxiety, and eating disorders. This hypothesis is supported by data emerging from biochemical studies on serum BDNF levels and genetic studies on the functional polymorphism Val66Met in the BDNF gene in patients and control subjects. Anxiety-related personality traits are associated with several mental disorders. However, they are also measurable in non-affected subjects and, so, may represent a useful "endophenotype" to study the biological correlation of the vulnerability factors in the general population. In this study, we analyzed putative correlations in subjects unaffected by mental disorders between personality traits, serum BDNF levels (N = 107), and the BDNF Val66Met genotype (N = 217). Furthermore, we tested the possible interactions between these variables. A significant correlation has been observed between high scores of harm avoidance (HA) measured by the temperament and character inventory (TCI), and low BDNF serum concentration (r = -0.253, P = 0.009). In addition, an association has been evidenced between low BDNF levels in serum and the BDNF Val/Val genotype (P = 0.021). By analyzing putative concomitant effects of different variables on HA scores in a regression model, we observed a significant correlation only with BDNF serum concentrations (P = 0.022). The study results suggest that a decrease in serum BDNF concentrations may represent a biochemical marker associated with anxiety personality traits also retrievable in the general population.

  7. Ethanol-BDNF interactions: Still More Questions than Answers

    OpenAIRE

    Davis, Margaret I.

    2008-01-01

    Brain Derived Neurotrophic Factor (BDNF) has emerged as a regulator of development, plasticity and, recently, addiction. Decreased neurotrophic activity may be involved in ethanol-induced neurodegeneration in the adult brain and in the etiology of alcohol-related neurodevelopmental disorders. This can occur through decreased expression of BDNF or through inability of the receptor to transduce signals in the presence of ethanol. In contrast, recent studies implicate region-specific up-regulati...

  8. Agonistic effect of polyunsaturated fatty acids (PUFAs and its metabolites on brain-derived neurotrophic factor (BDNF through molecular docking simulation

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    Vetrivel Umashankar

    2012-09-01

    Full Text Available Abstract Background Brain-derived neurotrophic factor (BDNF is a potent neurotrophic factor that is implicated in the regulation of food intake and body weight. Polyunsaturated fatty acids (PUFAs localised in cell membranes have been shown to alter the levels of BDNF in the brain, suggesting that PUFAs and BDNF could have physical interaction with each other. To decipher the molecular mechanism through which PUFAs modulates BDNF’s activity, molecular docking was performed for BDNF with PUFAs and its metabolites, with 4-Methyl Catechol as a control. Results Inferring from molecular docking studies, lipoxin A4 (LXA4, and a known anti-inflammatory bioactive metabolite derived from PUFAs, with a binding energy of −3.98 Kcal/mol and dissociation constant of 1.2mM showed highest binding affinity for BDNF in comparison to other PUFAs and metabolites considered in the study. Further, the residues Lys 18, Thr 20, Ala 21, Val 22, Phe 46, Glu 48, Lys 50, Lys 58, Thr 75, Gln 77, Arg 97 and Ile 98 form hot point motif, which on interaction enhances BDNF’s function. Conclusion These results suggest that PUFAs and their metabolites especially, LXA4, modulate insulin resistance by establishing a physical interaction with BDNF. Similar interaction(s was noted between BDNF and resolvins and protectins but were of lesser intensity compared to LXA4.

  9. Voluntary exercise protects against stress-induced decreases in brain-derived neurotrophic factor protein expression.

    Science.gov (United States)

    Adlard, P A; Cotman, C W

    2004-01-01

    Exercise is increasingly recognized as an intervention that can reduce CNS dysfunctions such as cognitive decline, depression and stress. Previously we have demonstrated that brain-derived neurotrophic factor (BDNF) is increased in the hippocampus following exercise. In this study we tested the hypothesis that exercise can counteract a reduction in hippocampal BDNF protein caused by acute immobilization stress. Since BDNF expression is suppressed by corticosterone (CORT), circulating CORT levels were also monitored. In animals subjected to 2 h immobilization stress, CORT was elevated immediately following, and at 1 h after the cessation of stress, but remained unchanged from baseline up to 24 h post-stress. The stress protocol resulted in a reduction in BDNF protein at 5 and 10 h post-stress that returned to baseline at 24 h. To determine if exercise could prevent this stress-induced reduction in BDNF protein, animals were given voluntary access to running wheels for 3 weeks prior to the stress. Stressed animals, in the absence of exercise, again demonstrated an initial elevation in CORT (at 0 h) and a subsequent decrease in hippocampal BDNF at the 10 h time point. Exercising animals, both non-stressed and stressed, demonstrated circulating CORT and hippocampal BDNF protein levels that were significantly elevated above control values at both time points examined (0 and 10 h post-stress). Thus, the persistently high CORT levels in exercised animals did not affect the induction of BDNF with exercise, and the effect of immobilization stress on BDNF protein was overcome. To examine the role of CORT in the stress-related regulation of BDNF protein, experiments were carried out in adrenalectomized (ADX) animals. BDNF protein was not downregulated as a result of immobilization stress in ADX animals, while there continued to be an exercise-induced upregulation of BDNF. This study demonstrates that CORT modulates stress-related alterations in BDNF protein. Further, exercise

  10. Meta-analysis and association of brain-derived neurotrophic factor (BDNF) gene with obsessive-compulsive disorder.

    Science.gov (United States)

    Zai, Gwyneth; Zai, Clement C; Arnold, Paul D; Freeman, Natalie; Burroughs, Eliza; Kennedy, James L; Richter, Margaret A

    2015-04-01

    Obsessive-compulsive disorder (OCD) is a severe psychiatric condition with a clear genetic component (Nicolini et al., 2009) in which neurodevelopmental mechanisms may be etiologically important. Brain-derived neurotrophic factor (BDNF) is an interesting candidate for molecular analysis in OCD on the basis of potential functional relevance, positive association studies, and reported interaction between this gene and other neurotransmitters implicated in this disorder.

  11. Sex-specific disruptions in spatial memory and anhedonia in a "two hit" rat model correspond with alterations in hippocampal brain-derived neurotrophic factor expression and signaling.

    Science.gov (United States)

    Hill, Rachel A; Klug, Maren; Kiss Von Soly, Szerenke; Binder, Michele D; Hannan, Anthony J; van den Buuse, Maarten

    2014-10-01

    Post-mortem studies have demonstrated reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus of schizophrenia and major depression patients. The "two hit" hypothesis proposes that two or more major disruptions at specific time points during development are involved in the pathophysiology of these mental illnesses. However, the role of BDNF in these "two hit" effects is unclear. Our aim was to behaviorally characterize a "two hit" rat model of developmental stress accompanied by an in-depth assessment of BDNF expression and signalling. Wistar rats were exposed to neonatal maternal separation (MS) stress and/or adolescent/young-adult corticosterone (CORT) treatment. In adulthood, models of cognitive and negative symptoms of mental illness were analyzed. The hippocampus was then dissected into dorsal (DHP) and ventral (VHP) regions and analyzed by qPCR for exon-specific BDNF gene expression or by Western blot for BDNF protein expression and downstream signaling. Male "two hit" rats showed marked disruptions in short-term spatial memory (Y-maze) which were absent in females. However, female "two hit" rats showed signs of anhedonia (sucrose preference test), which were absent in males. Novel object recognition and anxiety (elevated plus maze) were unchanged by either of the two "hits". In the DHP, MS caused a male-specific increase in BDNF Exons I, II, IV, VII, and IX mRNA but a decrease in mature BDNF and phosphorylated TrkB (pTrkB) protein expression in adulthood. In the VHP, BDNF transcript expression was unchanged; however, in female rats only, MS significantly decreased mature BDNF and pTrkB protein expression in adulthood. These data demonstrate that MS causes region-specific and sex-specific long-term effects on BDNF expression and signaling and, importantly, mRNA expression does not always infer protein expression. Alterations to BDNF signaling may mediate the sex-specific effects of developmental stress on anhedonic behaviors.

  12. Role of BDNF epigenetics in activity-dependent neuronal plasticity.

    Science.gov (United States)

    Karpova, Nina N

    2014-01-01

    Brain-derived neurotrophic factor (BDNF) is a key mediator of the activity-dependent processes in the brain that have a major impact on neuronal development and plasticity. Impaired control of neuronal activity-induced BDNF expression mediates the pathogenesis of various neurological and psychiatric disorders. Different environmental stimuli, such as the use of pharmacological compounds, physical and learning exercises or stress exposure, lead to activation of specific neuronal networks. These processes entail tight temporal and spatial transcriptional control of numerous BDNF splice variants through epigenetic mechanisms. The present review highlights recent findings on the dynamic and long-term epigenetic programming of BDNF gene expression by the DNA methylation, histone-modifying and microRNA machineries. The review also summarizes the current knowledge on the activity-dependent BDNF mRNA trafficking critical for rapid local regulation of BDNF levels and synaptic plasticity. Current data open novel directions for discovery of new promising therapeutic targets for treatment of neuropsychiatric disorders. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'. Copyright © 2013 Elsevier Ltd. All rights reserved.

  13. Chronic BDNF deficiency leads to an age-dependent impairment in spatial learning.

    Science.gov (United States)

    Petzold, Anne; Psotta, Laura; Brigadski, Tanja; Endres, Thomas; Lessmann, Volkmar

    2015-04-01

    Brain-derived neurotrophic factor (BDNF) is a crucial mediator of neural plasticity and, consequently, of memory formation. In hippocampus-dependent learning tasks BDNF also seems to play an essential role. However, there are conflicting results concerning the spatial learning ability of aging BDNF(+/-) mice in the Morris water maze paradigm. To evaluate the effect of chronic BDNF deficiency in the hippocampus on spatial learning throughout life, we conducted a comprehensive study to test differently aged BDNF(+/-) mice and their wild type littermates in the Morris water maze and to subsequently quantify their hippocampal BDNF protein levels as well as expression levels of TrkB receptors. We observed an age-dependent learning deficit in BDNF(+/-) animals, starting at seven months of age, despite stable hippocampal BDNF protein expression and continual decline of TrkB receptor expression throughout aging. Furthermore, we detected a positive correlation between hippocampal BDNF protein levels and learning performance during the probe trial in animals that showed a good learning performance during the long-term memory test.

  14. Low Concentration of BDNF in the Acute Phase of Ischemic Stroke as a Factor in Poor Prognosis in Terms of Functional Status of Patients.

    Science.gov (United States)

    Lasek-Bal, Anetta; Jędrzejowska-Szypułka, Halina; Różycka, Jagoda; Bal, Wiesław; Holecki, Michał; Duława, Jan; Lewin-Kowalik, Joanna

    2015-12-14

    BACKGROUND According to recent studies, brain-derived neurotrophic factor (BDNF) probably plays a role in development of cerebral ischemia and can be significant for the prognosis of improved mobility after stroke. The aim of this prospective study was to evaluate the blood concentration of BDNF during the 1st day of first-ever ischemic stroke and find a potential association between BDNF concentration and the neurological status in the acute period, as well as between BDNF and the functional status in the sub-acute phase of stroke. MATERIAL AND METHODS The prospective study involved 87 patients aged 39-99 years (42 women, 45 men) with first-in-life complete ischemic stroke. All study subjects underwent analysis as follows: BDNF blood concentration and neurological status according to NIHSS on the 1st day of stroke, comorbidities, etiological type of ischemic stroke by ASCOD, and functional status on the 14th and 90th day after the onset according to mRankin scale. RESULTS Mean concentration of BDNF in the study group was 9.96 ng/mL±5.21, median 10.39 ng/mL. Patients aged ≤65 years (25 individuals) had a significantly higher mean concentration of BDNF (11.94 ng/mL±4.46; median 12.34 ng/mL) than the older subjects (62 individuals) with a mean concentration of 9.17 ng/mL±5.32 (median 8.66 ng/mL). The mean score by mRankin scale on the 90th day was significantly higher among patients with lower concentrations of BDNF on the 1st day of stroke, which reflects their poorer functional status. The functional status on the 90th day was significantly worse (3-6 points by Rankin scale) in patients who had BDNF below the mean value in the acute phase of stroke. The independent factors for poor functional status of patients on the 90th day after stroke were a score >4 points by NIHSS (RR 1.14; 95% CI: 1.00-1.31; p=0.027) and the concentration of BDNF below the mean value (assessed on the 1st day of stroke) (RR 14.49; CI 4.60-45.45; p=0.000). CONCLUSIONS The neurological

  15. Hyperphagia, Severe Obesity, Impaired Cognitive Function, and Hyperactivity Associated With Functional Loss of One Copy of the Brain-Derived Neurotrophic Factor (BDNF) Gene

    OpenAIRE

    Gray, Juliette; Yeo, Giles S.H.; Cox, James J.; Morton, Jenny; Adlam, Anna-Lynne R.; Keogh, Julia M.; Yanovski, Jack A.; El Gharbawy, Areeg; Han, Joan C.; Tung, Y.C. Loraine; Hodges, John R.; Raymond, F Lucy; O’Rahilly, Stephen; Farooqi, I. Sadaf

    2006-01-01

    The neurotrophin brain-derived neurotrophic factor (BDNF) inhibits food intake, and rodent models of BDNF disruption all exhibit increased food intake and obesity, as well as hyperactivity. We report an 8-year-old girl with hyperphagia and severe obesity, impaired cognitive function, and hyperactivity who harbored a de novo chromosomal inversion, 46,XX,inv(11)(p13p15.3), a region encompassing the BDNF gene. We have identified the proximal inversion breakpoint that lies 850 kb telomeric of the...

  16. DNA methylation and single nucleotide variants in the brain-derived neurotrophic factor (BDNF and oxytocin receptor (OXTR genes are associated with anxiety/depression in older women

    Directory of Open Access Journals (Sweden)

    Yvon eChagnon

    2015-06-01

    Full Text Available Background: Environmental effects and personal experiences could be expressed in individuals through epigenetic non-structural changes such as DNA methylation. This methylation could up- regulate or down-regulate corresponding gene expressions and modify related phenotypes. DNA methylation increases with ageing and could be related to the late expression of some forms of mental disease. The objective of this study was to evaluate the association between anxiety disorders and/or depression in older women and DNA methylation for four genes related to anxiety or depression. Methods: Women aged 65 and older with (n =19 or without (n =24 anxiety disorders and/or major depressive episode (DSM-IV, were recruited. DNA methylation and single nucleotide variant (SNV were evaluated from saliva, respectively by pyrosequencing and by PCR, for the following genes: brain-derived neurotrophic factor (BDNF; rs6265, oxytocin receptor (OXTR; rs53576, serotonin transporter (SLC6A4; rs25531 and apolipoprotein E (APOE; rs429358 and rs7412. Results: A greater BDNF DNA methylation was observed in subjects with anxiety/depression compared to control group subjects(Mean: 2.92 SD: 0.74 vs. 2.34 SD: 0.42; p=0.0026.This difference was more pronounced in subjects carrying the BDNF rs6265 CT genotype (2.99 SD: 0.41 vs.2.27 SD: 0.26; p=0.0006 than those carrying the CC genotype (p=0.0332; no subjects with the TT genotype were observed. For OXTR, a greater DNA methylation was observed in subjects with anxiety/depression, but only for those carrying the AA genotype of the OXTR rs53576SNV, more particularly at one out of the seven CpGs studied (7.01 SD: 0.94 vs. 4.44 SD: 1.11; p=0.0063. No significant differences were observed for APOE and SLC6A4.Conclusion: These results suggest that DNA methylation in interaction with SNV variations in BDNF and OXTR, are associated with the occurrence of anxiety/depression in older women.

  17. Reduced hippocampal dendritic spine density and BDNF expression following acute postnatal exposure to di(2-ethylhexyl phthalate in male Long Evans rats.

    Directory of Open Access Journals (Sweden)

    Catherine A Smith

    Full Text Available Early developmental exposure to di(2-ethylhexyl phthalate (DEHP has been linked to a variety of neurodevelopmental changes, particularly in rodents. The primary goal of this work was to establish whether acute postnatal exposure to a low dose of DEHP would alter hippocampal dendritic morphology and BDNF and caspase-3 mRNA expression in male and female Long Evans rats. Treatment with DEHP in male rats led to a reduction in spine density on basal and apical dendrites of neurons in the CA3 dorsal hippocampal region compared to vehicle-treated male controls. Dorsal hippocampal BDNF mRNA expression was also down-regulated in male rats exposed to DEHP. No differences in hippocampal spine density or BDNF mRNA expression were observed in female rats treated with DEHP compared to controls. DEHP treatment did not affect hippocampal caspase-3 mRNA expression in male or female rats. These results suggest a gender-specific vulnerability to early developmental DEHP exposure in male rats whereby postnatal DEHP exposure may interfere with normal synaptogenesis and connectivity in the hippocampus. Decreased expression of BDNF mRNA may represent a molecular mechanism underlying the reduction in dendritic spine density observed in hippocampal CA3 neurons. These findings provide initial evidence for a link between developmental exposure to DEHP, reduced levels of BDNF and hippocampal atrophy in male rats.

  18. Reduced hippocampal dendritic spine density and BDNF expression following acute postnatal exposure to di(2-ethylhexyl) phthalate in male Long Evans rats.

    Science.gov (United States)

    Smith, Catherine A; Holahan, Matthew R

    2014-01-01

    Early developmental exposure to di(2-ethylhexyl) phthalate (DEHP) has been linked to a variety of neurodevelopmental changes, particularly in rodents. The primary goal of this work was to establish whether acute postnatal exposure to a low dose of DEHP would alter hippocampal dendritic morphology and BDNF and caspase-3 mRNA expression in male and female Long Evans rats. Treatment with DEHP in male rats led to a reduction in spine density on basal and apical dendrites of neurons in the CA3 dorsal hippocampal region compared to vehicle-treated male controls. Dorsal hippocampal BDNF mRNA expression was also down-regulated in male rats exposed to DEHP. No differences in hippocampal spine density or BDNF mRNA expression were observed in female rats treated with DEHP compared to controls. DEHP treatment did not affect hippocampal caspase-3 mRNA expression in male or female rats. These results suggest a gender-specific vulnerability to early developmental DEHP exposure in male rats whereby postnatal DEHP exposure may interfere with normal synaptogenesis and connectivity in the hippocampus. Decreased expression of BDNF mRNA may represent a molecular mechanism underlying the reduction in dendritic spine density observed in hippocampal CA3 neurons. These findings provide initial evidence for a link between developmental exposure to DEHP, reduced levels of BDNF and hippocampal atrophy in male rats.

  19. Brain-derived neurotrophic factor activation of NFAT (nuclear factor of activated T-cells)-dependent transcription: a role for the transcription factor NFATc4 in neurotrophin-mediated gene expression.

    Science.gov (United States)

    Groth, Rachel D; Mermelstein, Paul G

    2003-09-03

    A member of the neurotrophin family, brain-derived neurotrophic factor (BDNF) regulates neuronal survival and differentiation during development. Within the adult brain, BDNF is also important in neuronal adaptive processes, such as the activity-dependent plasticity that underlies learning and memory. These long-term changes in synaptic strength are mediated through alterations in gene expression. However, many of the mechanisms by which BDNF is linked to transcriptional and translational regulation remain unknown. Recently, the transcription factor NFATc4 (nuclear factor of activated T-cells isoform 4) was discovered in neurons, where it is believed to play an important role in long-term changes in neuronal function. Interestingly, NFATc4 is particularly sensitive to the second messenger systems activated by BDNF. Thus, we hypothesized that NFAT-dependent transcription may be an important mediator of BDNF-induced plasticity. In cultured rat CA3-CA1 hippocampal neurons, BDNF activated NFAT-dependent transcription via TrkB receptors. Inhibition of calcineurin blocked BDNF-induced nuclear translocation of NFATc4, thus preventing transcription. Further, phospholipase C was a critical signaling intermediate between BDNF activation of TrkB and the initiation of NFAT-dependent transcription. Both inositol 1,4,5-triphosphate (IP3)-mediated release of calcium from intracellular stores and activation of protein kinase C were required for BDNF-induced NFAT-dependent transcription. Finally, increased expression of IP3 receptor 1 and BDNF after neuronal exposure to BDNF was linked to NFAT-dependent transcription. These results suggest that NFATc4 plays a crucial role in neurotrophin-mediated synaptic plasticity.

  20. Sex and ovarian steroids modulate brain-derived neurotrophic factor (BDNF) protein levels in rat hippocampus under stressful and non-stressful conditions.

    Science.gov (United States)

    Franklin, Tamara B; Perrot-Sinal, Tara S

    2006-01-01

    Abnormal levels of brain-derived neurotrophic factor (BDNF) are associated with major depression, a disorder with a higher incidence in women than men. Stress affects BDNF levels in various brain regions and thus, a heightened stress response in females could contribute to the development of depression. As well, ovarian hormones directly affect brain levels of BDNF mRNA and protein. Two experiments were performed to investigate the effects of stress and sex and gonadal hormones on BDNF protein levels in CA1, CA3, and dentate gyrus (DG) subregions of the hippocampus. In the first experiment, male and female Sprague-Dawley rats were subjected to one hour of restraint stress or control handling prior to sacrifice. In the second experiment, fifty-one female rats were ovariectomized and separated into stress and control conditions, as described for the first experiment. Stressed and handled groups received a single injection of estrogen (E; 53h prior to stress), estrogen and progesterone (EP; E given at 53h and P given 5h prior to stress), or vehicle (OVX). In both experiments BDNF protein was quantified using an enzyme-linked immunosorbent enzyme assay (ELISA) in micropunches of hippocampus. Gonadally intact females had significantly higher levels of BDNF in CA3, but significantly lower levels in DG, relative to males. In CA3, stress significantly decreased BDNF in both males and females. In DG of ovariectomized female rats, the effects of stress were significantly different following EP vs. vehicle treatment. Thus, stress increased BDNF levels in EP-treated rats but decreased BDNF levels in vehicle-treated rats. Reduced trophic support in DG in the presence of estrogen and progesterone could jeopardize neurogenesis and under certain conditions could be a contributing factor to the hippocampal atrophy associated with stress-induced affective disorders. These results emphasize the need to consider sex, gonadal steroids, and hippocampal subregion when examining the

  1. Tumor necrosis factor-α increases brain-derived neurotrophic factor expression in trigeminal ganglion neurons in an activity-dependent manner.

    Science.gov (United States)

    Bałkowiec-Iskra, E; Vermehren-Schmaedick, A; Balkowiec, A

    2011-04-28

    Many chronic trigeminal pain conditions, such as migraine or temporo-mandibular disorders, are associated with inflammation within peripheral endings of trigeminal ganglion (TG) sensory neurons. A critical role in mechanisms of neuroinflammation is attributed to proinflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α (TNFα) that also contribute to mechanisms of persistent neuropathic pain resulting from nerve injury. However, the mechanisms of cytokine-mediated synaptic plasticity and nociceptor sensitization are not completely understood. In the present study, we examined the effects of TNFα on neuronal expression of brain-derived neurotrophic factor (BDNF), whose role in synaptic plasticity and sensitization of nociceptive pathways is well documented. We show that 4- and 24-h treatment with TNFα increases BDNF mRNA and protein, respectively, in neuron-enriched dissociated cultures of rat TG. TNFα increases the phosphorylated form of the cyclic AMP-responsive element binding protein (CREB), a transcription factor involved in regulation of BDNF expression in neurons, and activates transcription of BDNF exon IV (former exon III) and, to a lesser extent, exon VI (former exon IV), but not exon I. TNFα-mediated increase in BDNF expression is accompanied by increase in calcitonin gene-related peptide (CGRP), which is consistent with previously published studies, and indicates that both peptides are similarly regulated in TG neurons by inflammatory mediators. The effect of TNFα on BDNF expression is dependent on sodium influx through TTX-sensitive channels and on p38-mitogen-activated protein kinase. Moreover, electrical stimulation and forskolin, known to increase intracellular cAMP, potentiate the TNFα-mediated upregulation of BDNF expression. This study provides new evidence for a direct action of proinflammatory cytokines on TG primary sensory neurons, and reveals a mechanism through which TNFα stimulates de novo synthesis of BDNF in

  2. Brain Derived Neurotrophic Factor (BDNF) levels as a possible predictor of psychopathology in healthy twins at high and low risk for affective disorder.

    Science.gov (United States)

    Vinberg, Maj; Miskowiak, Kamilla; Kessing, Lars Vedel

    2014-01-01

    Brain Derived Neurotrophic Factor (BDNF) is a potential biomarker of affective disorder. However, longitudinal studies evaluating a potential predictive role of BDNF on subsequent psychopathology are lacking. The aim of this study was to investigate whether BDNF alone or in interaction with the BDNF Val66Met polymorphism predict onset of affective disorder in healthy individuals at heritable risk for affective disorder. In a high-risk study, we assessed whole blood levels of BDNF in 234 healthy monozygotic and dizygotic twins with or without a co-twin history of affective disorder (high and low risk twins, respectively). Participants were followed up longitudinally with questionnaires at 6-month intervals for mean seven years and then reassessed with a personal interview to obtain information about whether they had developed psychiatric illness. At follow-up 36 participants (15.4%) had developed psychiatric disorder. Cox regression analysis revealed that BDNF levels at baseline were not associated with onset of illness in this explorative study. Further, two-way interactions between BDNF levels and the Val66Met polymorphism or between familial risk and the Val66Met polymorphism did not predict illness onset.

  3. Antidepressant-like activity of resveratrol treatment in the forced swim test and tail suspension test in mice: the HPA axis, BDNF expression and phosphorylation of ERK.

    Science.gov (United States)

    Wang, Zhen; Gu, Jianhua; Wang, Xueer; Xie, Kai; Luan, Qinsong; Wan, Nianqing; Zhang, Qun; Jiang, Hong; Liu, Dexiang

    2013-11-01

    Resveratrol is a natural polyphenol enriched in Polygonum cuspidatum and has diverse biological activities. There is only limited information about the antidepressant-like effect of resveratrol. The present study assessed whether resveratrol treatment (20, 40 and 80mg/kg, i.p., 21days) has an antidepressant-like effect on the forced swim test (FST) and tail suspension test (TST) in mice and examined what its molecular targets might be. The results showed that resveratrol administration produced antidepressant-like effects in mice, evidenced by the reduced immobility time in the FST and TST, while it had no effect on the locomotor activity in the open field test. Resveratrol treatment significantly reduced serum corticosterone levels, which had been elevated by the FST and TST. Moreover, resveratrol increased brain-derived neurotrophic factor (BDNF) protein and extracellular signal-regulated kinase (ERK) phosphorylation levels in the prefrontal cortex and hippocampus. All of these antidepressant-like effects of resveratrol were essentially similar to those observed with the clinical antidepressant, fluoxetine. These results suggest that the antidepressant-like effects of resveratrol in the FST and TST are mediated, at least in part, by modulating hypothalamic-pituitary-adrenal axis, BDNF and ERK phosphorylation expression in the brain region of mice.

  4. Gene expression of BDNF and its receptors, TrkB and p75 in the uterus and oviduct of pregnant and non-pregnant ewes.

    Science.gov (United States)

    Mirshokraei, P; Hassanpour, H; Rahnama, A; Foster, W G

    2013-08-01

    To compare genes expression of BDNF and its receptors, TrkB and p75 between pregnant and non-pregnant uterine and oviductal tissues of ewes, semi-quantitative RT-PCR was performed. BDNF, TrkB and p75 genes are normally expressed in the ovine uterus and oviduct. The relative amounts of BDNF mRNA were increased in the uterine segments of the pregnant samples with compared to non-pregnant samples. This increasing was only significant (Ppregnant samples. In contrast, the relative amounts of BDNF mRNA were decreased in the oviductal segments of the pregnant samples and were undetectable in the isthmus. Variations of the relative amounts of TrkB and p75 mRNAs between the pregnant and non-pregnant samples were not significant (P>0.05) although TrkB mRNA in the caruncle and cervix and p75 mRNA in the cervix of pregnant samples were too less to be detected by RT-PCR method. It is probably that these changes of BDNF/receptors genes expression are necessary for normal pregnancy, and abnormal variations in the expression of these genes may be involved in the pathophysiological conditions.

  5. Blood BDNF concentrations reflect brain-tissue BDNF levels across species

    DEFF Research Database (Denmark)

    Klein, Anders B; Williamson, Rebecca; Santini, Martin A;

    2011-01-01

    Brain-derived neurotrophic factor (BDNF) is involved in synaptic plasticity, neuronal differentiation and survival of neurons. Observations of decreased serum BDNF levels in patients with neuropsychiatric disorders have highlighted the potential of BDNF as a biomarker, but so far there have been...... no studies directly comparing blood BDNF levels to brain BDNF levels in different species. We examined blood, serum, plasma and brain-tissue BDNF levels in three different mammalian species: rat, pig, and mouse, using an ELISA method. As a control, we included an analysis of blood and brain tissue from...... conditional BDNF knockout mice and their wild-type littermates. Whereas BDNF could readily be measured in rat blood, plasma and brain tissue, it was undetectable in mouse blood. In pigs, whole-blood levels of BDNF could not be measured with a commercially available ELISA kit, but pig plasma BDNF levels (mean...

  6. The role of brain-derived neurotrophic factor in the regulation of cell growth and gene expression in melanotrope cells of Xenopus laevis.

    NARCIS (Netherlands)

    Jenks, B.G.; Kuribara, M.; Kidane, A.H.; Kramer, B.M.; Roubos, E.W.; Scheenen, W.J.

    2012-01-01

    Brain-derived neurotrophic factor (BDNF) is, despite its name, also found outside the central nervous system (CNS), but the functional significance of this observation is largely unknown. This review concerns the expression of BDNF in the pituitary gland. While the presence of the neurotrophin in th

  7. Critical role of promoter IV-driven BDNF transcription in GABAergic transmission and synaptic plasticity in the prefrontal cortex.

    Science.gov (United States)

    Sakata, Kazuko; Woo, Newton H; Martinowich, Keri; Greene, Joshua S; Schloesser, Robert J; Shen, Liya; Lu, Bai

    2009-04-07

    Transcription of Bdnf is controlled by multiple promoters, which drive expression of multiple transcripts encoding for the same protein. Promoter IV contributes significantly to activity-dependent brain-derived neurotrophic factor (BDNF) transcription. We have generated promoter IV mutant mice (BDNF-KIV) by inserting a GFP-STOP cassette within the Bdnf exon IV locus. This genetic manipulation results in disruption of promoter IV-mediated Bdnf expression. BDNF-KIV animals exhibited significant deficits in GABAergic interneurons in the prefrontal cortex (PFC), particularly those expressing parvalbumin, a subtype implicated in executive function and schizophrenia. Moreover, disruption of promoter IV-driven Bdnf transcription impaired inhibitory but not excitatory synaptic transmission recorded from layer V pyramidal neurons in the PFC. The attenuation of GABAergic inputs resulted in an aberrant appearance of spike-timing-dependent synaptic potentiation (STDP) in PFC slices derived from BDNF-KIV, but not wild-type littermates. These results demonstrate the importance of promoter IV-dependent Bdnf transcription in GABAergic function and reveal an unexpected regulation of STDP in the PFC by BDNF.

  8. Childhood trauma and platelet brain-derived neurotrophic factor (BDNF) after a three month follow-up in patients with major depressive disorder.

    Science.gov (United States)

    Jeon, Hong Jin; Kang, Eun-Suk; Lee, Eun Ho; Jeong, Eu-Gene; Jeon, Ju-Ri; Mischoulon, David; Lee, Dongsoo

    2012-07-01

    A large amount of brain-derived neurotrophic factor (BDNF) is stored in the human platelets and only small amounts of it circulate in the plasma. However, a few studies have focused on platelet BDNF in patients with major depressive disorder (MDD) and childhood trauma. Our study population consisted of 105 MDD patients and 50 healthy controls. We used the mini-international neuropsychiatric interview (M.I.N.I.), the early trauma inventory self report-short form (ETISR-SF), as well as measured serum, plasma, and platelet BDNF at baseline, 1 month, and 3 month periods. There was a significant association between childhood trauma and platelet BDNF at baseline, 1 month, and 3 months, after adjusting for age, gender, education, body mass index, severity of depression, anxiety, alcohol consumption, and current stress. Conversely, plasma and serum BDNF did not have a significant association with childhood trauma. MDD patients revealed significantly higher levels of platelet BDNF in those with childhood trauma than in those without (t = 2.4, p = 0.018), and platelet BDNF was significantly higher in cases with sexual abuse on post-hoc analysis (p = 0.042). However, no significant differences were found in healthy controls, according to whether or not they had experienced childhood trauma. Platelet BDNF showed a significant correlation with severity of childhood trauma at baseline (r = 0.25, p = 0.012) and at 3 months (r = 0.38, p = 0.003) in MDD. In conclusion, platelet BDNF was significantly higher in MDD patients with childhood trauma than in those without, and it was correlated with severity of trauma.

  9. Expression of brain-derived neurotrophic factor and TrkB receptor in the sudden infant death syndrome brainstem.

    Science.gov (United States)

    Tang, Samantha; Machaalani, Rita; Waters, Karen A

    2012-01-15

    This study compared the expression of BDNF (proBDNF and rhBDNF forms) and its receptor TrkB, in the medulla of sudden infant death syndrome (SIDS) infants and infants who died from known causes (non-SIDS). This study also evaluated these markers in association with SIDS clinical risk factors including, sleep position, cigarette smoke exposure and gender. Brainstem tissue was immunohistochemically stained and quantitative analyses were made for eight nuclei of the caudal and rostral medulla. Compared to non-SIDS, SIDS infants had lower rhBDNF in the caudal nucleus of the solitary tract and higher TrkB in the caudal dorsal motor nucleus of the vagus. Within the SIDS cohort, prone sleep position was associated with lower rhBDNF in the caudal arcuate nucleus, and cigarette smoke exposure was associated with lower rhBDNF and TrkB in the inferior olivary nucleus. Abnormal expression of BDNF and TrkB suggests that neuroprotective functions of the BDNF/TrkB system may be reduced in respiratory-related nuclei of SIDS infants.

  10. Central nervous system rather than immune cell-derived BDNF mediates axonal protective effects early in autoimmune demyelination

    OpenAIRE

    Lee, De-Hyung; Geyer, Eva; Flach, Anne-Christine; Jung, Klaus; Gold, Ralf; Flügel, Alexander; Linker, Ralf; Lühder, Fred

    2011-01-01

    Brain-derived neurotrophic factor (BDNF) is involved in neuronal and glial development and survival. While neurons and astrocytes are its main cellular source in the central nervous system (CNS), bioactive BDNF is also expressed in immune cells and in lesions of multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). Previous data revealed that BDNF exerts neuroprotective effects in myelin oligodendrocyte glycoprotein-induced EAE. Using a conditional knock-out...

  11. Garcinol Upregulates GABAA and GAD65 Expression, Modulates BDNF-TrkB Pathway to Reduce Seizures in Pentylenetetrazole (PTZ)-Induced Epilepsy

    Science.gov (United States)

    Hao, Fang; Jia, Li-Hua; Li, Xiao-Wan; Zhang, Ying-Rui; Liu, Xue-Wu

    2016-01-01

    Background Epilepsy is the most predominant neurological disorder characterized by recurrent seizures. Despite treatment with antiepileptic drugs, epilepsy still is a challenge to treat, due to the associated adverse effects of the drugs. Previous investigations have shown critical roles of BDNF-TrkB signalling and expression of glutamic acid decarboxylase 65 (GAD65) and GABAA in the brain during epilepsy. Thus, drugs that could modulate BDNF-TrkB signal and expression of GAD65 and GABAA could aid in therapy. Recent experimental data have focussed on plant-derived compounds in treatments. Garcinol (camboginol), is a polyisoprenylated benzophenone derived from the fruit of Garcinia indica. We investigated the effects of garcinol in pentylenetetrazole (PTZ)-induced epileptic models. Material/Methods Seizure scores were measured in epilepsy kindled mice. Neuronal degeneration and apoptosis were assessed by Nissl staining, TUNEL assay, and Fluoro-Jade B staining. Immunohistochemistry was performed to evaluate cleaved caspase-3 expressions. Expression of BDNF, TrkB, GABAA, GAD65, Bad, Bcl-2, Bcl-xL, and Bax were determined by western blots. Results Significantly reduced seizure scores and mortality rates were observed with pretreatment with garcinol. Elevated expression of apoptotic proteins and caspase-3 in kindled mice were effectively downregulated by garcinol. Epileptogenic mice presented increased BDNF and TrkB with considerably decreased GABAA and GAD65 expression. Garcinol significantly enhanced GABAA and GAD65 while it suppressed BDNF and TrkB. Garcinol enhanced the performance of mice in Morris water maze tests. Conclusions Garcinol exerts neuroprotective effects via supressing apoptosis and modulating BDNF-TrkB signalling and GAD65/GABAA expressions and also enhanced cognition and memory of the mice. PMID:27855137

  12. Ativador do Plasminogênio Tecidual (tPA/ Fator Neurotrófico Derivado do Cérebro (BDNF e a Consolidação da Memória/ Tissue Plasminogen Activator (tPA/ Brain Derived Neurotrophic Factor (BDNF and the Consolidation of Memory

    Directory of Open Access Journals (Sweden)

    Rodolfo Souza de Faria

    2014-09-01

    Full Text Available O Fator Neurotrófico Derivado do Cérebro (BDNF participa de processos de plasticidade sináptica subjacentes à aprendizagem e memória. Esta proteína possui diversas isoformas, sendo a isoforma BDNF-maduro envolvida nas mudanças neuronais da memória. Além disso, foi demonstrado que a consolidação da memória aversiva depende do Ativador do Plasminogênio Tecidual (tPA, enzima que estabelece a formação do BDND-maduro na fenda sináptica garantindo os processos neuroplásticos da aprendizagem. Para esta revisão de literatura, foram selecionados 37 trabalhos, dentre eles 36 artigos científicos e 1 livro. A consolidação da memória requer a ativação gênica para síntese de novas proteínas, sendo a tPA e o BDNF algumas das principais moléculas neuronais expressas no hipocampo, amigdala, córtex frontal em diferentes momentos após o início da aprendizagem, ativando uma série de eventos moleculares que levam ao aumento da expressão de outras proteínas, garantindo assim a regulação fina da plasticidade neuronal necessária para a memória. The Brain Derived Neurotrophic Factor (BDNF participates in synaptic plasticity processes underlying learning and memory. This protein has several isoforms, mature-BDNF one isoform involved in neuronal memory changes. Furthermore, it was demonstrated that the consolidation of aversive memory depends on the tissue plasminogen activator (tPA, an enzyme that establishes the formation of the mature BDND-synaptic cleft, guaranteeing neuroplastic learning processes. For this literature review, we selected 37 works, including 36 scientific articles and one book. The consolidation of memory for gene activation requires new protein synthesis, tPA and BDNF and some of the major neuronal molecules expressed in the hippocampus, amygdala, frontal cortex at different times after the start of learning, activating a series of molecular events leading the increased expression of other proteins, thereby

  13. Brain-derived Neurotrophic Factor (BDNF)-TrkB Signaling in Inflammation-related Depression and Potential Therapeutic Targets.

    Science.gov (United States)

    Zhang, Ji-Chun; Yao, Wei; Hashimoto, Kenji

    2016-01-01

    Depression is the most prevalent and among the most debilitating of psychiatric disorders. The precise neurobiology of this illness is unknown. Several lines of evidence suggest that peripheral and central inflammation plays a role in depressive symptoms, and that anti-inflammatory drugs can improve depressive symptoms in patients with inflammation-related depression. Signaling via brain-derived neurotrophic factor (BDNF) and its receptor, tropomycin receptor kinase B (TrkB) plays a key role in the pathophysiology of depression and in the therapeutic mechanisms of antidepressants. A recent paper showed that lipopolysaccharide (LPS)-induced inflammation gave rise to depression-like phenotype by altering BDNF-TrkB signaling in the prefrontal cortex, hippocampus, and nucleus accumbens, areas thought to be involved in the antidepressant effects of TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF) and TrkB antagonist, ANA-12. Here we provide an overview of the tryptophan-kynurenine pathway and BDNF-TrkB signaling in the pathophysiology of inflammation-induced depression, and propose mechanistic actions for potential therapeutic agents. Additionally, the authors discuss the putative role of TrkB agonists and antagonists as novel therapeutic drugs for inflammation-related depression.

  14. BDNF/TrkB signaling protects HT-29 human colon cancer cells from EGFR inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Brunetto de Farias, Caroline [Cancer Research Laboratory, University Hospital Research Center (CPE-HCPA), Federal University of Rio Grande do Sul, 90035-003 Porto Alegre, RS (Brazil); Children' s Cancer Institute, 90420-140 Porto Alegre, RS (Brazil); Laboratory of Neuropharmacology and Neural Tumor Biology, Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, 90050-170 Porto Alegre, RS (Brazil); National Institute for Translational Medicine (INCT-TM), 90035-003 Porto Alegre, RS (Brazil); Heinen, Tiago Elias; Pereira dos Santos, Rafael [Cancer Research Laboratory, University Hospital Research Center (CPE-HCPA), Federal University of Rio Grande do Sul, 90035-003 Porto Alegre, RS (Brazil); Laboratory of Neuropharmacology and Neural Tumor Biology, Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, 90050-170 Porto Alegre, RS (Brazil); National Institute for Translational Medicine (INCT-TM), 90035-003 Porto Alegre, RS (Brazil); Abujamra, Ana Lucia [Cancer Research Laboratory, University Hospital Research Center (CPE-HCPA), Federal University of Rio Grande do Sul, 90035-003 Porto Alegre, RS (Brazil); Children' s Cancer Institute, 90420-140 Porto Alegre, RS (Brazil); National Institute for Translational Medicine (INCT-TM), 90035-003 Porto Alegre, RS (Brazil); Schwartsmann, Gilberto [Cancer Research Laboratory, University Hospital Research Center (CPE-HCPA), Federal University of Rio Grande do Sul, 90035-003 Porto Alegre, RS (Brazil); National Institute for Translational Medicine (INCT-TM), 90035-003 Porto Alegre, RS (Brazil); Department of Internal Medicine, School of Medicine, Federal University of Rio Grande do Sul, 90035-003 Porto Alegre, RS (Brazil); and others

    2012-08-24

    Highlights: Black-Right-Pointing-Pointer BDNF protected HT-29 colorectal cancer cells from the antitumor effect of cetuximab. Black-Right-Pointing-Pointer TrkB inhibition potentiated the antitumor effect of cetuximab. Black-Right-Pointing-Pointer BDNF/TrkB signaling might be involved in resistance to anti-EGFR therapy. -- Abstract: The clinical success of targeted treatment of colorectal cancer (CRC) is often limited by resistance to anti-epidermal growth factor receptor (EGFR) therapy. The neurotrophin brain-derived neurotrophic factor (BDNF) and its receptor TrkB have recently emerged as anticancer targets, and we have previously shown increased BDNF levels in CRC tumor samples. Here we report the findings from in vitro experiments suggesting that BDNF/TrkB signaling can protect CRC cells from the antitumor effects of EGFR blockade. The anti-EGFR monoclonal antibody cetuximab reduced both cell proliferation and the mRNA expression of BDNF and TrkB in human HT-29 CRC cells. The inhibitory effect of cetuximab on cell proliferation and survival was counteracted by the addition of human recombinant BDNF. Finally, the Trk inhibitor K252a synergistically enhanced the effect of cetuximab on cell proliferation, and this effect was blocked by BDNF. These results provide the first evidence that increased BDNF/TrkB signaling might play a role in resistance to EGFR blockade. Moreover, it is possible that targeting TrkB could potentiate the anticancer effects of anti-EGFR therapy.

  15. BDNF heightens the sensitivity of motor neurons to excitotoxic insults through activation of TrkB

    Science.gov (United States)

    Hu, Peter; Kalb, Robert G.; Walton, K. D. (Principal Investigator)

    2003-01-01

    The survival promoting and neuroprotective actions of brain-derived neurotrophic factor (BDNF) are well known but under certain circumstances this growth factor can also exacerbate excitotoxic insults to neurons. Prior exploration of the receptor through which BDNF exerts this action on motor neurons deflects attention away from p75. Here we investigated the possibility that BDNF acts through the receptor tyrosine kinase, TrkB, to confer on motor neurons sensitivity to excitotoxic challenge. We blocked BDNF activation of TrkB using a dominant negative TrkB mutant or a TrkB function blocking antibody, and found that this protected motor neurons against excitotoxic insult in cultures of mixed spinal cord neurons. Addition of a function blocking antibody to BDNF to mixed spinal cord neuron cultures is also neuroprotective indicating that endogenously produced BDNF participates in vulnerability to excitotoxicity. We next examined the intracellular signaling cascades that are engaged upon TrkB activation. Previously we found that inhibition of the phosphatidylinositide-3'-kinase (PI3'K) pathway blocks BDNF-induced excitotoxic sensitivity. Here we show that expression of a constitutively active catalytic subunit of PI3'K, p110, confers excitotoxic sensitivity (ES) upon motor neurons not incubated with BDNF. Parallel studies with purified motor neurons confirm that these events are likely to be occuring specifically within motor neurons. The abrogation of BDNF's capacity to accentuate excitotoxic insults may make it a more attractive neuroprotective agent.

  16. Physiology of BDNF: focus on hypothalamic function.

    Science.gov (United States)

    Tapia-Arancibia, Lucia; Rage, Florence; Givalois, Laurent; Arancibia, Sandor

    2004-07-01

    Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family which interacts with high-affinity protein kinase receptors (Trk) and the unselective p75(NGFR) receptor. The BDNF gene has a complex structure with multiple regulatory elements and four promoters that are differentially expressed in central or peripheral tissue. BDNF expression is regulated by neuronal activity or peripheral hormones. Neurotrophins regulate the survival and differentiation of neurons during development but growing evidence indicates that they are also involved in several functions in adulthood, including plasticity processes. BDNF expression in the central nervous system (CNS) is modified by various kinds of brain insult (stress, ischemia, seizure activity, hypoglycemia, etc.) and alterations in its expression may contribute to some pathologies such as depression, epilepsy, Alzheimer's, and Parkinson's disease. Apart from very traumatic situations, the brain functioning is resilient to stress and capable of adaptive plasticity. Neurotrophins might act as plasticity mediators enhancing this trait which seems to be crucial in adaptive processes. In addition to documenting all of the topics mentioned above in the CNS, we review the state of the art concerning neurotrophins and their receptors, including our personal contribution which is essentially focused on the stress response.

  17. Peripherally-derived BDNF promotes regeneration of ascending sensory neurons after spinal cord injury.

    Directory of Open Access Journals (Sweden)

    Xing-Yun Song

    Full Text Available BACKGROUND: The blood brain barrier (BBB and truncated trkB receptor on astrocytes prevent the penetration of brain derived neurotrophic factor (BDNF applied into the peripheral (PNS and central nervous system (CNS thus restrict its application in the treatment of nervous diseases. As BDNF is anterogradely transported by axons, we propose that peripherally derived and/or applied BDNF may act on the regeneration of central axons of ascending sensory neurons. METHODOLOGY/PRINCIPAL FINDINGS: The present study aimed to test the hypothesis by using conditioning lesion of the sciatic nerve as a model to increase the expression of endogenous BDNF in sensory neurons and by injecting exogenous BDNF into the peripheral nerve or tissues. Here we showed that most of regenerating sensory neurons expressed BDNF and p-CREB but not p75NTR. Conditioning-lesion induced regeneration of ascending sensory neuron and the increase in the number of p-Erk positive and GAP-43 positive neurons was blocked by the injection of the BDNF antiserum in the periphery. Enhanced neurite outgrowth of dorsal root ganglia (DRG neurons in vitro by conditioning lesion was also inhibited by the neutralization with the BDNF antiserum. The delivery of exogenous BDNF into the sciatic nerve or the footpad significantly increased the number of regenerating DRG neurons and regenerating sensory axons in the injured spinal cord. In a contusion injury model, an injection of BDNF into the footpad promoted recovery of motor functions. CONCLUSIONS/SIGNIFICANCE: Our data suggest that endogenous BDNF in DRG and spinal cord is required for the enhanced regeneration of ascending sensory neurons after conditioning lesion of sciatic nerve and peripherally applied BDNF may have therapeutic effects on the spinal cord injury.

  18. hBDNF-GFP基因转染神经干细胞对视神经损伤大鼠视网膜BDNF表达的影响%Effects of hBDNF-GFP gene-transfected neural stem cell transplantation on BDNF expression in the retina of rats following optic nerve crush injury

    Institute of Scientific and Technical Information of China (English)

    刘勇; 陈二涛; 冯东福; 潘栋超; 汪洋

    2009-01-01

    目的 探讨移植hBDNF-GFP基因转染神经干细胞后对视神经损伤大鼠视网膜BDNF表达的影响.方法 ①78只SD大鼠随机分为正常对照组(n=6)、视神经夹伤组(n=72).视神经夹伤组动物行右侧视神经夹伤后随机平均分为三个亚组:分别于玻璃体腔内注射0.01 mol/L PBS(PBS组),GFP基因转染神经干细胞(GFP-NSCs组)和hBDNF-GFP基因转染神经干细胞(hBDNF-GFP-NSCs组).各组动物单纯暴露左侧视神经作为假损伤组.分别于移植后3 d,7 d,14 d和28 d处死动物取视网膜,ELISA法检测各组视网膜中BDNF含量.②另取6只视神经损伤大鼠移植hBDNF-GFP-NSCs,分别于2周、4周和8周各处死2只大鼠,取眼球做冰冻切片观察移植细胞存活、迁移情况.③35只sD大鼠随机分为4组:正常对照组(n=5)、右眼视神经损伤NSCs治疗组(n=10)、GFP-NSCs治疗组(n=10)及hBDNF-GFP-NSCs治疗组(n=10).④各组于术后4周和8周分别处死5只大鼠,West-era-blot法检测视网膜组织中BDNF表达.结果 ①ELISA结果显示,正常对照组BDNF含量与假损伤组间比较差异无统计学意义(P>0.05),移植手术后第3天时,三个损伤亚组视网膜匀浆上清中hBDNF含量明显增加(与假损伤组比较P0.05);7 d时,GFP-NSCs组与假损伤组比较差异具有统计学意义(P0.05),PBS组与GFP-NSCs组间及hBDNF-GFP-NSCs组与GFP-NSCs组间差异具有统计学意义(P0.05). Three days after NSC transplantation, BDNF expression increased significantly in the three injured sub-groups compared with the sham-injury group, (P 0.05). Seven days after transplantation, there was a significant difference in BDNF expression between the GFP-NSC group and the sham-injury groups (P 0.05). Fourteen and 28 days after transplantation, BDNF expressions decreased in the PBS group and the GFP-NSC groups, while BDNF expressions in the hBDNF-GFP-NSC group increased significant-ly compared with the other three groups (P < 0.05); ②Frozen section showed that

  19. Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity.

    Science.gov (United States)

    Pang, Petti T; Teng, Henry K; Zaitsev, Eugene; Woo, Newton T; Sakata, Kazuko; Zhen, Shushuang; Teng, Kenneth K; Yung, Wing-Ho; Hempstead, Barbara L; Lu, Bai

    2004-10-15

    Long-term memory is thought to be mediated by protein synthesis-dependent, late-phase long-term potentiation (L-LTP). Two secretory proteins, tissue plasminogen activator (tPA) and brain-derived neurotrophic factor (BDNF), have been implicated in this process, but their relationship is unclear. Here we report that tPA, by activating the extracellular protease plasmin, converts the precursor proBDNF to the mature BDNF (mBDNF), and that such conversion is critical for L-LTP expression in mouse hippocampus. Moreover, application of mBDNF is sufficient to rescue L-LTP when protein synthesis is inhibited, which suggests that mBDNF is a key protein synthesis product for L-LTP expression.

  20. Expression and clinical significance of TrkB and its ligand BDNF in epithelial ovarian cancer%TrkB及其配体BDNF在卵巢上皮癌中的表达及其临床意义

    Institute of Scientific and Technical Information of China (English)

    李明伟; 刘继红

    2012-01-01

    Objective The current study was to explore the expression profile of TrkB/BDNF in ovarian epithelial cancer and their correlation with clinical pathology variables respectively. Methods TrkB/BDNF were examined in 10 normal ovarian, 17 benign ovarian epithelial tumor, 21 borderline ovarian epithelial tumor and 60 ovarian epithelial cancer tissue samples by immunohistochemical Streptomycin avidin - peroxidase (SP) method. Results The expression of TrkB and BDNF were negative in normal ovarian tissue and benign epithelial tumors, and the expression rate of TrkB and BDNF in borderline ovarian tumors and ovarian epithelial cancers (EOC) was 19. 0%, 71. 7% and 14. 0%, 51. 7% (P<0. 05) . The degree of TrkB/BDNF express was more strong in G3, I+F stage EOC than that in G1+G2, I + H stage EOC (P<0. 05) . TrkB expression was positively correlated with BDNF level in epithelial ovarian cancer (r=0. 43, PBDNF in ovarian epithelial cancer. TrkB may synergy with BDNF to promote tumorigenesis and development of epithelial ovarian cancer, it may be a target for EOC gene therapy.%目的 检测酪氨酸激酶B (tyrosine kinase,TrkB)及其配体脑源性神经营养因子(brain -derived neurotrophic factor,BDNF)在卵巢上皮癌(EOC)中的表达,并探讨其临床意义.方法 选择中山大学附属肿瘤医院病理存档的石蜡标本108例,其中10例正常卵巢、17例良性卵巢肿瘤、21例卵巢交界性肿瘤和60例卵巢上皮癌,采用免疫组化链霉素抗生物素蛋白-过氧化物酶法(SP法)检测TrkB及其配体BDNF蛋白的表达水平,分析其与临床病理因素之间的关系.结果 TrkB和BDNF蛋白在正常卵巢组织和良性卵巢上皮性肿瘤中无表达;在交界性和卵巢上皮性癌中的阳性表达率分别为19.0%、71.7%和14.0%、51.7%(P<0.05).TrkB和BDNF蛋白在EOC组中的表达水平与其FIGO分期及病理分级有关,在Ⅲ期+Ⅳ期、低分化组(G3)比

  1. Reduced levels of brain derived neurotrophic factor (BDNF) in the serum of diabetic retinopathy patients and in the retina of diabetic rats.

    Science.gov (United States)

    Ola, M Shamsul; Nawaz, Mohd Imtiaz; El-Asrar, Ahmed Abu; Abouammoh, Marwan; Alhomida, Abdullah S

    2013-04-01

    Diabetic retinopathy (DR) is widely recognized as a neurovascular disease. Retina, being a neuronal tissue of the eye, produces neurotrophic factors for its maintenance. However, diabetes dysregulates their levels and thereby may damage the retina. Among neurotrophins, brain derived neurotrophic factor (BDNF) is the most abundant in the retina. In this study, we investigated the level of BDNF in the serum of patients with DR and also in the serum and retina of streptozotocin-induced diabetic rats. The level of BDNF was significantly decreased in the serum of proliferative diabetic retinopathy patients as compared to that of non-diabetic healthy controls (25.5 ± 8.5-10.0 ± 8.1 ng/ml, p BDNF in the serum and retina of diabetic rats were also significantly reduced compared to that of non-diabetic controls (p TrkB) was significantly decreased in diabetic rat retina compared to that of non-diabetic controls as determined by Western blotting technique. Caspase-3 activity was increased in diabetic rat retina after 3 weeks of diabetes and remained elevated until 10 weeks, which negatively correlated with the level of BDNF (r = -0.544, p = 0.013). Our results indicate that reduced levels of BDNF in diabetes may cause apoptosis and neurodegeneration early in diabetic retina, which may lead to neuro-vascular damage later in DR.

  2. Intranasal insulin improves cerebral blood flow, Nrf-2 expression and BDNF in STZ (ICV)-induced memory impaired rats.

    Science.gov (United States)

    Rajasekar, N; Nath, Chandishwar; Hanif, Kashif; Shukla, Rakesh

    2017-03-15

    Insulin/insulin receptor signaling is involved in cognitive functions. Clinical studies have shown that intranasal insulin administration improves memory functions. However, the molecular mechanisms associated with improvement in memory functions are largely unexplored. Therefore, we investigated the protective effect of intranasal insulin in intracerebroventricular (ICV) streptozotocin (STZ) induced memory impairment in rats. Rats were injected with STZ (3mg/kg, ICV) bilaterally twice, on days 1 and 3 and intranasal insulin (2IU/rat/day) was given for 14days. Memory was assessed by Morris water maze test. Cerebral blood flow (CBF) was measured by laser-Doppler flowmetry. The biochemical and molecular studies were done in cortex and hippocampus of rat brain. STZ (ICV) administration caused memory impairment along with the reduction of CBF, ATP level, and Nrf-2 expression. Treatment with intranasal insulin significantly improved memory functions as well as restored CBF, ATP content and Nrf-2 expression in STZ injected rats. STZ administration stimulated oxidative-nitrosative stress as evidenced by a significant increase in ROS, malondialdehyde, NO level and inducible nitric oxide synthase expression and the decrease in glutathione level; which was normalized by intranasal insulin delivery. STZ-induced cholinergic dysfunction (AChE activity and α7-nAChR expression), and mitochondrial hypofunction was largely prevented by treatment with intranasal insulin. Intranasal insulin delivery successfully restored BDNF level and pCREB expression in STZ injected rats. The study shows the beneficial effects of intranasal insulin against STZ-induced memory impairment, which attributed to improved CBF, cholinergic function, brain energy metabolism, BDNF, Nrf-2 expression and antioxidative action. Copyright © 2016. Published by Elsevier Inc.

  3. Expression and cell localization of brain-derived neurotrophic factor and TrkB during zebrafish retinal development.

    Science.gov (United States)

    Germanà, A; Sánchez-Ramos, C; Guerrera, M C; Calavia, M G; Navarro, M; Zichichi, R; García-Suárez, O; Pérez-Piñera, P; Vega, Jose A

    2010-09-01

    Brain-derived neurotrophic factor (BDNF) signaling through TrkB regulates different aspects of neuronal development, including survival, axonal and dendritic growth, and synapse formation. Despite recent advances in our understanding of the functional significance of BDNF and TrkB in the retina, the cell types in the retina that express BDNF and TrkB, and the variations in their levels of expression during development, remain poorly defined. The goal of the present study is to determine the age-dependent changes in the levels of expression and localization of BDNF and TrkB in the zebrafish retina. Zebrafish retinas from 10 days post-fertilization (dpf) to 180 dpf were used to perform PCR, Western blot and immunohistochemistry. Both BDNF and TrkB mRNAs, and BDNF and full-length TrkB proteins were detected at all ages sampled. The localization of these proteins in the retina was very similar at all time points studied. BDNF immunoreactivity was found in the outer nuclear layer, the outer plexiform layer and the inner plexiform layer, whereas TrkB immunoreactivity was observed in the inner plexiform layer and, to a lesser extent, in the ganglion cell layer. These results demonstrate that the pattern of expression of BDNF and TrkB in the retina of zebrafish remains unchanged during postembryonic development and adult life. Because TrkB expression in retina did not change with age, cells expressing TrkB may potentially be able to respond during the entire lifespan of zebrafish to BDNF either exogenously administered or endogenously produced, acting through paracrine mechanisms.

  4. TrkB/BDNF Signaling Regulates Photoreceptor Progenitor Cell Fate Decisions

    OpenAIRE

    Turner, Brian A.; Sparrow, Janet; Cai, Bolin; Monroe, Julie; Mikawa, Takashi; Hempstead, Barbara L.

    2006-01-01

    Neurotrophins, via activation of Trk receptor tyrosine kinases, serve as mitogens, survival factors and regulators of arborization during retinal development. Brain-derived neurotrophic factor (BDNF) and TrkB regulate neuronal arborization and survival in late retinal development. However, TrkB is expressed during early retinal developmet where its functions are unclear. To assess TrkB/BDNF actions in the early chick retina, replication-incompetent retroviruses were utilized to over-express a...

  5. Phosphorylation of the growth factors bFGF, NGF and BDNF: a prerequisite for their biological activity.

    Science.gov (United States)

    Klumpp, Susanne; Kriha, Dorothee; Bechmann, Gunther; Maassen, Alexander; Maier, Sandra; Pallast, Stefanie; Hoell, Patrick; Krieglstein, Josef

    2006-01-01

    The aim of this work was to test whether growth factors such as basic fibroblast growth factor (bFGF), nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) undergo autophosphorylation and whether this affects their biological activity. Incubation of those growth factors with [gamma-(32)P]ATP resulted in phosphorylation in vitro. The phosphate bond was resistant to alkaline pH, yet acid-labile. Addition of alkaline phosphatase resulted in time and protein dependent dephosphorylation. Concomitantly, alkaline phosphatase abolished the neuroprotective effect of those growth factors upon oxygen and glucose deprivation and upon staurosporine-induced cell death. For those studies, we were using primary cultures of cortical and hippocampal neurons from embryonic and neonatal rats. Incubation of bFGF with non-hydrolyzable ATP-gammaS resulted in phosphorylation and in neuroprotection resistant to alkaline phosphatase. We conclude that bFGF, NGF and BDNF undergo autophosphorylation on site(s) other than serine, threonine, tyrosine and/or ATP-binding, and that this binding of phosphate is essential for neuroprotection in vivo.

  6. BDNF and its receptors in human myasthenic thymus: implications for cell fate in thymic pathology.

    Science.gov (United States)

    Berzi, Angela; Ayata, C Korcan; Cavalcante, Paola; Falcone, Chiara; Candiago, Elisabetta; Motta, Teresio; Bernasconi, Pia; Hohlfeld, Reinhard; Mantegazza, Renato; Meinl, Edgar; Farina, Cinthia

    2008-07-15

    Here we show that in myasthenic thymus several cell types, including thymic epithelial cells (TEC) and immune cells, were the source and the target of the neurotrophic factor brain-derived growth factor (BDNF). Interestingly, many actively proliferating medullary thymocytes expressed the receptor TrkB in vivo in involuted thymus, while this population was lost in hyperplastic or neoplastic thymuses. Furthermore, in hyperplastic thymuses the robust coordinated expression of BDNF in the germinal centers together with the receptor p75NTR on all proliferating B cells strongly suggests that this factor regulates germinal center reaction. Finally, all TEC dying of apoptosis expressed BDNF receptors, indicating that this neurotrophin is involved in TEC turnover. In thymomas both BDNF production and receptor expression in TEC were strongly hindered. This may represent an attempt of tumour escape from cell death.

  7. Both 5' and 3' flanks regulate Zebrafish brain-derived neurotrophic factor gene expression

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    Heinrich Gerhard

    2004-05-01

    Full Text Available Abstract Background Precise control of developmental and cell-specific expression of the brain-derived neurotrophic factor (BDNF gene is essential for normal neuronal development and the diverse functions of BDNF in the adult organism. We previously showed that the zebrafish BDNF gene has multiple promoters. The complexity of the promoter structure and the mechanisms that mediate developmental and cell-specific expression are still incompletely understood. Results Comparison of pufferfish and zebrafish BDNF gene sequences as well as 5' RACE revealed three additional 5' exons and associated promoters. RT-PCR with exon-specific primers showed differential developmental and organ-specific expression. Two exons were detected in the embryo before transcription starts. Of the adult organs examined, the heart expressed a single 5' exon whereas the brain, liver and eyes expressed four of the seven 5' exons. Three of the seven 5' exons were not detectable by RT-PCR. Injection of promoter/GFP constructs into embryos revealed distinct expression patterns. The 3' flank profoundly affected expression in a position-dependent manner and a highly conserved sequence (HCS1 present in 5' exon 1c in a dehancer-like manner. Conclusions The zebrafish BDNF gene is as complex in its promoter structure and patterns of differential promoter expression as is its murine counterpart. The expression of two of the promoters appears to be regulated in a temporally and/or spatially highly circumscribed fashion. The 3' flank has a position-dependent effect on expression, either by affecting transcription termination or post-transcriptional steps. HCS1, a highly conserved sequence in 5' exon 1c, restricts expression to primary sensory neurons. The tools are now available for detailed genetic and molecular analyses of zebrafish BDNF gene expression.

  8. Brain-derived neurotrophic factor (BDNF) enhances GABA transport by modulating the trafficking of GABA transporter-1 (GAT-1) from the plasma membrane of rat cortical astrocytes.

    Science.gov (United States)

    Vaz, Sandra H; Jørgensen, Trine N; Cristóvão-Ferreira, Sofia; Duflot, Sylvie; Ribeiro, Joaquim A; Gether, Ulrik; Sebastião, Ana M

    2011-11-25

    The γ-aminobutyric acid (GABA) transporters (GATs) are located in the plasma membrane of neurons and astrocytes and are responsible for termination of GABAergic transmission. It has previously been shown that brain derived neurotrophic factor (BDNF) modulates GAT-1-mediated GABA transport in nerve terminals and neuronal cultures. We now report that BDNF enhances GAT-1-mediated GABA transport in cultured astrocytes, an effect mostly due to an increase in the V(max) kinetic constant. This action involves the truncated form of the TrkB receptor (TrkB-t) coupled to a non-classic PLC-γ/PKC-δ and ERK/MAPK pathway and requires active adenosine A(2A) receptors. Transport through GAT-3 is not affected by BDNF. To elucidate if BDNF affects trafficking of GAT-1 in astrocytes, we generated and infected astrocytes with a functional mutant of the rat GAT-1 (rGAT-1) in which the hemagglutinin (HA) epitope was incorporated into the second extracellular loop. An increase in plasma membrane of HA-rGAT-1 as well as of rGAT-1 was observed when both HA-GAT-1-transduced astrocytes and rGAT-1-overexpressing astrocytes were treated with BDNF. The effect of BDNF results from inhibition of dynamin/clathrin-dependent constitutive internalization of GAT-1 rather than from facilitation of the monensin-sensitive recycling of GAT-1 molecules back to the plasma membrane. We therefore conclude that BDNF enhances the time span of GAT-1 molecules at the plasma membrane of astrocytes. BDNF may thus play an active role in the clearance of GABA from synaptic and extrasynaptic sites and in this way influence neuronal excitability.

  9. Functional interactions between steroid hormones and neurotrophin BDNF

    Institute of Scientific and Technical Information of China (English)

    Tadahiro; Numakawa; Daisaku; Yokomaku; Misty; Richards; Hiroaki; Hori; Naoki; Adachi; Hiroshi; Kunugi

    2010-01-01

    Brain-derived neurotrophic factor(BDNF),a critical neurotrophin,regulates many neuronal aspects including cell differentiation,cell survival,neurotransmission,and synaptic plasticity in the central nervous system(CNS) .Though BDNF has two types of receptors,high affinity tropomyosin-related kinase(Trk) B and low affinity p75 receptors,BDNF positively exerts its biological effects on neurons via activation of TrkB and of resultant intracellular signaling cascades including mitogenactivated protein kinase/extracellular signal-regulated protein kinase,phospholipase Cγ,and phosphoinositide 3-kinase pathways.Notably,it is possible that alteration in the expression and/or function of BDNF in the CNS is involved in the pathophysiology of various brain diseases such as stroke,Parkinson’s disease,Alzheimer’s disease,and mental disorders.On the other hand,glucocorticoids,stress-induced steroid hormones,also putatively contribute to the pathophysiology of depression.Interestingly,in addition to the reduction in BDNF levels due to increased glucocorticoid exposure,current reports demonstrate possible interactions between glucocorticoids and BDNF-mediated neuronal functions. Other steroid hormones,such as estrogen,are involved in not only sexual differentiation in the brain,but also numerous neuronal events including cell survival and synaptic plasticity.Furthermore,it is well known that estrogen plays a role in the pathophysiology of Parkinson’s disease,Alzheimer’s disease,and mental illness,while serving to regulate BDNF expression and/or function.Here,we present a broad overview of the current knowledge concerning the association between BDNF expression/function and steroid hormones(glucocorticoids and estrogen).

  10. BDNF Variants May Modulate Long-Term Visual Memory Performance in a Healthy Cohort

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    Nesli Avgan

    2017-03-01

    Full Text Available Brain-derived neurotrophic factor (BDNF is involved in numerous cognitive functions including learning and memory. BDNF plays an important role in synaptic plasticity in humans and rats with BDNF shown to be essential for the formation of long-term memories. We previously identified a significant association between the BDNF Val66Met polymorphism (rs6265 and long-term visual memory (p-value = 0.003 in a small cohort (n = 181 comprised of healthy individuals who had been phenotyped for various aspects of memory function. In this study, we have extended the cohort to 597 individuals and examined multiple genetic variants across both the BDNF and BDNF-AS genes for association with visual memory performance as assessed by the Wechsler Memory Scale—Fourth Edition subtests Visual Reproduction I and II (VR I and II. VR I assesses immediate visual memory, whereas VR II assesses long-term visual memory. Genetic association analyses were performed for 34 single nucleotide polymorphisms genotyped on Illumina OmniExpress BeadChip arrays with the immediate and long-term visual memory phenotypes. While none of the BDNF and BDNF-AS variants were shown to be significant for immediate visual memory, we found 10 variants (including the Val66Met polymorphism (p-value = 0.006 that were nominally associated, and three variants (two variants in BDNF and one variant in the BDNF-AS locus that were significantly associated with long-term visual memory. Our data therefore suggests a potential role for BDNF, and its anti-sense transcript BDNF-AS, in long-term visual memory performance.

  11. BDNF Variants May Modulate Long-Term Visual Memory Performance in a Healthy Cohort

    Science.gov (United States)

    Avgan, Nesli; Sutherland, Heidi G.; Spriggens, Lauren K.; Yu, Chieh; Ibrahim, Omar; Bellis, Claire; Haupt, Larisa M.; Shum, David H. K.; Griffiths, Lyn R.

    2017-01-01

    Brain-derived neurotrophic factor (BDNF) is involved in numerous cognitive functions including learning and memory. BDNF plays an important role in synaptic plasticity in humans and rats with BDNF shown to be essential for the formation of long-term memories. We previously identified a significant association between the BDNF Val66Met polymorphism (rs6265) and long-term visual memory (p-value = 0.003) in a small cohort (n = 181) comprised of healthy individuals who had been phenotyped for various aspects of memory function. In this study, we have extended the cohort to 597 individuals and examined multiple genetic variants across both the BDNF and BDNF-AS genes for association with visual memory performance as assessed by the Wechsler Memory Scale—Fourth Edition subtests Visual Reproduction I and II (VR I and II). VR I assesses immediate visual memory, whereas VR II assesses long-term visual memory. Genetic association analyses were performed for 34 single nucleotide polymorphisms genotyped on Illumina OmniExpress BeadChip arrays with the immediate and long-term visual memory phenotypes. While none of the BDNF and BDNF-AS variants were shown to be significant for immediate visual memory, we found 10 variants (including the Val66Met polymorphism (p-value = 0.006)) that were nominally associated, and three variants (two variants in BDNF and one variant in the BDNF-AS locus) that were significantly associated with long-term visual memory. Our data therefore suggests a potential role for BDNF, and its anti-sense transcript BDNF-AS, in long-term visual memory performance. PMID:28304362

  12. BDNF Variants May Modulate Long-Term Visual Memory Performance in a Healthy Cohort.

    Science.gov (United States)

    Avgan, Nesli; Sutherland, Heidi G; Spriggens, Lauren K; Yu, Chieh; Ibrahim, Omar; Bellis, Claire; Haupt, Larisa M; Shum, David H K; Griffiths, Lyn R

    2017-03-17

    Brain-derived neurotrophic factor (BDNF) is involved in numerous cognitive functions including learning and memory. BDNF plays an important role in synaptic plasticity in humans and rats with BDNF shown to be essential for the formation of long-term memories. We previously identified a significant association between the BDNF Val66Met polymorphism (rs6265) and long-term visual memory (p-value = 0.003) in a small cohort (n = 181) comprised of healthy individuals who had been phenotyped for various aspects of memory function. In this study, we have extended the cohort to 597 individuals and examined multiple genetic variants across both the BDNF and BDNF-AS genes for association with visual memory performance as assessed by the Wechsler Memory Scale-Fourth Edition subtests Visual Reproduction I and II (VR I and II). VR I assesses immediate visual memory, whereas VR II assesses long-term visual memory. Genetic association analyses were performed for 34 single nucleotide polymorphisms genotyped on Illumina OmniExpress BeadChip arrays with the immediate and long-term visual memory phenotypes. While none of the BDNF and BDNF-AS variants were shown to be significant for immediate visual memory, we found 10 variants (including the Val66Met polymorphism (p-value = 0.006)) that were nominally associated, and three variants (two variants in BDNF and one variant in the BDNF-AS locus) that were significantly associated with long-term visual memory. Our data therefore suggests a potential role for BDNF, and its anti-sense transcript BDNF-AS, in long-term visual memory performance.

  13. Lithium-Induced Neuroprotection is Associated with Epigenetic Modification of Specific BDNF Gene Promoter and Altered Expression of Apoptotic-Regulatory Proteins

    Directory of Open Access Journals (Sweden)

    Tushar eDwivedi

    2015-01-01

    Full Text Available Bipolar disorder (BD, one of the most debilitating mental disorders, is associated with increased morbidity and mortality. Lithium is the first line of treatment option for BD and is often used for maintenance therapy. Recently, the neuroprotective action of lithium has gained tremendous attention, given that BD is associated with structural and functional abnormalities of the brain. However, the precise molecular mechanism by which lithium exerts its neuroprotective action is not clearly understood. In hippocampal neurons, the effects of lithium on neuronal viability against glutamate-induced cytotoxicity, dendritic length and number, and expression and methylation of BDNF promoter exons and expression of apoptotic regulatory genes were studied. In rat hippocampal neurons, lithium not only increased dendritic length and number, but also neuronal viability against glutamate-induced cytotoxicity. While lithium increased the expression of BDNF as well as genes associated with neuroprotection such as Bcl2 and Bcl-XL, it decreased the expression of pro-apoptotic genes Bax, Bad, and caspases 3. Interestingly, lithium activated transcription of specific exon IV to induce BDNF gene expression. This was accompanied by hypomethylation of BDNF exon IV promoter. This study delineates mechanisms by which lithium mediates its effects in protecting neurons.

  14. Brain-derived neurotrophic factor (BDNF) serum basal levels is not affected by power training in mobility-limited older adults - A randomized controlled trial

    DEFF Research Database (Denmark)

    Hvid, Lars G; Nielsen, Martin KF; Simonsen, Casper

    2017-01-01

    Brain-derived neurotrophic factor (BDNF) is a potential important factor involved in neuroplasticity, and may be a mediator for eliciting adaptations in neuromuscular function and physical function in older individuals following physical training. As power training taxes the neural system to a very...... not appear to be a major mechanistic factor mediating neuroplasticity in mobility-limited older adults....

  15. Analysis of the Expression and Polymorphism of APOE, HSP, BDNF, and GRIN2B Genes Associated with the Neurodegeneration Process in the Pathogenesis of Primary Open Angle Glaucoma

    Directory of Open Access Journals (Sweden)

    Alicja Nowak

    2015-01-01

    Full Text Available Glaucoma is characterized by optic neuropathy of the RGC or retinal nerve fiber. The aim of this study was to evaluate a relationship between the neurodegenerative genes’ polymorphisms of the APOE (rs449647, BDNF (rs2030324, GRIN2B (rs3764028, and HSP70-1 (rs1043618 and the occurrence risk of POAG and to investigate its effect on allele-specific gene expression. Genomic DNA was extracted from peripheral blood. Analysis of the genes’ polymorphisms was performed using PCR-RFLP. The level of mRNA expression was determined by QRT-PCR. We showed a statistically significant association of BDNF and APOE genes’ polymorphisms with a risk of POAG occurrence. There was a statistically significant association of the rs2030324 polymorphism with progression of POAG based on cup disc ratio value and rs1043618 polymorphism based on nerve fiber index and rim area. Furthermore, we found that mean HSP70-1 mRNA expression was significantly lower in the case of individuals with the G/G genotype than in the case of minor allele carriers, that is, G/C and C/C. We also found that BDNF and HSP70-1 expression level are associated with the progression of POAG based on rim area value. In conclusion, our results suggest that BDNF, APOE, and HSP70-1 genes might be associated with a risk of POAG occurrence in the Polish population.

  16. Analysis of the expression and polymorphism of APOE, HSP, BDNF, and GRIN2B genes associated with the neurodegeneration process in the pathogenesis of primary open angle glaucoma.

    Science.gov (United States)

    Nowak, Alicja; Majsterek, Ireneusz; Przybyłowska-Sygut, Karolina; Pytel, Dariusz; Szymanek, Katarzyna; Szaflik, Jerzy; Szaflik, Jacek P

    2015-01-01

    Glaucoma is characterized by optic neuropathy of the RGC or retinal nerve fiber. The aim of this study was to evaluate a relationship between the neurodegenerative genes' polymorphisms of the APOE (rs449647), BDNF (rs2030324), GRIN2B (rs3764028), and HSP70-1 (rs1043618) and the occurrence risk of POAG and to investigate its effect on allele-specific gene expression. Genomic DNA was extracted from peripheral blood. Analysis of the genes' polymorphisms was performed using PCR-RFLP. The level of mRNA expression was determined by QRT-PCR. We showed a statistically significant association of BDNF and APOE genes' polymorphisms with a risk of POAG occurrence. There was a statistically significant association of the rs2030324 polymorphism with progression of POAG based on cup disc ratio value and rs1043618 polymorphism based on nerve fiber index and rim area. Furthermore, we found that mean HSP70-1 mRNA expression was significantly lower in the case of individuals with the G/G genotype than in the case of minor allele carriers, that is, G/C and C/C. We also found that BDNF and HSP70-1 expression level are associated with the progression of POAG based on rim area value. In conclusion, our results suggest that BDNF, APOE, and HSP70-1 genes might be associated with a risk of POAG occurrence in the Polish population.

  17. Regulation of brain-derived neurotrophic factor gene expression after transient middle cerebral artery occlusion with and without brain damage.

    Science.gov (United States)

    Kokaia, Z; Zhao, Q; Kokaia, M; Elmér, E; Metsis, M; Smith, M L; Siesjö, B K; Lindvall, O

    1995-11-01

    Levels of mRNA for c-fos, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), TrkB, and TrkC were studied using in situ hybridization in the rat brain at different reperfusion times after unilateral middle cerebral artery occlusion (MCAO). Short-term (15 min) MCAO, which does not cause neuronal death, induced elevated BDNF mRNA expression confined to ipsilateral frontal and cingulate cortices outside the ischemic area. With a longer duration of MCAO (2 h), which leads to cortical infarction, the increase was more marked and elevated BDNF mRNA levels were also detected bilaterally in dentate granule cells and CA1 and CA3 pyramidal neurons. Maximum expression was found after 2 h of reperfusion. At 24 h BDNF mRNA expression had returned to control values. In the ischemic core of the parietal cortex only scattered neurons were expressing high levels of BDNF mRNA after 15 min and 2 h of MCAO. Analysis of different BDNF transcripts showed that MCAO induced a marked increase of exon III mRNA but only small increases of exon I and II mRNAs in cortex and hippocampus. In contrast to BDNF mRNA, elevated expression of c-fos mRNA was observed in the entire ipsilateral cerebral cortex, including the ischemic core, after both 15 min and 2 h of MCAO. Two hours of MCAO also induced transient, bilateral increases of NGF and TrkB mRNA levels and a decrease of NT-3 mRNA expression, confined to dentate granule cells. The upregulation of BDNF mRNA expression in cortical neurons after MCAO is probably triggered by glutamate through a spreading depression-like mechanism. The lack of response of the BDNF gene in the ischemic core may be due to suppression of signal transduction or transcription factor synthesis caused by the ischemia. The observed pattern of gene expression after MCAO agrees well with a neuroprotective role of BDNF in cortical neurons. However, elevated levels of NGF and BDNF protein could also increase synaptic efficacy in the

  18. Genipin is active via modulating monoaminergic transmission and levels of brain-derived neurotrophic factor (BDNF) in rat model of depression.

    Science.gov (United States)

    Wang, Q-S; Tian, J-S; Cui, Y-L; Gao, S

    2014-09-05

    Genipin, an important bioactive component from Gardenia jasminoides Eills, was demonstrated to possess antidepressant-like effects in a previous study. However, the molecular mechanism of antidepressant-like effects on genipin was not clear. The present study aimed to investigate the possible mechanism of antidepressant-like effects on genipin with a chronic unpredictable mild stress (CUMS)-induced depression model in rats. In CUMS-induced depressive rats, bodyweight and 1% sucrose consumption decreased significantly compared with the normal control group. Furthermore, these changes could be significantly reversed by genipin application. The levels of 5-hydroxytryptamine (5-HT), norepinephrine (NE) in the hippocampus decreased and the level of 5-hydroxyindole acetic acid (5-HIAA) increased in the CUMS-induced depressive rats. However, pre-treatments with genipin significantly increased the levels of 5-HT, NE and decreased the level of 5-HIAA in the hippocampus. The concentration of cAMP in the hippocampus was increased by genipin compared to the CUMS-exposed model group. The mRNA expressions of 5-hydroxytryptamine 1A receptor (5-HT1AR), cAMP response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in rats were decreased exposed to CUMS, which were reversed by genipin-treated rats exposed to CUMS. Compared to the CUMS-exposed model group, the mRNA expression of 5-hydroxytryptamine 2A receptor (5-HT(2A)R) was decreased significantly by genipin-treated rats. The mRNA and protein expression of CREB, BDNF were increased in genipin-treated rats compared to the CUMS-exposed model group. Moreover, the levels of corticosterone in serum were decreased by genipin-treated compared to the CUMS-exposed model group. These results suggest that the possible mechanism of antidepressant-like effects on genipin, at least in one part, resulted from monoaminergic neurotransmitter system and the potential dysfunctional regulation of the post-receptor signaling

  19. Early-life infection leads to altered BDNF and IL-1beta mRNA expression in rat hippocampus following learning in adulthood.

    Science.gov (United States)

    Bilbo, Staci D; Barrientos, Ruth M; Eads, Andrea S; Northcutt, Alexis; Watkins, Linda R; Rudy, Jerry W; Maier, Steven F

    2008-05-01

    Neonatal bacterial infection in rats leads to profound hippocampal-dependent memory impairments following a peripheral immune challenge in adulthood. Here, we determined whether neonatal infection plus an immune challenge in adult rats is associated with impaired induction of brain-derived neurotrophic factor (BDNF) within the hippocampus (CA1, CA3, and dentate gyrus) following fear conditioning. BDNF is well characterized for its critical role in learning and memory. Rats injected on postnatal day 4 with PBS (vehicle) or Escherichia coli received as adults either no conditioning or a single 2min trial of fear conditioning. Half of the rats in the conditioned group then received a peripheral injection of 25mug/kg lipopolysaccharide (LPS) and all were sacrificed 1 or 4h later. Basal (unconditioned) BDNF mRNA did not differ between groups. However, following conditioning, neonatal infection with E. coli led to decreased BDNF mRNA induction in all regions compared to PBS-treated rats. This decrease in E. coli-treated rats was accompanied by a large increase in IL-1beta mRNA in CA1. Taken together, these data indicate that early infection strongly influences the induction of IL-1beta and BDNF within distinct regions of the hippocampus, which likely contribute to observed memory impairments in adulthood.

  20. Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and its implication in executive functions in adult offspring of alcohol-dependent probands.

    Science.gov (United States)

    Benzerouk, Farid; Gierski, Fabien; Gorwood, Philip; Ramoz, Nicolas; Stefaniak, Nicolas; Hübsch, Bérengère; Kaladjian, Arthur; Limosin, Frédéric

    2013-06-01

    Impairment of executive functions (EFs) mediated by the prefrontal lobe is regarded as a cognitive endophenotype of alcohol dependence, being observed both in probands and in healthy offspring. Given its impact on the anatomy of the prefrontal cortex, the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism may well be involved in this specific endophenotype. Forty-six healthy adult children of alcoholics (HACA) and 82 healthy controls (HC) took part in the study. All the participants were assessed with the Diagnostic Interview for Genetic Studies, and their family histories of alcohol and substance use were assessed with the Family Informant Schedule and Criteria. The Trail Making Test, Arithmetic Switching Task, Stroop Color-Word Test and Wisconsin Card Sorting Test were administered to assess EFs. An overall executive factor score was calculated using factorial analyses. Genotyping of the BDNF Val66Met polymorphism was performed using the TaqMan® allelic discrimination assay. HACA had significantly lower EFs performance than HC. Genetic analysis showed that BDNF genotype distributions were in Hardy-Weinberg equilibrium in the HACA and HC. Genotype and allele distributions did not differ significantly between the two groups. Participants with the Met allele performed significantly more poorly than participants with the Val allele, and a group by allele interaction was observed, the BDNF Met allele being associated with a poorer executive factor score in the HACA group. These results suggest that the BDNF Val66Met polymorphism may contribute to alcohol dependence vulnerability via lower EFs performance.

  1. Acute and chronic interference with BDNF/TrkB-signaling impair LTP selectively at mossy fiber synapses in the CA3 region of mouse hippocampus.

    Science.gov (United States)

    Schildt, Sandra; Endres, Thomas; Lessmann, Volkmar; Edelmann, Elke

    2013-08-01

    Brain-derived neurotrophic factor (BDNF) signaling via TrkB crucially regulates synaptic plasticity in the brain. Although BDNF is abundant at hippocampal mossy fiber (MF) synapses, which critically contribute to hippocampus dependent memory, its role in MF synaptic plasticity (long-term potentiation, LTP) remained largely unclear. Using field potential recordings in CA3 of adult heterozygous BDNF knockout (ko, BDNF+/-) mice we observed impaired (∼50%) NMDAR-independent MF-LTP. In contrast to MF synapses, LTP at neighboring associative/commissural (A/C) fiber synapses remained unaffected. To exclude that impaired MF-LTP in BDNF+/- mice was due to developmental changes in response to chronically reduced BDNF levels, and to prove the importance of acute availability of BDNF in MF-LTP, we also tested effects of acute interference with BDNF/TrkB signaling. Inhibition of TrkB tyrosine kinase signaling with k252a, or with the selective BDNF scavenger TrkB-Fc, both inhibited MF-LTP to the same extent as observed in BDNF+/- mice. Basal synaptic transmission, short-term plasticity, and synaptic fatigue during LTP induction were not significantly altered by treatment with k252a or TrkB-Fc, or by chronic BDNF reduction in BDNF+/- mice. Since the acute interference with BDNF-signaling did not completely block MF-LTP, our results provide evidence that an additional mechanism besides BDNF induced TrkB signaling contributes to this type of LTP. Our results prove for the first time a mechanistic action of acute BDNF/TrkB signaling in presynaptic expression of MF-LTP in adult hippocampus.

  2. Harpagoside ameliorates the amyloid-β-induced cognitive impairment in rats via up-regulating BDNF expression and MAPK/PI3K pathways.

    Science.gov (United States)

    Li, J; Ding, X; Zhang, R; Jiang, W; Sun, X; Xia, Z; Wang, X; Wu, E; Zhang, Y; Hu, Y

    2015-09-10

    So far, no effective disease-modifying therapies for Alzheimer's disease (AD) aiming at protecting or reversing neurodegeneration of the disease have been established yet. The present work aims to elucidate the effect of Harpagoside (abbreviated HAR), an iridoid glycosides purified from the Chinese medicinal herb Scrophularia ningpoensis, on neurodegeneration induced by β-amyloid peptide (Aβ) and the underlying molecular mechanism. Here we show that HAR exerts neuroprotective effects against Aβ neurotoxicity. Rats injected aggregated Aβ₁₋₄₀ into the bilateral hippocampus displayed impaired spatial learning and memory ability in a Y-maze test and novel object recognition test, while HAR treatment ameliorated Aβ₁₋₄₀-induced behavioral deficits. Moreover, administration of HAR increased the expression levels of brain-derived neurotrophic factor (BDNF) and activated the extracellular-regulated protein kinase (ERK) and the phosphatidylinositol 3-kinase (PI3-kinase) pathways both in the cerebral cortex and hippocampus of the Aβ₁₋₄₀-insulted rat model. Furthermore, in cultured primary cortical neurons, Aβ₁₋₄₂ induced significant decrease of choline acetyltransferase (ChAT)-positive neuron number and neurite outgrowth length, both of which were dose dependently increased by HAR. In addition, HAR pretreatment also significantly attenuated the decrease of cell viability in Aβ₁₋₄₂-injured primary cortical neurons. Finally, when K252a, an inhibitor of Trk tyrosine kinases, and a BDNF neutralizing antibody were added to the culture medium 2 h prior to HAR addition, the protective effect of HAR on Aβ₁₋₄₂-induced neurodegeneration in the primary cortical neuron was almost inhibited. Taken together, HAR exerting neuroprotection effect and ameliorating learning and memory deficit appears to be associated, at least in part, with up-regulation of BDNF content as well as activating its downstream signaling pathways, e.g., MAPK

  3. Dendritically targeted Bdnf mRNA is essential for energy balance and response to leptin.

    Science.gov (United States)

    Liao, Guey-Ying; An, Juan Ji; Gharami, Kusumika; Waterhouse, Emily G; Vanevski, Filip; Jones, Kevin R; Xu, Baoji

    2012-03-18

    Mutations in the Bdnf gene, which produces transcripts with either short or long 3' untranslated regions (3' UTRs), cause human obesity; however, the precise role of brain-derived neurotrophic factor (BDNF) in the regulation of energy balance is unknown. Here we show the relationship between Bdnf mRNA with a long 3' UTR (long 3' UTR Bdnf mRNA), leptin, neuronal activation and body weight. We found that long 3' UTR Bdnf mRNA was enriched in the dendrites of hypothalamic neurons and that insulin and leptin could stimulate its translation in dendrites. Furthermore, mice harboring a truncated long Bdnf 3' UTR developed severe hyperphagic obesity, which was completely reversed by viral expression of long 3' UTR Bdnf mRNA in the hypothalamus. In these mice, the ability of leptin to activate hypothalamic neurons and inhibit food intake was compromised despite normal activation of leptin receptors. These results reveal a novel mechanism linking leptin action to BDNF expression during hypothalamic-mediated regulation of body weight, while also implicating dendritic protein synthesis in this process.

  4. Aging and infection reduce expression of specific brain-derived neurotrophic factor mRNAs in hippocampus.

    Science.gov (United States)

    Chapman, Timothy R; Barrientos, Ruth M; Ahrendsen, Jared T; Hoover, Jennifer M; Maier, Steven F; Patterson, Susan L

    2012-04-01

    Aging increases the likelihood of cognitive decline after negative life events such as infection or injury. We have modeled this increased vulnerability in aged (24-month-old), but otherwise unimpaired F344xBN rats. In these animals, but not in younger (3-month-old) counterparts, a single intraperitoneal injection of E. coli leads to specific deficits in long-term memory and long-lasting synaptic plasticity in hippocampal area CA1-processes strongly dependent on brain-derived neurotrophic factor (BDNF). Here we have investigated the effects of age and infection on basal and fear-conditioning-stimulated expression of Bdnf in hippocampus. We performed in situ hybridization with 6 probes recognizing: total (pan-)BDNF mRNA, the 4 predominant 5' exon-specific transcripts (I, II, IV, and VI), and BDNF mRNAs with a long 3' untranslated region (3' UTR). In CA1, aging reduced basal levels and fear-conditioning-induced expression of total BDNF mRNA, exon IV-specific transcripts, and transcripts with long 3' UTRs; effects of infection were similar and sometimes compounded the effects of aging. In CA3, aging reduced all of the transcripts to some degree; infection had no effect. Effects in dentate were minimal. Northern blot analysis confirmed an aging-associated loss of total BDNF mRNA in areas CA1 and CA3, and revealed a parallel, preferential loss of BDNF mRNA transcripts with long 3' UTRs.

  5. Low-level laser therapy for traumatic brain injury in mice increases brain derived neurotrophic factor (BDNF) and synaptogenesis.

    Science.gov (United States)

    Xuan, Weijun; Agrawal, Tanupriya; Huang, Liyi; Gupta, Gaurav K; Hamblin, Michael R

    2015-06-01

    Transcranial low-level laser (light) therapy (LLLT) is a new non-invasive approach to treating a range of brain disorders including traumatic brain injury (TBI). We (and others) have shown that applying near-infrared light to the head of animals that have suffered TBI produces improvement in neurological functioning, lessens the size of the brain lesion, reduces neuroinflammation, and stimulates the formation of new neurons. In the present study we used a controlled cortical impact TBI in mice and treated the mice either once (4 h post-TBI, 1-laser), or three daily applications (3-laser) with 810 nm CW laser 36 J/cm(2) at 50 mW/cm(2). Similar to previous studies, the neurological severity score improved in laser-treated mice compared to untreated TBI mice at day 14 and continued to further improve at days 21 and 28 with 3-laser being better than 1-laser. Mice were sacrificed at days 7 and 28 and brains removed for immunofluorescence analysis. Brain-derived neurotrophic factor (BDNF) was significantly upregulated by laser treatment in the dentate gyrus of the hippocampus (DG) and the subventricular zone (SVZ) but not in the perilesional cortex (lesion) at day 7 but not at day 28. Synapsin-1 (a marker for synaptogenesis, the formation of new connections between existing neurons) was significantly upregulated in lesion and SVZ but not DG, at 28 days but not 7 days. The data suggest that the benefit of LLLT to the brain is partly mediated by stimulation of BDNF production, which may in turn encourage synaptogenesis. Moreover the pleiotropic benefits of BDNF in the brain suggest LLLT may have wider applications to neurodegenerative and psychiatric disorders. Neurological Severity Score (NSS) for TBI mice.

  6. Early raise of BDNF in hippocampus suggests induction of posttranscriptional mechanisms by antidepressants

    Directory of Open Access Journals (Sweden)

    Barlati Sergio

    2009-05-01

    Full Text Available Abstract Background The neurotrophin BDNF has been implicated in the regulation of neuroplasticity, gene expression, and synaptic function in the adult brain, as well as in the pathophysiology of neuropsychiatric disorders and the mechanism of action of antidepressants. Antidepressant treatments have been shown to increase the expression of BDNF mRNA, although the changes measured were found to be different depending on various factors. A few studies only have measured levels of BDNF protein after antidepressant treatments, and poor correlation was found between mRNA and protein changes. We studied the time course of expression of BDNF mRNA and protein during drug treatments, in order to elucidate the temporal profile of regulation of this effector and whether mRNA and protein levels correlate. Rat groups were treated for 1, 2 or 3 weeks with fluoxetine or reboxetine; in additional groups drug treatment was followed by a washout week (3+1. Total BDNF mRNA was measured by Real Time PCR, pro- and mature BDNF proteins were measured by Western blot. Results We found that mature BDNF protein is induced more rapidly than mRNA, by both drugs in hippocampus (weeks 1–2 and by reboxetine in prefrontal/frontal cortex (week 1. The temporal profile of BDNF protein expression was largely inconsistent with that of mRNA, which followed the protein induction and reached a peak at week 3. Conclusion These results suggest that BDNF protein is rapidly elevated by antidepressant treatments by posttranscriptional mechanisms, and that induction of BDNF mRNA is a slower process.

  7. Expression of brain-derived neurotrophic factor in rat hippocampus following focal cerebral ischemic injury

    Institute of Scientific and Technical Information of China (English)

    Yingping Li; Ruifang Guo; Kaifeng Lu

    2008-01-01

    BACKGROUND: The functional role of brain-derived neurotrophic factor (BDNF) is enhanced following cerebral ischemic injury providing neurons with an important self-protection mechanism in early stage ischemia/hypoxia.OBJECTIVE: To investigate the expression pattern of BDNF in different rat hippocampal regions following focal cerebral ischemic injury.DESIGN, TIME AND SETTING: We performed a comparative and neurobiological study of animals in the Department of Histology and Embryology and the Central Laboratory, Hebei Medical University from March to December 2003.MATERIALS: Forty healthy Sprague Dawley rats were randomly divided into a cerebral ischemla group and a sham operation group, with 20 rats per group.METHODS: In the cerebral ischemia group, we occluded the right middle cerebral artery with a suture,threading it to a depth of 17-19 mm. In the sham operation group, the threading depth was approximately 10 mm.MAIN OUTCOME MEASURES: We analyzed the expression of BDNF in different hippocampal regions by immunohistochemical staining of brain sections taken on post-operative days 7, 14, 21 and 30.RESULTS: Sham operation group: We observed a number of a few BDNF-positive cells with light staining in the hippocampal CAI CA4 regions and dentate gyrus. Cerebral ischemia group: compared with the sham operation group, BDNF increased on day 7, significantly increased on day 14, and reached a peak on day 21 (P < 0.05). Furthermore, immunologically reactive products were darkly stained, and neurons had long axons.BDNF was particularly highly expressed in the hippocampal CA3 and CA4 regions and dentate gyrus.CONCLUSION: Cerebral ischemic injury can damage hippocampal neurons. Neurons can increase their anti-ischemic capacity by increasing BDNF expression in the hippocampal CA3 and CA4 regions and dentate gyrus.

  8. Individual differences in novelty seeking predict subsequent vulnerability to social defeat through a differential epigenetic regulation of brain-derived neurotrophic factor expression.

    Science.gov (United States)

    Duclot, Florian; Kabbaj, Mohamed

    2013-07-03

    Some personality traits, including novelty seeking, are good predictors of vulnerability to stress-related mood disorders in both humans and rodents. While high-novelty-seeking rats [high responders (HRs)] are vulnerable to the induction of depressive-like symptoms by social defeat stress, low-novelty-seeking rats [low responders (LRs)] are not. Here, we show that such individual differences are critically regulated by hippocampal BDNF. While LR animals exhibited an increase in BDNF levels following social defeat, HR individuals did not. This difference in hippocampal BDNF expression promoted the vulnerability of HR and the resilience of LR rats. Indeed, preventing activation of BDNF signaling by infusing the BDNF scavenger TrkB-Fc into the dentate gyrus of the hippocampus of LR rats led to social defeat-induced social avoidance, whereas its activation in HR rats by the TrkB agonist 7,8-dihydroxyflavone promoted social approach. Along with the changes in BDNF expression following defeat, we report in LR animals a downregulation of the inactive BDNF receptor TrkB.T1, associated with an activation of CREB through Akt-mediated signaling, but not MSK1-mediated signaling. In HR animals, none of these molecules were affected by social defeat. Importantly, the BDNF upregulation involved an epigenetically controlled transcription of bdnf exon VI, associated with a coherent regulation of relevant epigenetic factors. Altogether, our data support the importance of hippocampal BDNF regulation in response to stressful events. Moreover, we identify a specific and adaptive regulation of bdnf exon VI in the hippocampus as a critical regulator of stress resilience, and strengthen the importance of epigenetic factors in mediating stress-induced adaptive and maladaptive responses in different individuals.

  9. Light-Emitting Diode (LED) therapy improves occipital cortex damage by decreasing apoptosis and increasing BDNF-expressing cells in methanol-induced toxicity in rats.

    Science.gov (United States)

    Ghanbari, Amir; Ghareghani, Majid; Zibara, Kazem; Delaviz, Hamdallah; Ebadi, Elham; Jahantab, Mohammad Hossein

    2017-05-01

    Methanol-induced retinal toxicity, frequently associated with elevated free radicals and cell edema, is characterized by progressive retinal ganglion cell (RGC) death and vision loss. Previous studies investigated the effect of photomodulation on RGCs, but not the visual cortex. In this study, the effect of 670nm Light-Emitting Diode (LED) therapy on RGCs and visual cortex recovery was investigated in a seven-day methanol-induced retinal toxicity protocol in rats. Methanol administration showed a reduction in the number of RGCs, loss of neurons (neuronal nuclear antigen, NeuN+), activation of glial fibrillary acidic protein (GFAP+) expressing cells, suppression of brain-derived neurotrophic factor (BDNF+) positive cells, increase in apoptosis (caspase 3+) and enhancement of nitric oxide (NO) release in serum and brain. On the other hand, LED therapy significantly reduced RGC death, in comparison to the methanol group. In addition, the number of BDNF positive cells was significantly higher in the visual cortex of LED-treated group, in comparison to methanol-intoxicated and control groups. Moreover, LED therapy caused a significant decrease in cell death (caspase 3+ cells) and a significant reduction in the NO levels, both in serum and brain tissue, in comparison to methanol-intoxicated rats. Overall, LED therapy demonstrated a number of beneficial effects in decreasing oxidative stress and in functional recovery of RGCs and visual cortex. Our data suggest that LED therapy could be a potential condidate as a non-invasive approach for treatment of retinal damage, which needs further clinicl studies. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  10. The Pattern of Brain-Derived Neurotrophic Factor Gene Expression in the Hippocampus of Diabetic Rats

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    Iraj Salehi

    2010-06-01

    Full Text Available Objective(sThe aim of this study was to evaluate the effects of regular exercise in preventing diabetes complication in the hippocampus of streptozotocin (STZ-induced diabetic rat.Materials and MethodsA total of 48 male wistar rats were divided into four groups (control, control exercise, diabetic and diabetic exercise. Diabetes was induced by injection of single dose of STZ. Exercise was performed for one hr every day, over a period of 8 weeks. The antioxidant enzymes (SOD, GPX, CAT and GR and oxidant indexes with brain-derived neurotrophic factor (BDNF protein and its mRNA and apoptosis were measured in hippocampus of rats. ResultsA significant decrease in antioxidant enzymes activities and increased malondialdehyde (MDA level were observed in diabetic rats (P= 0.004. In response to exercise, antioxidant enzymes activities increased (P= 0.004. In contrast, MDA level decreased in diabetic rats (P= 0.004. Induction of diabetes caused an increase of BDNF protein and its mRNA expression. In response to exercise, BDNF protein and its mRNA expression reduced in hippocampus of diabetic rats. ConclusionDiabetes induced oxidative stress and increased BDNF gene expression. Exercise ameliorated oxidative stress and decreased BDNF gene expression.

  11. Serotonin regulates brain-derived neurotrophic factor expression in select brain regions during acute psychological stress

    Institute of Scientific and Technical Information of China (English)

    De-guo Jiang; Shi-li Jin; Gong-ying Li; Qing-qing Li; Zhi-ruo Li; Hong-xia Ma; Chuan-jun Zhuo; Rong-huan Jiang; Min-jie Ye

    2016-01-01

    Previous studies suggest that serotonin (5-HT) might interact with brain-derived neurotrophic factor (BDNF) during the stress response. However, the relationship between 5-HT and BDNF expression under purely psychological stress is unclear. In this study, one hour before psychological stress exposure, the 5-HT1A receptor agonist 8-OH-DPAT or antagonist MDL73005, or the 5-HT2A receptor agonist DOI or antagonist ketanserin were administered to rats exposed to psychological stress. Immunohistochemistry andin situ hybridization revealed that after psychological stress, with the exception of the ventral tegmental area, BDNF protein and mRNA expression levels were higher in the 5-HT1A and the 5-HT2A receptor agonist groups compared with the solvent control no-stress or psychological stress group in the CA1 and CA3 of the hippocampus, prefrontal cortex, central amygdaloid nucleus, dorsomedial hypothalamic nucleus, dentate gyrus, shell of the nucleus accumbens and the midbrain periaqueductal gray. There was no signiifcant difference between the two agonist groups. In contrast, after stress exposure, BDNF protein and mRNA expression levels were lower in the 5-HT1A and 5-HT2A receptor antagonist groups than in the solvent control non-stress group, with the exception of the ventral tegmental area. Our ifndings suggest that 5-HT regulates BDNF expression in a rat model of acute psychological stress.

  12. Serotonin regulates brain-derived neurotrophic factor expression in select brain regions during acute psychological stress

    Directory of Open Access Journals (Sweden)

    De-guo Jiang

    2016-01-01

    Full Text Available Previous studies suggest that serotonin (5-HT might interact with brain-derived neurotrophic factor (BDNF during the stress response. However, the relationship between 5-HT and BDNF expression under purely psychological stress is unclear. In this study, one hour before psychological stress exposure, the 5-HT1A receptor agonist 8-OH-DPAT or antagonist MDL73005, or the 5-HT2A receptor agonist DOI or antagonist ketanserin were administered to rats exposed to psychological stress. Immunohistochemistry and in situ hybridization revealed that after psychological stress, with the exception of the ventral tegmental area, BDNF protein and mRNA expression levels were higher in the 5-HT1A and the 5-HT2A receptor agonist groups compared with the solvent control no-stress or psychological stress group in the CA1 and CA3 of the hippocampus, prefrontal cortex, central amygdaloid nucleus, dorsomedial hypothalamic nucleus, dentate gyrus, shell of the nucleus accumbens and the midbrain periaqueductal gray. There was no significant difference between the two agonist groups. In contrast, after stress exposure, BDNF protein and mRNA expression levels were lower in the 5-HT1A and 5-HT2A receptor antagonist groups than in the solvent control non-stress group, with the exception of the ventral tegmental area. Our findings suggest that 5-HT regulates BDNF expression in a rat model of acute psychological stress.

  13. Serotonin regulates brain-derived neurotrophic factor expression in select brain regions during acute psychological stress.

    Science.gov (United States)

    Jiang, De-Guo; Jin, Shi-Li; Li, Gong-Ying; Li, Qing-Qing; Li, Zhi-Ruo; Ma, Hong-Xia; Zhuo, Chuan-Jun; Jiang, Rong-Huan; Ye, Min-Jie

    2016-09-01

    Previous studies suggest that serotonin (5-HT) might interact with brain-derived neurotrophic factor (BDNF) during the stress response. However, the relationship between 5-HT and BDNF expression under purely psychological stress is unclear. In this study, one hour before psychological stress exposure, the 5-HT1A receptor agonist 8-OH-DPAT or antagonist MDL73005, or the 5-HT2A receptor agonist DOI or antagonist ketanserin were administered to rats exposed to psychological stress. Immunohistochemistry and in situ hybridization revealed that after psychological stress, with the exception of the ventral tegmental area, BDNF protein and mRNA expression levels were higher in the 5-HT1A and the 5-HT2A receptor agonist groups compared with the solvent control no-stress or psychological stress group in the CA1 and CA3 of the hippocampus, prefrontal cortex, central amygdaloid nucleus, dorsomedial hypothalamic nucleus, dentate gyrus, shell of the nucleus accumbens and the midbrain periaqueductal gray. There was no significant difference between the two agonist groups. In contrast, after stress exposure, BDNF protein and mRNA expression levels were lower in the 5-HT1A and 5-HT2A receptor antagonist groups than in the solvent control non-stress group, with the exception of the ventral tegmental area. Our findings suggest that 5-HT regulates BDNF expression in a rat model of acute psychological stress.

  14. EFFECTS OF REPEATEDLY HEADING A SOCCER BALL ON SERUM LEVELS OF TWO NEUROTROPHIC FACTORS OF BRAIN TISSUE, BDNF AND NGF, IN PROFESSIONAL SOCCER PLAYERS

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    B. Bamac

    2011-09-01

    Full Text Available The present study determined the effects of heading training on serum nerve growth factor (NGF and brain-derived neurotrophic factor (BDNF levels in soccer players. Seventeen professional level male soccer players (mean ± SD, age 24 ± 4.4 years, were recruited from a 3rd league team. Each player completed 15 approved headings in about 20-25 minutes. Venous blood samples were obtained from soccer players before and after the heading training for analysis. Levels of NGF and BDNF in the serum were determined by a commercially available enzyme-linked immunosorbent assay (ELISA kit. Mean ± SD serum NGF levels were 18.71 ± 3.36 pg·ml-1 before training and 31.41 ± 7.89 pg·ml-1 after training (p=0.000. Mean ± SD serum BDNF levels were 22.32 ± 3.62 pg·ml-1 before training and 55.41 ± 12.59 pg·ml-1 after training (p=0.000. In this study heading a soccer ball was found to cause an increase in serum concentrations of NGF and BDNF. We suggest that the microtrauma caused by repetitive heading and/or the course of survival of the injured neurons may lead to increased NGF and BDNF levels.

  15. proBDNF negatively regulates neuronal remodeling, synaptic transmission, and synaptic plasticity in hippocampus.

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    Yang, Jianmin; Harte-Hargrove, Lauren C; Siao, Chia-Jen; Marinic, Tina; Clarke, Roshelle; Ma, Qian; Jing, Deqiang; Lafrancois, John J; Bath, Kevin G; Mark, Willie; Ballon, Douglas; Lee, Francis S; Scharfman, Helen E; Hempstead, Barbara L

    2014-05-08

    Experience-dependent plasticity shapes postnatal development of neural circuits, but the mechanisms that refine dendritic arbors, remodel spines, and impair synaptic activity are poorly understood. Mature brain-derived neurotrophic factor (BDNF) modulates neuronal morphology and synaptic plasticity, including long-term potentiation (LTP) via TrkB activation. BDNF is initially translated as proBDNF, which binds p75(NTR). In vitro, recombinant proBDNF modulates neuronal structure and alters hippocampal long-term plasticity, but the actions of endogenously expressed proBDNF are unclear. Therefore, we generated a cleavage-resistant probdnf knockin mouse. Our results demonstrate that proBDNF negatively regulates hippocampal dendritic complexity and spine density through p75(NTR). Hippocampal slices from probdnf mice exhibit depressed synaptic transmission, impaired LTP, and enhanced long-term depression (LTD) in area CA1. These results suggest that proBDNF acts in vivo as a biologically active factor that regulates hippocampal structure, synaptic transmission, and plasticity, effects that are distinct from those of mature BDNF. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  16. Effects of brain-derived neurotrophic factor (BDNF) and electrical stimulation on survival and function of cochlear spiral ganglion neurons in deafened, developing cats.

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    Leake, Patricia A; Stakhovskaya, Olga; Hetherington, Alexander; Rebscher, Stephen J; Bonham, Ben

    2013-04-01

    Both neurotrophic support and neural activity are required for normal postnatal development and survival of cochlear spiral ganglion (SG) neurons. Previous studies in neonatally deafened cats demonstrated that electrical stimulation (ES) from a cochlear implant can promote improved SG survival but does not completely prevent progressive neural degeneration. Neurotrophic agents combined with an implant may further improve neural survival. Short-term studies in rodents have shown that brain-derived neurotrophic factor (BDNF) promotes SG survival after deafness and may be additive to trophic effects of stimulation. Our recent study in neonatally deafened cats provided the first evidence of BDNF neurotrophic effects in the developing auditory system over a prolonged duration Leake et al. (J Comp Neurol 519:1526-1545, 2011). Ten weeks of intracochlear BDNF infusion starting at 4 weeks of age elicited significant improvement in SG survival and larger soma size compared to contralateral. In the present study, the same deafening and BDNF infusion procedures were combined with several months of ES from an implant. After combined BDNF + ES, a highly significant increase in SG numerical density (>50 % improvement re: contralateral) was observed, which was significantly greater than the neurotrophic effect seen with ES-only over comparable durations. Combined BDNF + ES also resulted in a higher density of myelinated radial nerve fibers within the osseous spiral lamina. However, substantial ectopic and disorganized sprouting of these fibers into the scala tympani also occurred, which may be deleterious to implant function. EABR thresholds improved (re: initial thresholds at time of implantation) on the chronically stimulated channels of the implant. Terminal electrophysiological studies recording in the inferior colliculus (IC) revealed that the basic cochleotopic organization was intact in the midbrain in all studied groups. In deafened controls or after ES-only, lower IC

  17. Ultrastructural localisation of intramuscular expression of BDNF mRNA by silver-gold intensified non-radioactive in situ hybridisation

    NARCIS (Netherlands)

    Liem, RSB; Brouwer, N; Copray, JCVM

    2001-01-01

    A non-radioactive in situ hybridisation method is described for the detection of low intramuscular levels of brain-derived neurotrophic factor (BDNF) mRNA at the electron microscope level. Application of high-grade silver-gold intensification of the diaminobenzidine end product of in situ hybridisat

  18. Alterations of serum levels of BDNF-related miRNAs in patients with depression.

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    You-Jie Li

    Full Text Available Depression is a serious and potentially life-threatening mental disorder with unknown etiology. Emerging evidence shows that brain-derived neurotrophic factor (BDNF and microRNAs (miRNAs play critical roles in the etiology of depression. Here this study was aimed to identify and characterize the roles of BDNF and its putative regulatory miRNAs in depression. First, we identified that miR-182 may be a putative miRNA that regulates BDNF levels by bioinformatic studies, and characterized the effects of miR-182 on the BDNF levels using cell-based studies, side by side with miR-132 (a known miRNA that regulates BDNF expression. We showed that treatment of miR-132 and miR-182 respectively decreased the BDNF protein levels in a human neuronal cell model, supporting the regulatory roles of miR-132 and miR-182 on the BDNF expression. Furthermore, we explored the roles of miR-132 and miR-182 on the BDNF levels in depression using human subjects by assessing their serum levels. Compared with the healthy controls, patients with depression showed lower serum BDNF levels (via the enzyme-linked immunosorbent assays and higher serum miR-132 and miR-182 levels (via the real-time PCR. Finally, the Pearson's (or Spearman's correlation coefficient was calculated to study whether there was a relationship among the Self-Rating Depression Scale score, the serum BDNF levels, and serum BDNF-related miRNA levels. Our results revealed that there was a significant negative correlation between the SDS scores and the serum BDNF levels, and a positive correlation between the SDS scores and miR-132 levels. In addition, we found a reverse relationship between the serum BDNF levels and the miR-132/miR-182 levels in depression. Collectively, we provided evidence supporting that miR-182 is a putative BDNF-regulatory miRNA, and suggested that the serum BDNF and its related miRNAs may be utilized as important biomarkers in the diagnosis or as therapeutic targets of depression.

  19. Neurochemical properties of BDNF-containing neurons projecting to rostral ventromedial medulla in the ventrolateral periaqueductal gray

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    Jun-Bin eYin

    2014-11-01

    Full Text Available The periaqueductal gray (PAG modulates nociception via a descending pathway that relays in the rostral ventromedial medulla (RVM and terminates in the spinal cord. Previous behavioral pharmacology and electrophysiological evidence suggests that brain-derived neurotrophic factor (BDNF plays an important role in descending pain modulation, likely through the PAG-RVM pathway. However, there still lacks detailed information on the distribution of BDNF, activation of BDNF-containing neurons projecting to RVM in the condition of pain, and neurochemical properties of these neurons within the PAG. Through fluorescent in situ hybridization (FISH and immunofluorescent staining, the homogenous distributions of BDNF mRNA and protein were observed in the four subregions of PAG. Both neurons and astrocytes expressed BDNF, but not microglias. By combining retrograde tracing methods and formalin pain model, there were more BDNF-containing neurons projecting to RVM being activated in the ventrolateral PAG (vlPAG than other subregions of PAG. The neurochemical properties of BDNF-containing projection neurons in the vlPAG were investigated. BDNF-containing projection neurons expressed auto receptor Tropomyosin-related kinase B (TrkB in addition to serotonin (5-HT, neurotensin (NT, substance P (SP, calcitonin gene related peptide (CGRP, nitric oxide synthase (NOS, and parvalbumin (PV but not tyrosine decarboxylase (TH. It is speculated that BDNF released from projection neurons in the vlPAG might participate in the descending pain modulation through enhancing the presynaptic release of other neuroactive substances (NSs in the RVM.

  20. Systemic delivery of recombinant brain derived neurotrophic factor (BDNF) in the R6/2 mouse model of Huntington's disease.

    Science.gov (United States)

    Giampà, Carmela; Montagna, Elena; Dato, Clemente; Melone, Mariarosa A B; Bernardi, Giorgio; Fusco, Francesca Romana

    2013-01-01

    Loss of huntingtin-mediated BDNF gene transcription has been shown to occur in HD and thus contribute to the degeneration of the striatum. Several studies have indicated that an increase in BDNF levels is associated with neuroprotection and amelioration of neurological signs in animal models of HD. In a recent study, an increase in BDNF mRNA and protein levels was recorded in mice administered recombinant BDNF peripherally. Chronic, indwelling osmotic mini-pumps containing either recombinant BDNF or saline were surgically placed in R6/2 or wild-type mice from 4 weeks of age until euthanasia. Neurological evaluation (paw clasping, rotarod performance, locomotor activity in an open field) was performed. After transcardial perfusion, histological and immunohistochemical studies were performed. We found that BDNF- treated R6/2 mice survived longer and displayed less severe signs of neurological dysfunction than the vehicle treated ones. Primary outcome measures such as brain volume, striatal atrophy, size and morphology of striatal neurons, neuronal intranuclear inclusions and microglial reaction confirmed a neuroprotective effect of the compound. BDNF was effective in increasing significantly the levels of activated CREB and of BDNF the striatal spiny neurons. Moreover, systemically administered BDNF increased the synthesis of BDNF as demonstrated by RT-PCR, and this might account for the beneficial effects observed in this model.

  1. Association Between Smoking, Nicotine Dependence, and BDNF Val(66)Met Polymorphism with BDNF Concentrations in Serum

    NARCIS (Netherlands)

    Jamal, Mumtaz; Van der Does, Willem; Elzinga, Bernet M.; Molendijk, Marc L.; Penninx, Brenda W. J. H.

    2015-01-01

    Introduction: Nicotine use is associated with the upregulation of brain-derived neurotrophic factor (BDNF) in serum. An association between smoking and the BDNF Val(66)Met polymorphism has also been found. The aim of this study is to examine the levels of serum BDNF in never-smokers, former smokers,

  2. Association Between Smoking, Nicotine Dependence, and BDNF Val(66)Met Polymorphism with BDNF Concentrations in Serum

    NARCIS (Netherlands)

    Jamal, Mumtaz; Van der Does, Willem; Elzinga, Bernet M.; Molendijk, Marc L.; Penninx, Brenda W. J. H.

    Introduction: Nicotine use is associated with the upregulation of brain-derived neurotrophic factor (BDNF) in serum. An association between smoking and the BDNF Val(66)Met polymorphism has also been found. The aim of this study is to examine the levels of serum BDNF in never-smokers, former smokers,

  3. DNA methylation profiles of the brain-derived neurotrophic factor (BDNF gene as a potent diagnostic biomarker in major depression.

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    Manabu Fuchikami

    Full Text Available Major depression, because of its recurring and life-threatening nature, is one of the top 10 diseases for global disease burden. Major depression is still diagnosed on the basis of clinical symptoms in patients. The search for specific biological markers is of great importance to advance the method of diagnosis for depression. We examined the methylation profile of 2 CpG islands (I and IV at the promoters of the brain-derived neurotrophic factor (BDNF gene, which is well known to be involved in the pathophysiology of depression. We analyzed genomic DNA from peripheral blood of 20 Japanese patients with major depression and 18 healthy controls to identify an appropriate epigenetic biomarker to aid in the establishment of an objective system for the diagnosis of depression. Methylation rates at each CpG unit was measured using a MassArray® system (SEQUENOM, and 2-dimensional hierarchical clustering analyses were undertaken to determine the validity of these methylation profiles as a diagnostic biomarker. Analyses of the dendrogram from methylation profiles of CpG I, but not IV, demonstrated that classification of healthy controls and patients at the first branch completely matched the clinical diagnosis. Despite the small number of subjects, our results indicate that classification based on the DNA methylation profiles of CpG I of the BDNF gene may be a valuable diagnostic biomarker for major depression.

  4. Long Non-coding RNA in Neurons: New Players in Early Response to BDNF Stimulation.

    Science.gov (United States)

    Aliperti, Vincenza; Donizetti, Aldo

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) is a neurotrophin family member that is highly expressed and widely distributed in the brain. BDNF is critical for neural survival and plasticity both during development and in adulthood, and dysfunction in its signaling may contribute to a number of neurodegenerative disorders. Deep understanding of the BDNF-activated molecular cascade may thus help to find new biomarkers and therapeutic targets. One interesting direction is related to the early phase of BDNF-dependent gene expression regulation, which is responsible for the activation of selective gene programs that lead to stable functional and structural remodeling of neurons. Immediate-early coding genes activated by BDNF are under investigation, but the involvement of the non-coding RNAs is largely unexplored, especially the long non-coding RNAs (lncRNAs). lncRNAs are emerging as key regulators that can orchestrate different aspects of nervous system development, homeostasis, and plasticity, making them attractive candidate markers and therapeutic targets for brain diseases. We used microarray technology to identify differentially expressed lncRNAs in the immediate response phase of BDNF stimulation in a neuronal cell model. Our observations on the putative functional role of lncRNAs provide clues to their involvement as master regulators of gene expression cascade triggered by BDNF.

  5. Chronic antidepressant administration alleviates frontal and hippocampal BDNF deficits in CUMS rat.

    Science.gov (United States)

    Zhang, Yang; Gu, Fenghua; Chen, Jia; Dong, Wenxin

    2010-12-17

    Stress activates the hypothalamo-pituitary-adrenal (HPA) axis, regulates the expression of brain-derived neurotrophic factor (BDNF) in the brain, and mediates mood. Antidepressants alleviate stress and up-regulate BDNF gene expression. In this study, we investigated the effect of chronic unpredictable mild stress (CUMS) and the different kinds of antidepressant treatments on the HPA axis and the BDNF expression in the rat brain. Adult Wistar male rats were exposed to a six-week CUMS procedure and received different antidepressant treatments including venlafaxine, mirtazapine, and fluoxetine. Immunohistochemistry and real-time PCR were used to measure BDNF expression levels in the rat brain, and ELISAs were used to investigate the plasma corticosterone (CORT) and adrenocorticotropic hormone (ACTH) levels. CUMS significantly decreased the BDNF protein level in the DG, CA1, and CA3 of the hippocampus and increased plasma CORT level. Chronic antidepressant treatments all significantly increased BDNF protein levels in the hippocampus and the pre-frontal cortex. In addition, venlafaxine and mirtazapine inhibited the increase of plasma CORT level. These results suggested that an increase in the BDNF level in the brain could be a pivotal mechanism of various antidepressants to exert their therapeutic effects.

  6. Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism influences the association of the methylome with maternal anxiety and neonatal brain volumes.

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    Chen, Li; Pan, Hong; Tuan, Ta Anh; Teh, Ai Ling; MacIsaac, Julia L; Mah, Sarah M; McEwen, Lisa M; Li, Yue; Chen, Helen; Broekman, Birit F P; Buschdorf, Jan Paul; Chong, Yap Seng; Kwek, Kenneth; Saw, Seang Mei; Gluckman, Peter D; Fortier, Marielle V; Rifkin-Graboi, Anne; Kobor, Michael S; Qiu, Anqi; Meaney, Michael J; Holbrook, Joanna D

    2015-02-01

    Early life environments interact with genotype to determine stable phenotypic outcomes. Here we examined the influence of a variant in the brain-derived neurotropic factor (BDNF) gene (Val66Met), which underlies synaptic plasticity throughout the central nervous system, on the degree to which antenatal maternal anxiety associated with neonatal DNA methylation. We also examined the association between neonatal DNA methylation and brain substructure volume, as a function of BDNF genotype. Infant, but not maternal, BDNF genotype dramatically influences the association of antenatal anxiety on the epigenome at birth as well as that between the epigenome and neonatal brain structure. There was a greater impact of antenatal maternal anxiety on the DNA methylation of infants with the methionine (Met)/Met compared to both Met/valine (Val) and Val/Val genotypes. There were significantly more cytosine-phosphate-guanine sites where methylation levels covaried with right amygdala volume among Met/Met compared with both Met/Val and Val/Val carriers. In contrast, more cytosine-phosphate-guanine sites covaried with left hippocampus volume in Val/Val infants compared with infants of the Met/Val or Met/Met genotype. Thus, antenatal Maternal Anxiety × BDNF Val66Met Polymorphism interactions at the level of the epigenome are reflected differently in the structure of the amygdala and the hippocampus. These findings suggest that BDNF genotype regulates the sensitivity of the methylome to early environment and that differential susceptibility to specific environmental conditions may be both tissue and function specific.

  7. The role of brain-derived neurotrophic factor in the regulation of cell growth and gene expression in melanotrope cells of Xenopus laevis.

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    Jenks, Bruce G; Kuribara, Miyuki; Kidane, Adhanet H; Kramer, Bianca M R; Roubos, Eric W; Scheenen, Wim J J M

    2012-07-01

    Brain-derived neurotrophic factor (BDNF) is, despite its name, also found outside the central nervous system (CNS), but the functional significance of this observation is largely unknown. This review concerns the expression of BDNF in the pituitary gland. While the presence of the neurotrophin in the mammalian pituitary gland is well documented its functional significance remains obscure. Studies on the pars intermedia of the pituitary of the amphibian Xenopus laevis have shown that BDNF is produced by the neuroendocrine melanotrope cells, its expression is physiologically regulated, and the melanotrope cells themselves express receptors for the neurotrophin. The neurotrophin has been shown to act as an autocrine factor on the melanotrope to promote cell growth and regulate gene expression. In doing so BDNF supports the physiological function of the cell to produce and release α-melanophore-stimulating hormone for the purpose of adjusting the animal's skin color to that of its background.

  8. Peripheral lipopolysaccharide administration transiently affects expression of brain-derived neurotrophic factor, corticotropin and proopiomelanocortin in mouse brain.

    Science.gov (United States)

    Schnydrig, Sabine; Korner, Lukas; Landweer, Svenja; Ernst, Beat; Walker, Gaby; Otten, Uwe; Kunz, Dieter

    2007-12-11

    Peripheral inflammation induced by intraperitoneal (i.p.) injection of Lipopolysaccharide (LPS) is known to cause functional impairments in the brain affecting memory and learning. One of mechanisms may be the interference with neurotrophin (NT) expression and function. In the current study we administered a single, high dose of LPS (3mg/kg, i.p.) into mice and investigated changes in brain-derived neurotrophic factor (BDNF) gene expression within 1-6 days after LPS injection. Crude synaptosomes were isolated from brain tissue and subjected to Western-blot analyses. We found transient reductions in synaptosomal proBDNF- and BDNF protein expression, with a maximal decrease at day 3 as compared to saline injected controls. The time course of reduction of BDNF mRNA in whole brain extracts parallels the decrease in protein levels in synaptosomes. LPS effects in the central nervous system (CNS) are known to crucially involve the activation of the hypothalamic-pituitary-adrenal (HPA) axis. We analysed the time course of corticotropin releasing hormone (CRH)- and proopiomelanocortin (POMC) mRNA expression. As observed for BDNF-, CRH- and POMC mRNA levels are also significantly reduced on day 3 indicating a comparable time course. These results suggest that peripheral inflammation causes a reduction of trophic supply in the brain, including BDNF at synaptic sites. The mechanisms involved could be a negative feedback of the activated HPA axis.

  9. Intracerebroventricular 4-methylcatechol (4-MC) ameliorates chronic pain associated with depression-like behavior via induction of brain-derived neurotrophic factor (BDNF).

    Science.gov (United States)

    Fukuhara, Kayoko; Ishikawa, Kozo; Yasuda, Seiko; Kishishita, Yusuke; Kim, Hae-Kyu; Kakeda, Takahiro; Yamamoto, Misa; Norii, Takafumi; Ishikawa, Toshizo

    2012-08-01

    Neuropathic pain concurrent with mood disorder from peripheral nerve injury is a serious clinical problem that significantly affects quality of life. Recent studies have suggested that a lack of brain-derived neurotrophic factor (BDNF) in the limbic system may cause this pain-emotion. BDNF is induced in cultured neurons by 4-methylcatechol (4-MC), but the role of 4-MC-induced BDNF in pain-emotion is poorly understood. Thus, we assessed the possible involvement of BDNF in brain in depression-like behavior during chronic pain following peripheral nerve injury. In addition, we examined whether intracerebroventricular (i.c.v.) 4-MC prevents chronic pain in rats and produces an antidepressant effect. Sprague-Dawley rats implanted intracerebroventricularly with a PE-10 tube were subjected to chronic constriction injury (CCI). Pain was assessed by a reduction in paw withdrawal latency (PWL) to heat stimuli after CCI. We also used a forced swimming testing (FST; time of immobility, in seconds) from day 14 to day 21 after CCI. Modulation of pain and emotional behavior was performed by injection of PD0325901 (a MEK1/2 inhibitor). 4-MC (100 nM) was continuously administered i.c.v. for 3 days during the period from day 14 to day 21 after CCI. To block analgesic and antidepressant effects, anti-BDNF antibody or K252a (a TrkB receptor inhibitor) was injected in combination with 4-MC. Naloxone was also coadministered to confirm the analgesic effect of 4-MC. During the chronic stage after CCI, the rats showed a sustained decrease in PWL (thermal hyperalgesia) associated with extension of the time of immobility (depression-like behavior). PD0325901 significantly reduced the decrease in PWL and the increased time of immobility after CCI. The decreased PWL and increased time of immobility were also reduced by 4-MC and by treatment with an ERK1/2 inhibitor. These effects of 4-MC i.c.v. were reversed by anti-BDNF and K252a. The analgesic effect of 4-MC i.c.v. was also antagonized by

  10. Expression of the CHOP-inducible carbonic anhydrase CAVI-b is required for BDNF-mediated protection from hypoxia.

    Science.gov (United States)

    Matthews, Tori A; Abel, Allyssa; Demme, Chris; Sherman, Teresa; Pan, Pei-wen; Halterman, Marc W; Parkkila, Seppo; Nehrke, Keith

    2014-01-16

    Carbonic anhydrases (CAs) comprise a family of zinc-containing enzymes that catalyze the reversible hydration of carbon dioxide. CAs contribute to a myriad of physiological processes, including pH regulation, anion transport and water balance. To date, 16 known members of the mammalian alpha-CA family have been identified. Given that the catalytic family members share identical reaction chemistry, their physiologic roles are influenced greatly by their tissue and sub-cellular locations. CAVI is the lone secreted CA and exists in both saliva and the gastrointestinal mucosa. An alternative, stress-inducible isoform of CAVI (CAVI-b) has been shown to be expressed from a cryptic promoter that is activated by the CCAAT/Enhancer-Binding Protein Homologous Protein (CHOP). The CAVI-b isoform is not secreted and is currently of unknown physiological function. Here we use neuronal models, including a model derived using Car6 and CHOP gene ablations, to delineate a role for CAVI-b in ischemic protection. Our results demonstrate that CAVI-b expression, which is increased through CHOP-signaling in response to unfolded protein stress, is also increased by oxygen-glucose deprivation (OGD). While enforced expression of CAVI-b is not sufficient to protect against ischemia, CHOP regulation of CAVI-b is necessary for adaptive changes mediated by BDNF that reduce subsequent ischemic damage. These results suggest that CAVI-b comprises a necessary component of a larger adaptive signaling pathway downstream of CHOP.

  11. Brain-derived Neurotrophic Factor in Megakaryocytes.

    Science.gov (United States)

    Chacón-Fernández, Pedro; Säuberli, Katharina; Colzani, Maria; Moreau, Thomas; Ghevaert, Cedric; Barde, Yves-Alain

    2016-05-06

    The biosynthesis of endogenous brain-derived neurotrophic factor (BDNF) has thus far been examined in neurons where it is expressed at very low levels, in an activity-dependent fashion. In humans, BDNF has long been known to accumulate in circulating platelets, at levels far higher than in the brain. During the process of blood coagulation, BDNF is released from platelets, which has led to its extensive use as a readily accessible biomarker, under the assumption that serum levels may somehow reflect brain levels. To identify the cellular origin of BDNF in platelets, we established primary cultures of megakaryocytes, the progenitors of platelets, and we found that human and rat megakaryocytes express the BDNF gene. Surprisingly, the pattern of mRNA transcripts is similar to neurons. In the presence of thapsigargin and external calcium, the levels of the mRNA species leading to efficient BDNF translation rapidly increase. Under these conditions, pro-BDNF, the obligatory precursor of biologically active BDNF, becomes readily detectable. Megakaryocytes store BDNF in α-granules, with more than 80% of them also containing platelet factor 4. By contrast, BDNF is undetectable in mouse megakaryocytes, in line with the absence of BDNF in mouse serum. These findings suggest that alterations of BDNF levels in human serum as reported in studies dealing with depression or physical exercise may primarily reflect changes occurring in megakaryocytes and platelets, including the ability of the latter to retain and release BDNF.

  12. c-fos modulates brain-derived neurotrophic factor mRNA expression in mouse hippocampal CA3 and dentate gyrus neurons.

    Science.gov (United States)

    Dong, Mei; Wu, Yongfei; Fan, Yunxia; Xu, Ming; Zhang, Jianhua

    2006-05-29

    Excess neuronal excitation by glutamate induces neuron cell death, which may contribute to the pathogenesis of acute brain injuries and neurodegenerative diseases. Our previous studies using a mouse with hippocampal c-fos gene deletion showed that c-fos regulates neuronal excitability and excitotoxicity. Moreover, a delayed induction of brain-derived neurotrophic factor (BDNF) protein expression in response to kainic acid (KA) treatment was found in c-fos mutant mice compared to wildtype controls, suggesting that c-fos is important in the temporal control of BDNF induction. To further investigate mechanisms of in vivo regulation of c-fos on BDNF expression, we studied the expression of BDNF mRNA and its colocalization with c-Fos protein in the hippocampal formation in the presence and absence of KA. By in situ hybridization, we observed that the c-fos mutant and wildtype mice exhibited similar basal expression of BDNF in the absence of KA. In contrast, the KA-induced BDNF mRNA levels were significantly different in wildtype and c-fos mutant mice in CA3 and dentate gyrus regions. Our findings indicate that c-fos regulates expression of BDNF in distinct neuron populations of the hippocampal formation in vivo.

  13. Effect of miR-185 * on BDNF/TrkB signaling pathway expression in epileptic neurons%miR-185∗对癫痫海马神经元中 BDNF-TrkB 通路表达的影响

    Institute of Scientific and Technical Information of China (English)

    蔡浩; 李江丽; 谢伟; 常伟; 宋毅军

    2015-01-01

    ABSTRACT:Objective To study the BDNF/TrkB signaling pathway in the epilepsy model of hippocampal neurons and the regulatory effect of on it.Methods The primary hippocampal neurons cultured in vitro for 7 days were randomly divided into seven groups:control group,epilepsy group,control+BDNF group,epilepsy+BDNF group,control + miR-185 ∗ group,epilepsy + miR-185 ∗ group,and epilepsy + miR-185 ∗ + BDNF group.We constructed miR-185 ∗ lentivirus vector and observed the changes of BDNF/TrkB pathway expression after transfaction of miR-185 ∗ by immunohistochemistry,patch clamp technique and Western blot technique.Results Compared with the control+BDNF group,the phosphorylated TrkB (pTrkB)/TrkB value was significantly lower in epilepsy+BDNF group (P < 0.05 )and control group (P < 0.001 ).Compared with the epilepsy group,the phosphorylated TrkB (pTrkB)/TrkB value was significantly higher in epilepsy+BDNF group (P <0.05).Compared with the epilepsy+miR-185 ∗ +BDNF group,the phosphorylated TrkB (pTrkB)/TrkB value was significantly lower in epilepsy + BDNF group and epilepsy + miR-185 ∗ group (P < 0.001 ).BDNF could promote the signaling conduction and miR-185 ∗ could remove the inhibition of BDNF/TrkB signaling.Conclusion BDNF can activate the BDNF/TrkB signaling pathway and transfection with miR-185 ∗ can relieve the inhibition of BDNF/TrkB signaling pathway of epileptic state by up-regulating the expression of TrkB.%目的:研究海马神经元癫痫模型中的 BDNF/TrkB 信号通路及 miR-185∗对其的调控。方法构建 miR-185∗表达载体。体外培养海马神经元,7 d 后将其随机分为正常组、癫痫组、正常+BDNF 组、癫痫+BDNF 组、正常转染miR-185∗ 组、癫痫转染 miR-185∗ 组、癫痫转染 miR-185∗ +BDNF 组。免疫荧光、膜片钳及免疫印迹技术观察转染miR-185∗ 后 BDNF/TrkB 通路的表达变化。结果癫痫+BDNF 组海马神经元细胞的 TrkB 蛋白磷酸化水平较正常+BDNF

  14. Fluoxetine-induced change in rat brain expression of brain-derived neurotrophic factor varies depending on length of treatment.

    Science.gov (United States)

    De Foubert, G; Carney, S L; Robinson, C S; Destexhe, E J; Tomlinson, R; Hicks, C A; Murray, T K; Gaillard, J P; Deville, C; Xhenseval, V; Thomas, C E; O'Neill, M J; Zetterström, T S C

    2004-01-01

    Recent studies indicate that brain-derived neurotrophic factor (BDNF) may be implicated in the clinical action of antidepressant drugs. Repeated (2-3 weeks) administration of antidepressant drugs increases BDNF gene expression. The onset of this response as well as concomitant effects on the corresponding BDNF protein is however, unclear. The present study investigated the effects of acute and chronic administration of the selective serotonin reuptake inhibitor, fluoxetine (10mg/kg p.o.), upon regional rat brain levels of BDNF mRNA and protein expression. To improve the clinical significance of the study, fluoxetine was administered orally and mRNA and protein levels were determined ex vivo using the techniques of in situ hybridisation histochemistry and immunocytochemistry respectively. Direct measurement of BDNF protein was also carried out using enzyme-linked immunosorbent assay (ELISA). Four days of once daily oral administration of fluoxetine induced decreases in BDNF mRNA (hippocampus, medial habenular and paraventricular thalamic nuclei). Whilst 7 days of treatment showed a non-significant increase in BDNF mRNA, there were marked and region-specific increases following 14 days of treatment. BDNF protein levels remained unaltered until 21 days of fluoxetine treatment, when the numbers of BDNF immunoreactive cells were increased, reaching significance in the pyramidal cell layer of CA1 and CA3 regions of Ammon's horn (CA1 and CA3) but not in the other sub-regions of the hippocampus. Indicative of the highly regional change within the hippocampus, the ELISA method failed to demonstrate significant up-regulation at 21 days, measuring levels of BDNF protein in the whole hippocampus. In contrast to the detected time dependent and biphasic response of the BDNF gene, activity-regulated, cytoskeletal-associated protein (Arc) mRNA showed a gradual increase during the 14-day course of treatment. The results presented here show that BDNF is expressed differentially

  15. Low-level laser therapy promotes dendrite growth via upregulating brain-derived neurotrophic factor expression

    Science.gov (United States)

    Meng, Chengbo; He, Zhiyong; Xing, Da

    2014-09-01

    Downregulation of brain-derived neurotrophic factor (BDNF) in the hippocampus occurs early in the progression of Alzheimer's disease (AD). Since BDNF plays a critical role in neuronal survival and dendrite growth, BDNF upregulation may contribute to rescue dendrite atrophy and cell loss in AD. Low-level laser therapy (LLLT) has been demonstrated to regulate neuronal function both in vitro and in vivo. In the present study, we found that LLLT rescued neurons loss and dendritic atrophy via the increase of both BDNF mRNA and protein expression. In addition, dendrite growth was improved after LLLT, characterized by upregulation of PSD95 expression, and the increase in length, branching, and spine density of dendrites in hippocampal neurons. Together, these studies suggest that upregulation of BDNF with LLLT can ameliorate Aβ-induced neurons loss and dendritic atrophy, thus identifying a novel pathway by which LLLT protects against Aβ-induced neurotoxicity. Our research may provide a feasible therapeutic approach to control the progression of Alzheimer's disease.

  16. Differential expression of brain-derived neurotrophic factor transcripts after pilocarpine-induced seizure-like activity is related to mode of Ca2+ entry.

    Science.gov (United States)

    Poulsen, F R; Lauterborn, J; Zimmer, J; Gall, C M

    2004-01-01

    Activity-dependent brain-derived neurotrophic factor (BDNF) expression is Ca2+-dependent, yet little is known about the Ca2+ channel contributions that might direct selective expression of the multiple BDNF transcripts. Here, effects of pilocarpine-induced seizure activity on total BDNF expression and on the individual sensitivity of BDNF transcripts to glutamate receptor and Ca2+ channel blockers were evaluated using hippocampal slice cultures and in situ hybridization of transcript-specific cRNA probes directed against mRNAs for the four 5' exons (I-IV) of the BDNF gene. mRNAs for nerve growth factor (NGF) and tyrosine kinase B (trkB) also were studied. Pilocarpine (5 mM) induced a dose- and time-dependent increase in total BDNF (exon V) mRNA expression in the dentate granule cells and CA3-CA1 pyramidal cells with maximal effects at 6 and 24 h, respectively. Increases were blocked by co-treatment with the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX: 25 microM) and the N-methyl-d-aspartic acid receptor antagonist 2-amino-5-phosphonovaleric acid (APV; 25 microM), whereas the L-type voltage sensitive Ca2+ channel blocker nifedipine (20 microM) was without detectable effect. Maximal NGF and trkB mRNA expression was induced by pilocarpine at 4 and 12 h, respectively. For the individual BDNF transcripts, APV blocked pilocarpine-induced increases in transcript II, whereas nifedipine blocked increases in transcripts I and III. Transcript IV levels were not altered by treatment. These results indicate that transcript II makes the greatest contribution to pilocarpine effects on total BDNF mRNA content in this model and provides evidence for regional and Ca2+ channel-specific differences in activity-dependent regulation of the different BDNF transcripts in hippocampus.

  17. Temporal changes in the expression of brain-derived neurotrophic factor mRNA in the ventromedial nucleus of the hypothalamus of the developing rat brain.

    Science.gov (United States)

    Sugiyama, Nobuhiro; Kanba, Shigenobu; Arita, Jun

    2003-07-04

    Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family, which is important for the growth, differentiation, and survival of neurons during development. We have performed a detailed mapping of BDNF mRNA in the neonatal rat brain using a quantitative in situ hybridization technique. At postnatal day (PND) 4, hypothalamic structures showed only modest expression of BDNF mRNA, with the exception of the ventromedial nucleus (VMN), where expression was higher than that detected in the hippocampus. Abundant BDNF mRNA was also found in the bed nucleus of the anterior commissure, retrosplenial granular cortex, and the posteroventral part of the medial amygdaloid nucleus. Messenger RNAs encoding other neurotrophins, including nerve growth factor (NGF) and neurotrophin-3 (NT-3) and the BDNF receptor trkB, were not selectively localized in neonatal VMN. During subsequent developmental stages, BDNF mRNA expression in the VMN changed dynamically, peaking at PND 4 and falling to minimal levels in the adult brain. In contrast, the low levels of BDNF mRNA observed in the CA3 region of the hippocampus increased to adult levels following PND 10. As the VMN undergoes sexual differentiation, we compared BDNF, NGF, NT-3, and trkB mRNA expression in the VMN in males and females at embryonic day 20 and PND 4, but found no differences between them. These results suggest that localized and high level expression of BDNF mRNA in the neonatal VMN plays an important role in its neural organization and functional development.

  18. Brain-derived neurotrophic factor and Bcl-2 expression in rat brain areas following chronic morphine treatment

    Institute of Scientific and Technical Information of China (English)

    Huiping Yu; Hua Hu; Huaqing Meng; Wei Deng; Yixiao Fu; Qinghua Luo

    2011-01-01

    The ventral tegmental area and the locus coeruleus are associated with psychological and physical dependence of opioid addiction. To date, very little is known about brain-derived neurotrophic factor (BDNF) and Bcl-2 gene and protein changes following morphine addiction. The present study utilized immunohistochemistry and in situ hybridization techniques, which revealed that there were increased BDNF levels, but decreased Bcl-2 levels in the prefrontal cortex, locus coeruleus, hippocampus, and the ventral tegmental area during morphine-dependence formation and abstinence. However, the levels of BDNF remained unchanged, and Bcl-2 expression was increased in the nucleus accumbens. These results showed that BDNF and Bcl-2 are involved in the development of morphine dependence, and precipitation of abstinence syndrome.

  19. BDNF in schizophrenia, depression and corresponding animal models.

    Science.gov (United States)

    Angelucci, F; Brenè, S; Mathé, A A

    2005-04-01

    Understanding the etiology and pathogenesis schizophrenia and depression is a major challenge facing psychiatry. One hypothesis is that these disorders are secondary to a malfunction of neurotrophic factors. Inappropriate neurotrophic support during brain development could lead to structural disorganisation in which neuronal networks are established in a nonoptimal manner. Inadequate neurotrophic support in adult individuals could ultimately be an underlying mechanism leading to decreased capacity of brain to adaptive changes and increased vulnerability to neurotoxic damage. Brain-derived neurotrophic factor (BDNF) is a mediator involved in neuronal survival and plasticity of dopaminergic, cholinergic, and serotonergic neurons in the central nervous system (CNS). In this review, we summarize findings regarding altered BDNF in schizophrenia and depression and animal models, as well as the effects of antipsychotic and antidepressive treatments on the expression of BDNF.

  20. Mature brain-derived neurotrophic factor and its receptor TrkB are upregulated in human glioma tissues.

    Science.gov (United States)

    Xiong, Jing; Zhou, L I; Lim, Yoon; Yang, Miao; Zhu, Yu-Hong; Li, Zhi-Wei; Fu, Deng-Li; Zhou, Xin-Fu

    2015-07-01

    There are two forms of brain-derived neurotrophic factor (BDNF), precursor of BDNF (proBDNF) and mature BDNF, which each exert opposing effects through two different transmembrane receptor signaling systems, consisting of p75 neurotrophin receptor (p75NTR) and tyrosine receptor kinase B (TrkB). Previous studies have demonstrated that proBDNF promotes cell death and inhibits the growth and migration of C6 glioma cells through p75NTR in vitro, while mature BDNF has opposite effects on C6 glioma cells. It is hypothesized that mature BDNF is essential in the development of malignancy in gliomas. However, histological data obtained in previous studies were unable distinguish mature BDNF from proBDNF due to the lack of specific antibodies. The present study investigated the expression of mature BDNF using a specific sheep monoclonal anti-mature BDNF antibody in 42 human glioma tissues of different grades and 10 control tissues. The correlation between mature BDNF and TrkB was analyzed. Mature BDNF expression was significantly increased in high-grade gliomas, and was positively correlated with the malignancy of the tumor and TrkB receptor expression. The present data have demonstrated that increased levels of mature BDNF contribute markedly to the development of malignancy of human gliomas through the primary BDNF receptor TrkB.

  1. Exercise does not protect against MPTP-induced neurotoxicity in BDNF haploinsufficient mice.

    Directory of Open Access Journals (Sweden)

    Kim M Gerecke

    Full Text Available Exercise has been demonstrated to potently protect substantia nigra pars compacta (SN dopaminergic neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP-induced neurotoxicity. One mechanism proposed to account for this neuroprotection is the upregulation of neurotrophic factors. Several neurotrophic factors, including Brain Derived Neurotrophic Factor (BDNF, have been shown to upregulate in response to exercise. In order to determine if exercise-induced neuroprotection is dependent upon BDNF, we compared the neuroprotective effects of voluntary exercise in mice heterozygous for the BDNF gene (BDNF+/- with strain-matched wild-type (WT mice. Stereological estimates of SNpc DA neurons from WT mice allowed 90 days exercise via unrestricted running demonstrated complete protection against the MPTP-induced neurotoxicity. However, BDNF+/- mice allowed 90 days of unrestricted exercise were not protected from MPTP-induced SNpc DA neuron loss. Proteomic analysis comparing SN and striatum from 90 day exercised WT and BDNF+/- mice showed differential expression of proteins related to energy regulation, intracellular signaling and trafficking. These results suggest that a full genetic complement of BDNF is critical for the exercise-induced neuroprotection of SNpc DA neurons.

  2. Estrogen and exercise interact to regulate brain-derived neurotrophic factor mRNA and protein expression in the hippocampus.

    Science.gov (United States)

    Berchtold, N C; Kesslak, J P; Pike, C J; Adlard, P A; Cotman, C W

    2001-12-01

    We investigated the possibility that estrogen and exercise interact in the hippocampus and regulate brain-derived neurotrophic factor (BDNF), a molecule increasingly recognized for its role in plasticity and neuron function. An important aspect of this study is to examine the effect of different time intervals between estrogen loss and estrogen replacement intervention. We demonstrate that in the intact female rat, physical activity increases hippocampal BDNF mRNA and protein levels. However, the exercise effect on BDNF up-regulation is reduced in the absence of estrogen, in a time-dependent manner. In addition, voluntary activity itself is stimulated by the presence of estrogen. In exercising animals, estrogen deprivation reduced voluntary activity levels, while estrogen replacement restored activity to normal levels. In sedentary animals, estrogen deprivation (ovariectomy) decreased baseline BDNF mRNA and protein, which were restored by estrogen replacement. Despite reduced activity levels in the ovariectomized condition, exercise increased BDNF mRNA levels in the hippocampus after short-term (3 weeks) estrogen deprivation. However, long-term estrogen-deprivation blunted the exercise effect. After 7 weeks of estrogen deprivation, exercise alone no longer affected either BDNF mRNA or protein levels. However, exercise in combination with long-term estrogen replacement increased BDNF protein above the effects of estrogen replacement alone. Interestingly, protein levels across all conditions correlated most closely with mRNA levels in the dentate gyrus, suggesting that expression of mRNA in this hippocampal region may be the major contributor to the hippocampal BDNF protein pool. The interaction of estrogen, physical activity and hippocampal BDNF is likely to be an important issue for maintenance of brain health, plasticity and general well-being, particularly in women.

  3. Effects of dietary Na+ deprivation on epithelial Na+ channel (ENaC, BDNF, and TrkB mRNA expression in the rat tongue

    Directory of Open Access Journals (Sweden)

    Stähler Frauke

    2009-03-01

    Full Text Available Abstract Background In rodents, dietary Na+ deprivation reduces gustatory responses of primary taste fibers and central taste neurons to lingual Na+ stimulation. However, in the rat taste bud cells Na+ deprivation increases the number of amiloride sensitive epithelial Na+ channels (ENaC, which are considered as the "receptor" of the Na+ component of salt taste. To explore the mechanisms, the expression of the three ENaC subunits (α, β and γ in taste buds were observed from rats fed with diets containing either 0.03% (Na+ deprivation or 1% (control NaCl for 15 days, by using in situ hybridization and real-time quantitative RT-PCR (qRT-PCR. Since BDNF/TrkB signaling is involved in the neural innervation of taste buds, the effects of Na+ deprivation on BDNF and its receptor TrkB expression in the rat taste buds were also examined. Results In situ hybridization analysis showed that all three ENaC subunit mRNAs were found in the rat fungiform taste buds and lingual epithelia, but in the vallate and foliate taste buds, only α ENaC mRNA was easily detected, while β and γ ENaC mRNAs were much less than those in the fungiform taste buds. Between control and low Na+ fed animals, the numbers of taste bud cells expressing α, β and γ ENaC subunits were not significantly different in the fungiform, vallate and foliate taste buds, respectively. Similarly, qRT-PCR also indicated that Na+ deprivation had no effect on any ENaC subunit expression in the three types of taste buds. However, Na+ deprivation reduced BDNF mRNA expression by 50% in the fungiform taste buds, but not in the vallate and foliate taste buds. The expression of TrkB was not different between control and Na+ deprived rats, irrespective of the taste papillae type. Conclusion The findings demonstrate that dietary Na+ deprivation does not change ENaC mRNA expression in rat taste buds, but reduces BDNF mRNA expression in the fungiform taste buds. Given the roles of BDNF in survival of

  4. BDNF Evokes Release of Endogenous Cannabinoids at Layer 2/3 Inhibitory Synapses in the Neocortex

    OpenAIRE

    2010-01-01

    The neurotrophin brain-derived neurotrophic factor (BDNF) is a potent regulator of inhibitory synaptic transmission, although the locus of this effect and the underlying mechanisms are controversial. We explored a potential interaction between BDNF and endogenous cannabinoid (endocannabinoid) signaling because activation of type 1 cannabinoid (CB1) receptors potently regulates γ-aminobutyric acid (GABA) release and both trkB tyrosine kinase receptors and CB1 receptors are highly expressed at ...

  5. Regulation of BDNF-mediated transcription of immediate early gene Arc by intracellular calcium and calmodulin

    OpenAIRE

    Zheng, Fei; Luo, Yongneng; Wang, Hongbing

    2009-01-01

    The induction of the immediate early gene Arc is strongly implicated in synaptic plasticity. Although the role of ERK was demonstrated, the regulation of Arc expression is largely unknown. In this study, we investigated the major signaling pathways underlying brain-derived neurotrophic factor (BDNF)-mediated Arc transcription in cultured cortical neurons. The BDNF-stimulated Arc transcription was solely regulated by the Ras-Raf-MAPK signaling through ERK, but not by phosphoinositide 3-kinase ...

  6. Effects of chronic multiple stress on learning and memory and the expression of Fyn, BDNF, TrkB in the hippocampus of rats

    Institute of Scientific and Technical Information of China (English)

    LI Xiao-heng; LIU Neng-bao; ZHANG Min-hai; ZHOU Yan-ling; LIAO Jia-wan; LIU Xiang-qian; CHEN Hong-wei

    2007-01-01

    Background The effect of chronic stress on cognitive functions has been one of the hot topics in neuroscience. But there has been much controversy over its mechanism. The aim of this study was to investigate the effects of chronic multiple stress on spatial learning and memory as well as the expression of Fyn, BDNF and TrkB in the hippocampus of rats.Methods Adult rats were randomly divided into control and chronic multiple stressed groups. Rats in the multiple stressed group were irregularly and alternatively exposed to situations of vertical revolution, sleep expropriation and restraint lasting for 6 weeks, 6 hours per day with night illumination for 6 weeks. Before and after the period of chronic multiple stresses, the performance of spatial learning and memory of all rats was measured using the Morris Water Maze (MWM). The expression of Fyn, BDNF and TrkB proteins in the hippocampus was assayed by Western blotting and immunohistochemical methods. The levels of Fyn and TrkB mRNAs in the hippocampus of rats were detected by RT-PCR technique.Results The escape latency in the control group and the stressed group were 15.63 and 8.27 seconds respectively.The performance of spatial learning and memory of rats was increased in chronic multiple stressed group (P<0.05). The levels of Fyn, BDNF and TrkB proteins in the stressed group were higher than those of the control group (P<0.05). The results of immunoreactivity showed that Fyn was present in the CA3 region of the hippocampus and BDNF positive particles were distributed in the nuclei of CA1 and CA3 pyramidal cells as well as DG granular cells. Quantitative analysis indicated that level of Fyn mRNA was also upregulated in the hippocampus of the stressed group (P<0.05).Conclusions Chronic multiple stress can enhance spatial learning and memory function of rats. The expression of Fyn,BDNF and TrkB proteins and the level of Fyn mRNA are increased in the stessed rat hippocampus. These suggest that Fyn and BDNF

  7. Gene and protein analysis of brain derived neurotrophic factor expression in relation to neurological recovery induced by an enriched environment in a rat stroke model.

    Science.gov (United States)

    Hirata, Kenji; Kuge, Yuji; Yokota, Chiaki; Harada, Akina; Kokame, Koichi; Inoue, Hiroyasu; Kawashima, Hidekazu; Hanzawa, Hiroko; Shono, Yuji; Saji, Hideo; Minematsu, Kazuo; Tamaki, Nagara

    2011-05-20

    Although an enriched environment enhances functional recovery after ischemic stroke, the mechanism underlying this effect remains unclear. We previously reported that brain derived neurotrophic factor (BDNF) gene expression decreased in rats housed in an enriched environment for 4 weeks compared to those housed in a standard cage for the same period. To further clarify the relationship between the decrease in BDNF and functional recovery, we investigated the effects of differential 2-week housing conditions on the mRNA of BDNF and protein levels of proBDNF and mature BDNF (matBDNF). After transient occlusion of the right middle cerebral artery of male Sprague-Dawley rats, we divided the rats into two groups: (1) an enriched group housed multiply in large cages equipped with toys, and (2) a standard group housed alone in small cages without toys. Behavioral tests before and after 2-week differential housing showed better neurological recovery in the enriched group than in the standard group. Synaptophysin immunostaining demonstrated that the density of synapses in the peri-infarct area was increased in the enriched group compared to the standard group, while infarct volumes were not significantly different. Real-time reverse transcription polymerase chain reaction, Western blotting and immunostaining all revealed no significant difference between the groups. The present results suggest that functional recovery cannot be ascribed to an increase in matBDNF or a decrease in proBDNF but rather to other underlying mechanisms.

  8. Hippocampal BDNF signaling restored with chronic asiaticoside treatment in depression-like mice.

    Science.gov (United States)

    Luo, Liu; Liu, Xiao-Long; Mu, Rong-Hao; Wu, Yong-Jing; Liu, Bin-Bin; Geng, Di; Liu, Qing; Yi, Li-Tao

    2015-05-01

    Brain-derived neurotrophic factor (BDNF) plays a key role in the regulation of depression in the brain. Recently, increasing studies have focused on the antidepressant-like mechanism of BDNF and its downstream signaling pathway. A previous study has shown that asiaticoside produced an antidepressant-like action in the mouse tail suspension test and forced swimming test. However, the neurotrophic mechanism that is affected by asiaticoside is unclear. Our present study aimed to verify whether asiaticoside produces an antidepressant-like effect through the activation of BDNF signaling in chronic unpredictable mild stress (CUMS). The results showed that mice treated with asiaticoside for four weeks reversed the decreased sucrose preference and increased immobility time that was observed in CUMS mice. In addition, we found that asiaticoside up-regulated BDNF, PSD-95 and synapsin I expression only in the hippocampus but not in the frontal cortex in both non-stressed and CUMS mice. However, K252a, an inhibitor of BDNF receptor tropomyosin-related kinase receptor B (TrkB), completely abolished the antidepressant-like effect of asiaticoside. Moreover, the expression of hippocampal BDNF, PSD-95 and synapsin I that had increased with asiaticoside also declined with K252a pretreatment. In conclusion, our study implies that it is possible that asiaticoside exerts its antidepressant-like action by activating BDNF signaling in the hippocampus.

  9. Effects of maternal stress during pregnancy on learning and memory via hippocampal BDNF, Arc (Arg3.1) expression in offspring.

    Science.gov (United States)

    Guan, Su-Zhen; Ning, Li; Tao, Ning; Lian, Yu-Long; Liu, Ji-Wen; Ng, Tzi Bun

    2016-09-01

    The intrauterine environment has a significant long-term impact on individual's life, this study was designed to investigate the effect of stress during pregnancy on offspring's learning and memory abilities and analyze its mechanisms from the expression of BDNF and Arc in the hippocampus of the offspring. A rat model of maternal chronic stress during pregnancy was mating from 3rd day during been subjecting to chronic unpredictable mild stress (CUMS). The body weights and behavioral changes were recorded, and plasma corticosterone levels were determined by radioimmunoassay. The learning and memory abilities of the offspring were measured by Morris water maze testing from PND 42. The expression of hippocampal BDNF and Arc mRNA and protein were respectively measured using RT-PCR and Western blotting. Results indicated that an elevation was observed in the plasma corticosterone level of rat model of maternal chronic stress during pregnancy, a reduction in the crossing and rearing movement times and the preference for sucrose. The body weight of maternal stress's offspring was lower than the control group, and the plasma corticosterone level was increased. Chronic stress during pregnancy had a significant impact on the spatial learning and memory of the offspring. The expression of BDNF mRNA and protein, Arc protein in offspring of maternal stress during pregnancy was attenuated and some relationships existed between these parameters. Collectively, these findings disclose that long-time maternal stress during pregnancy could destroy spatial learning and memory abilities of the offspring, the mechanism of which is related to been improving maternal plasma corticosterone and reduced hippocampal BDNF, Arc of offspring rats.

  10. Neurotensin-polyplex-mediated brain-derived neurotrophic factor gene delivery into nigral dopamine neurons prevents nigrostriatal degeneration in a rat model of early Parkinson’s disease

    OpenAIRE

    2015-01-01

    Background The neurotrophin Brain-Derived Neurotrophic Factor (BDNF) influences nigral dopaminergic neurons via autocrine and paracrine mechanisms. The reduction of BDNF expression in Parkinson’s disease substantia nigra (SN) might contribute to the death of dopaminergic neurons because inhibiting BDNF expression in the SN causes parkinsonism in the rat. This study aimed to demonstrate that increasing BDNF expression in dopaminergic neurons of rats with one week of 6-hydroxydopamine lesion re...

  11. Brain-derived neurotrophic factor promotes vesicular glutamate transporter 3 expression and neurite outgrowth of dorsal root ganglion neurons through the activation of the transcription factors Etv4 and Etv5.

    Science.gov (United States)

    Liu, Dong; Liu, Zhen; Liu, Huaxiang; Li, Hao; Pan, Xinliang; Li, Zhenzhong

    2016-03-01

    Brain-derived neurotrophic factor (BDNF) is critical for sensory neuron survival and is necessary for vesicular glutamate transporter 3 (VGLUT3) expression. Whether the transcription factors Etv4 and Etv5 are involved in these BDNF-induced effects remains unclear. In the present study, primary cultured dorsal root ganglion (DRG) neurons were used to test the link between BDNF and transcription factors Etv4 and Etv5 on VGLUT3 expression and neurite outgrowth. BDNF promoted the mRNA and protein expression of Etv4 and Etv5 in DRG neurons. These effects were blocked by extracellular signal-regulated protein kinase 1/2 (ERK1/2) inhibitor PD98059 but not phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 or phospholipase C-γ (PLC-γ) inhibitor U73122. Etv4 siRNA and Etv5 siRNA effectively blocked the VGLUT3 expression and neurite elongation induced by BNDF. The overexpression of Etv4 or Etv5 potentiated the effects of BNDF-induced neurite elongation and growth-associated protein 43 (GAP-43), medium neurofilament (NF-M), and light neurofilament (NF-L) expression while these effects could be inhibited by Etv4 and Etv5 siRNA. These data imply that Etv4 and Etv5 are essential transcription factors in modulating BDNF/TrkB signaling-mediated VGLUT3 expression and neurite outgrowth. BDNF, through the ERK1/2 signaling pathway, activates Etv4 and Etv5 to initiate GAP-43 expression, promote neurofilament (NF) protein expression, induce neurite outgrowth, and mediate VGLUT3 expression for neuronal function improvement. The biological effects initiated by BDNF/TrkB signaling linked to E26 transformation-specific (ETS) transcription factors are important to elucidate neuronal differentiation, axonal regeneration, and repair in various pathological states.

  12. Effect of Prenatal Protein Malnutrition on Long-Term Potentiation and BDNF Protein Expression in the Rat Entorhinal Cortex after Neocortical and Hippocampal Tetanization

    Directory of Open Access Journals (Sweden)

    Alejandro Hernández

    2008-01-01

    Full Text Available Reduction of the protein content from 25 to 8% casein in the diet of pregnant rats results in impaired neocortical long-term potentiation (LTP of the offspring together with lower visuospatial memory performance. The present study was aimed to investigate whether this type of maternal malnutrition could result in modification of plastic capabilities of the entorhinal cortex (EC in the adult progeny. Unlike normal eutrophic controls, 55–60-day-old prenatally malnourished rats were unable to develop LTP in the medial EC to tetanizing stimulation delivered to either the ipsilateral occipital cortex or the CA1 hippocampal region. Tetanizing stimulation of CA1 also failed to increase the concentration of brain-derived neurotrophic factor (BDNF in the EC of malnourished rats. Impaired capacity of the EC of prenatally malnourished rats to develop LTP and to increase BDNF levels during adulthood may be an important factor contributing to deficits in learning performance having adult prenatally malnourished animals.

  13. Effect of prenatal protein malnutrition on long-term potentiation and BDNF protein expression in the rat entorhinal cortex after neocortical and hippocampal tetanization.

    Science.gov (United States)

    Hernández, Alejandro; Burgos, Héctor; Mondaca, Mauricio; Barra, Rafael; Núñez, Héctor; Pérez, Hernán; Soto-Moyano, Rubén; Sierralta, Walter; Fernández, Victor; Olivares, Ricardo; Valladares, Luis

    2008-01-01

    Reduction of the protein content from 25 to 8% casein in the diet of pregnant rats results in impaired neocortical long-term potentiation (LTP) of the offspring together with lower visuospatial memory performance. The present study was aimed to investigate whether this type of maternal malnutrition could result in modification of plastic capabilities of the entorhinal cortex (EC) in the adult progeny. Unlike normal eutrophic controls, 55-60-day-old prenatally malnourished rats were unable to develop LTP in the medial EC to tetanizing stimulation delivered to either the ipsilateral occipital cortex or the CA1 hippocampal region. Tetanizing stimulation of CA1 also failed to increase the concentration of brain-derived neurotrophic factor (BDNF) in the EC of malnourished rats. Impaired capacity of the EC of prenatally malnourished rats to develop LTP and to increase BDNF levels during adulthood may be an important factor contributing to deficits in learning performance having adult prenatally malnourished animals.

  14. Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase

    DEFF Research Database (Denmark)

    Matthews, V B; Åström, Maj-Brit; Chan, M H S

    2009-01-01

    AIMS/HYPOTHESIS: Brain-derived neurotrophic factor (BDNF) is produced in skeletal muscle, but its functional significance is unknown. We aimed to determine the signalling processes and metabolic actions of BDNF. METHODS: We first examined whether exercise induced BDNF expression in humans. Next, C2......(79)) were analysed, as was fatty acid oxidation (FAO). Finally, we electroporated a Bdnf vector into the tibialis cranialis muscle of mice. RESULTS: BDNF mRNA and protein expression were increased in human skeletal muscle after exercise, but muscle-derived BDNF appeared not to be released...... into the circulation. Bdnf mRNA and protein expression was increased in muscle cells that were electrically stimulated. BDNF increased phosphorylation of AMPK and ACCbeta and enhanced FAO both in vitro and ex vivo. The effect of BDNF on FAO was AMPK-dependent, since the increase in FAO was abrogated in cells infected...

  15. The neuroprotective role of acupuncture and activation of the BDNF signaling pathway.

    Science.gov (United States)

    Lin, Dong; De La Pena, Ike; Lin, Lili; Zhou, Shu-Feng; Borlongan, Cesar V; Cao, Chuanhai

    2014-02-21

    Recent studies have been conducted to examine the neuroprotective effects of acupuncture in many neurological disorders. Although the neuroprotective effects of acupuncture has been linked to changes in signaling pathways, accumulating evidence suggest the participation of endogenous biological mediators, such as the neurotrophin (NT) family of proteins, specifically, the brain derived neurotrophic factor (BDNF). Accordingly, acupuncture can inhibit neurodegeneration via expression and activation of BDNF. Moreover, recent studies have reported that acupuncture can increase ATP levels at local stimulated points. We have also demonstrated that acupuncture could activate monocytes and increase the expression of BDNF via the stimulation of ATP. The purpose of this article is to review the recent findings and ongoing studies on the neuroprotective roles of acupuncture and therapeutic implications of acupuncture-induced activation of BDNF and its signaling pathway.

  16. The Neuroprotective Role of Acupuncture and Activation of the BDNF Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Dong Lin

    2014-02-01

    Full Text Available Recent studies have been conducted to examine the neuroprotective effects of acupuncture in many neurological disorders. Although the neuroprotective effects of acupuncture has been linked to changes in signaling pathways, accumulating evidence suggest the participation of endogenous biological mediators, such as the neurotrophin (NT family of proteins, specifically, the brain derived neurotrophic factor (BDNF. Accordingly, acupuncture can inhibit neurodegeneration via expression and activation of BDNF. Moreover, recent studies have reported that acupuncture can increase ATP levels at local stimulated points. We have also demonstrated that acupuncture could activate monocytes and increase the expression of BDNF via the stimulation of ATP. The purpose of this article is to review the recent findings and ongoing studies on the neuroprotective roles of acupuncture and therapeutic implications of acupuncture-induced activation of BDNF and its signaling pathway.

  17. Maternal prenatal anxiety and child brain-derived neurotrophic factor (BDNF) genotype: effects on internalizing symptoms from 4 to 15 years of age.

    Science.gov (United States)

    O'Donnell, Kieran J; Glover, Vivette; Holbrook, Joanna D; O'Connor, Thomas G

    2014-11-01

    Multiple behavioral and health outcomes, including internalizing symptoms, may be predicted from prenatal maternal anxiety, depression, or stress. However, not all children are affected, and those that are can be affected in different ways. Here we test the hypothesis that the effects of prenatal anxiety are moderated by genetic variation in the child's brain-derived neurotrophic factor (BDNF) gene, using the Avon Longitudinal Study of Parents and Children population cohort. Internalizing symptoms were assessed from 4 to 13 years of age using the Strengths and Difficulties Questionnaire (n = 8,584); a clinical interview with the adolescents was conducted at age 15 years (n = 4,704). Obstetric and psychosocial risk and postnatal maternal symptoms were included as covariates. Results show that prenatal maternal anxiety predicted internalizing symptoms, including with the diagnostic assessment at 15 years. There was a main effect of two BDNF polymorphisms (rs6265 [val66met] and rs11030104) on internalizing symptoms up to age 13. There was also genetic moderation of the prenatal anxiety effect by different BDNF polymorphisms (rs11030121 and rs7124442), although significant effects were limited to preadolescence. The findings suggest a role for BDNF gene-environment interactions in individual vulnerability to the effects of prenatal anxiety on child internalizing symptoms.

  18. Lithium chloride administration prevents spatial learning and memory impairment in repeated cerebral ischemia-reperfusion mice by depressing apoptosis and increasing BDNF expression in hippocampus.

    Science.gov (United States)

    Fan, Mingyue; Jin, Wei; Zhao, Haifeng; Xiao, Yining; Jia, Yanqiu; Yin, Yu; Jiang, Xin; Xu, Jing; Meng, Nan; Lv, Peiyuan

    2015-09-15

    Lithium has been reported to have neuroprotective effects, but the preventive and treated role on cognition impairment and the underlying mechanisms have not been determined. In the present study, C57Bl/6 mice were subjected to repeated bilateral common carotid artery occlusion to induce the learning and memory deficits. 2 mmol/kg or 5 mmol/kg of lithium chloride (LiCl) was injected intraperitoneally per day before (for 7 days) or post (for 28 days) the operation. This repeated cerebral ischemia-reperfusion (IR) induced dynamic overexpression of ratio of Bcl-2/Bax and BDNF in hippocampus of mice. LiCl pretreatment and treatment significantly decreased the escape latency and increased the percentage of time that the mice spent in the target quadrant in Morris water maze. 2 mmol/kg LiCl evidently reversed the morphologic changes, up-regulated the survival neuron count and increased the BDNF gene and protein expression. 5 mmol/kg pre-LiCl significantly increased IR-stimulated reduce of Bcl-2/Bax and p-CREB/CREB. These results described suggest that pre-Li and Li treatment may induce a pronounced prevention on cognitive impairment. These effects may relay on the inhibition of apoptosis and increasing BDNF and p-CREB expression.

  19. Functional and structural specific roles of activity-driven BDNF within circuits formed by single spiny stellate neurons of the barrel cortex

    Directory of Open Access Journals (Sweden)

    Qian-Quan eSun

    2014-11-01

    Full Text Available Brain derived neurotrophic factor (BDNF plays key roles in several neurodevelopmental disorders and actions of pharmacological treatments. However it is uncealr how specific BDNF’s effects are on diffeerent circuit components. Current studies have largely focused on the role of BDNF in modification of synaptic development. The precise roles of BDNF in the refinement of a functional circuit in vivo remain unclear. Val66Met polymorphism of BDNF may be associated with increased risk for cognitive impairments and is mediated at least in part by activity-dependent trafficking and/or secretion of BDNF. Using mutant mice that lacked activity-driven BDNF expression (bdnf-KIV, we previously reported that experience regulation of the cortical GABAergic network is mediated by activity-driven BDNF expression. Here, we demonstrate that activity-driven BDNF’s effects on circuits formed by the layer IV spiny stellate cells are highly specific. Structurally, dendritic but not axonal morphology was altered in the mutant. Physiologically, GABAergic but not glutamatergic synapses were severely affected. The effects on GABA transmission occurs via presynaptic alteration of calcium-dependent release probability. These results suggest that neuronal activity through activity-driven BDNF expression, can selectively regulate specific features of layer IV circuits in vivo. We postulate that the role of activity-dependent BDNF is to modulate the computational ability of circuits that relate to the gain control (i.e. feed-forward inhibition; whereas the basic wiring of circuits relevant to the sensory pathway is spared. Gain control modulation within cortical circuits has broad impact on cognitive processing and brain state-transitions. Cognitive behavior and mode is determined by brain states, thus the studying of circuit alteration by endogenous BDNF provides insights into the cellular and molecular mechanisms of diseases mediated by BDNF.

  20. [Blockade of NMDA receptor enhances corticosterone-induced downregulation of brain-derived neurotrophic factor gene expression in the rat hippocampus through cAMP response element binding protein pathway].

    Science.gov (United States)

    Feng, Hao; Lu, Li-Min; Huang, Ying; Zhu, Yi-Chun; Yao, Tai

    2005-10-25

    High concentration of corticosterone leads to morphological and functional impairments in hippocampus, ranging from a reversible atrophy of pyramidal CA3 apical dendrites to the impairment of long-term potentiation (LTP) and hippocampus-dependent learning and memory. Glutamate and N-methyl-D-aspartate (NMDA) receptor play an important role in this effect. Because of the importance of brain-derived neurotrophic factor (BDNF) in the functions of the hippocampal neurons, alteration of the expression of BDNF is thought to be involved in the corticosterone effect on the hippocampus. To determine whether change in BDNF in the hippocampus is involved in the corticosterone effect, we injected corticosterone (2 mg/kg, s.c.) to Sprague-Dawley rats and measured the mRNA, proBDNF and mature BDNF protein levels in the hippocampus. We also measured the phosphorylation level of the transcription factor cAMP response element binding protein (CREB). Furthermore, we intraperitoneally injected NMDA receptor antagonist MK801 (0.1 mg/kg) 30 min before corticosterone administration to investigate whether and how MK801 affected the regulation of BDNF gene expression by corticosterone. Our results showed that 3 h after single s.c. injection of corticsterone, the expression of BDNF mRNA, proBDNF and mature BDNF protein decreased significantly (PBDNF gene expression in the rat hippocampus by corticosterone. We also found that either applying corticosterone or co-applying corticosterone with MK801 downregulated the phosphoration level of CREB, the latter (corticosterone plus MK801) being more effective (PBDNF gene expression in the rat hippocampus through CREB pathway and that blockade of NMDA receptor enhances this effect of corticosterone in reducing BDNF expression.

  1. Expression of TrkB and TrkC but not BDNF mRNA in neurochemically identified interneurons in rat visual cortex in vivo and in organotypic cultures.

    Science.gov (United States)

    Gorba, T; Wahle, P

    1999-04-01

    The mammalian visual cortex contains morphologically diverse populations of interneurons whose neurochemical properties are believed to be regulated by neurotrophic factors. This requires the expression of neurotrophin receptors. We have analysed whether brain-derived neurotrophic factor (BDNF), its receptor trkB and the NT-3 receptor trkC are expressed in interneurons of rat visual cortex in vivo, and in organotypic visual cortex cultures, paying particular attention to the subsets of neuropeptidergic neurons. In situ hybridization in combination with immunofluorescence for calcium-binding proteins and neuropeptides revealed that BDNF is not expressed in interneurons in vivo or in vitro. For the neurotrophin receptors we found in vivo at postnatal day 70 (P70) that approximately 80% of the parvalbumin-immunoreactive (-ir), but only 50% of the intensely calbindin-ir, and only 20% of the calretinin-ir neurons express trkB. Double labelling with neuropeptides revealed that approximately 50% of the neuropeptide Y-ir and approximately 50% of the somatostatin-ir neurons express trkB in a laminar-specific way. Only 25% of the vasoactive intestinal polypeptide (VIP)-ir neurons coexpress trkB. The coexpression of neuropeptide Y with trkB, but not with BDNF or trkC, was confirmed with a double in situ hybridization. In contrast, the percentages differed in the immature cortex; at P14 70% of the NPY-ir neurons and 46% of the calretinin-ir neurons revealed trkB expression, while the ratio for calbindin-ir cells was fairly constant (59%). From the interneuron populations studied, only 12% of the parvalbumin-ir neurons expressed trkC. A triple labelling revealed that some neurons coexpressed both trk mRNAs, while others had only trkC. The analysis of interneurons in organotypic cultures yielded very similar results. The results indicate that trkB ligands synthesized by pyramidal neurons influence neuropeptide or calcium-binding protein expression in a paracrine or transsynaptic

  2. Control of extracellular cleavage of ProBDNF by high frequency neuronal activity

    OpenAIRE

    Nagappan, Guhan; Zaitsev, Eugene; Senatorov, Vladimir V.; Yang, Jianmin; Hempstead, Barbara L.; Lu, Bai

    2009-01-01

    Pro- and mature neurotrophins often elicit opposing biological effects. For example, mature brain-derived neurotrophic factor (mBDNF) is critical for long-term potentiation induced by high-frequency stimulation, whereas proBDNF facilitate long-term depression induced by low-frequency stimulation. Because mBDNF is derived from proBDNF by endoproteolytic cleavage, mechanisms regulating the cleavage of proBDNF may control the direction of BDNF regulation. Using methods that selectively detect pr...

  3. Time-dependent contribution of non neuronal cells to BDNF production after ischemic stroke in rats.

    OpenAIRE

    Béjot, Yannick; Tessier, Anne; Cachia, Claire; Giroud, Maurice; Mossiat, Claude; Bertrand, Nathalie; Garnier, Philippe; Marie, Christine

    2011-01-01

    International audience; Although brain-derived neurotrophic factor (BDNF) plays a central role in recovery after cerebral ischemia, little is known about cells involved in BDNF production after stroke. The present study testes the hypothesis that neurons are not the unique source of neosynthesized BDNF after stroke and that non neuronal-BDNF producing cells differ according to the delay after stroke induction. For this purpose, cellular localization of BDNF and BDNF content of each hemisphere...

  4. Androgen-dependent loss of muscle BDNF mRNA in two mouse models of SBMA.

    Science.gov (United States)

    Halievski, Katherine; Henley, Casey L; Domino, Laurel; Poort, Jessica E; Fu, Martina; Katsuno, Masahisa; Adachi, Hiroaki; Sobue, Gen; Breedlove, S Marc; Jordan, Cynthia L

    2015-07-01

    Transgenic expression of neurotrophic factors in skeletal muscle has been found to protect mice from neuromuscular disease, including spinal bulbar muscular atrophy (SBMA), triggering renewed interest in neurotrophic factors as therapeutic agents for treating neuromuscular disease. Because SBMA is an androgen-dependent disease, and brain-derived neurotrophic factor (BDNF) mediates effects of androgens on neuromuscular systems, we asked whether BDNF expression is impaired in two different transgenic (Tg) mouse models of SBMA, the so called "97Q" and "myogenic" SBMA models. The 97Q model globally overexpresses a full length human AR with 97 glutamine repeats whereas the myogenic model of SBMA overexpresses a wild-type rat androgen receptor (AR) only in skeletal muscle fibers. Using quantitative PCR, we find that muscle BDNF mRNA declines in an androgen-dependent manner in both models, paralleling changes in motor function, with robust deficits (6-8 fold) in both fast and slow twitch muscles of impaired Tg males. Castration rescues or reverses disease-related deficits in muscle BDNF mRNA in both models, paralleling its effect on motor function. Moreover, when disease is acutely induced in Tg females, both motor function and muscle BDNF mRNA expression plummet, with the deficit in muscle BDNF emerging before overt motor dysfunction. That androgen-dependent motor dysfunction is tightly associated with a robust and early down-regulation of muscle BDNF mRNA suggests that BDNF delivered to skeletal muscle may have therapeutic value for SBMA. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. BDNF pro-peptide regulates dendritic spines via caspase-3.

    Science.gov (United States)

    Guo, J; Ji, Y; Ding, Y; Jiang, W; Sun, Y; Lu, B; Nagappan, G

    2016-06-16

    The precursor of brain-derived neurotrophic factor (BDNF) (proBDNF) is enzymatically cleaved, by either intracellular (furin/PC1) or extracellular proteases (tPA/plasmin/MMP), to generate mature BDNF (mBDNF) and its pro-peptide (BDNF pro-peptide). Little is known about the function of BDNF pro-peptide. We have developed an antibody that specifically detects cleaved BDNF pro-peptide, but not proBDNF or mBDNF. Neuronal depolarization elicited a marked increase in extracellular BDNF pro-peptide, suggesting activity-dependent regulation of its extracellular levels. Exposure of BDNF pro-peptide to mature hippocampal neurons in culture dramatically reduced dendritic spine density. This effect was mediated by caspase-3, as revealed by studies with pharmacological inhibitors and genetic knockdown. BDNF pro-peptide also increased the number of 'elongated' mitochondria and cytosolic cytochrome c, suggesting the involvement of mitochondrial-caspase-3 pathway. These results, along with BDNF pro-peptide effects recently reported on growth cones and long-term depression (LTD), suggest that BDNF pro-peptide is a negative regulator of neuronal structure and function.

  6. Locally Produced BDNF Promotes Sclerotic Change in Alveolar Bone after Nerve Injury

    Science.gov (United States)

    Ida-Yonemochi, Hiroko; Yamada, Yurie; Yoshikawa, Hiroyuki

    2017-01-01

    Brain-derived neurotrophic factor (BDNF), which is released due to nerve injury, is known to promote the natural healing of injured nerves. It is often observed that damage of mandibular canal induces local sclerotic changes in alveolar bone. We reported that peripheral nerve injury promotes the local production of BDNF; therefore, it was possible to hypothesize that peripheral nerve injury affects sclerotic changes in the alveolar bone. This study aimed to evaluate the effect of BDNF on osteogenesis using in vitro osteoblast-lineage cell culture and an in vivo rat osteotomy model. MC3T3-E1 cells were cultured with BDNF and were examined for cell proliferative activity, chemotaxis and mRNA expression levels of osteoblast differentiation markers. For in vivo study, inferior alveolar nerve (IAN) injury experiments and mandibular cortical osteotomy were performed using a rat model. In the osteotomy model, exogenous BDNF was applied to bone surfaces after corticotomy of the mandible, and we morphologically analyzed the new bone formation. As a result, mRNA expression of osteoblast differentiation marker, osteocalcin, was significantly increased by BDNF, although cell proliferation and migration were not affected. In the in vivo study, osteopontin-positive new bone formation was significantly accelerated in the BDNF-grafted groups, and active bone remodeling, involving trkB-positive osteoblasts and osteocytes, continued after 28 days. In conclusion, BDNF stimulated the differentiation of MC3T3-E1 cells and it promoted new bone formation and maturation. These results suggested that local BDNF produced by peripheral nerve injury contributes to accelerating sclerotic changes in the alveolar bone. PMID:28072837

  7. [Voluntary wheel running enhances cell proliferation and expression levels of BDNF, IGF1 and WNT4 in dentate gyrus of adult mice].

    Science.gov (United States)

    Yu, Jia-Ling; Ma, Li; Ma, Lan; Tao, Ye-Zheng

    2014-10-25

    Adult hippocampal neurogenesis plays important roles in learning, memory and mood regulation. External factors, such as physical exercise, have been found to modulate adult hippocampal neurogenesis. Voluntary running enhances cell proliferation in subgranular zone (SGZ) and increases the number of new born neurons in rodents, but underlying mechanisms are not fully understood. In this study, we used BrdU assay to identify proliferating cells in 2-month-old C57BL/6 mice after 15 days of voluntary wheel running test. mRNA and protein levels for several neural factors in dentate gyrus, Ammon's horn, and cortex were also analyzed by RT-qPCR and Western blot assay after 15 days of voluntary wheel running. Our data show that voluntary wheel running for 15 days elevated the number of proliferation cells in dentate gyrus and significantly up-regulated the mRNA levels of Bdnf, Igf1 and Wnt4. The protein levels of BDNF and IGF1 in dentate gyrus were also increased after voluntary wheel running. These results indicate that the increase of adult hippocampal neurogenesis caused by voluntary wheel running for 15 days might be through up-regulating BDNF, IGF1 and WNT4 in dentate gyrus.

  8. Differential expression of brain-derived neurotrophic factor transcripts after pilocarpine-induced seizure-like activity is related to mode of Ca2+ entry

    DEFF Research Database (Denmark)

    Poulsen, F R; Lauterborn, J; Zimmer, J;

    2004-01-01

    ) and tyrosine kinase B (trkB) also were studied. Pilocarpine (5 mM) induced a dose- and time-dependent increase in total BDNF (exon V) mRNA expression in the dentate granule cells and CA3-CA1 pyramidal cells with maximal effects at 6 and 24 h, respectively. Increases were blocked by co-treatment with the alpha......Activity-dependent brain-derived neurotrophic factor (BDNF) expression is Ca2+-dependent, yet little is known about the Ca2+ channel contributions that might direct selective expression of the multiple BDNF transcripts. Here, effects of pilocarpine-induced seizure activity on total BDNF expression...... and on the individual sensitivity of BDNF transcripts to glutamate receptor and Ca2+ channel blockers were evaluated using hippocampal slice cultures and in situ hybridization of transcript-specific cRNA probes directed against mRNAs for the four 5' exons (I-IV) of the BDNF gene. mRNAs for nerve growth factor (NGF...

  9. The expression mechanism of the residual LTP in the CA1 region of BDNF k.o. mice is insensitive to NO synthase inhibition.

    Science.gov (United States)

    Lessmann, Volkmar; Stroh-Kaffei, Sigrid; Steinbrecher, Violetta; Edelmann, Elke; Brigadski, Tanja; Kilb, Werner; Luhmann, Heiko J

    2011-05-19

    BDNF and nitric oxide signaling both contribute to long-term potentiation (LTP) at glutamatergic synapses, but to date, few studies analyzed the interaction of both signaling cascades in the same synaptic pathway. Here we addressed the question whether the residual LTP in the CA1 region of hippocampal slices from heterozygous BDNF knockout mice (BDNF⁺/⁻) is dependent on nitric oxide (NO) signaling. Extracellular recording of synaptic field potentials elicited by presynaptic Schaffer collateral stimulation was performed in the CA1 region of hippocampal slices of 4- to 6-week-old mice, and LTP was induced by a theta burst stimulation protocol. Application of the nitric oxide inhibitor L-NAME (200 μM) strongly inhibited LTP by 70% in wildtype animals. This inhibition of LTP was not a consequence of altered basal synaptic properties. In CA1 of BDNF⁺/⁻ mice, stimulated with the same theta burst protocol, LTP was reduced by 50% as compared to wildtype animals. This impairment in the expression of LTP in BDNF⁺/⁻ mice did not result from an increased synaptic fatigue. The residual LTP in BDNF⁺/⁻ was not further reduced by preincubation of slices with L-NAME. These results suggest that BDNF and NO share overlapping intracellular signaling cascades to mediate LTP in CA1, and part of their signaling cascades are most likely arranged consecutively in the signaling pathway mediating LTP.

  10. Human obesity associated with an intronic SNP in the brain-derived neurotrophic factor locus

    Science.gov (United States)

    Brain-derived neurotrophic factor (BDNF) plays a key role in energy balance. In population studies, SNPs of the BDNF locus have been linked to obesity, but the mechanism by which these variants cause weight gain is unknown. Here, we examined human hypothalamic BDNF expression in association with 44 ...

  11. Stress and trauma: BDNF control of dendritic-spine formation and regression.

    Science.gov (United States)

    Bennett, M R; Lagopoulos, J

    2014-01-01

    Chronic restraint stress leads to increases in brain derived neurotrophic factor (BDNF) mRNA and protein in some regions of the brain, e.g. the basal lateral amygdala (BLA) but decreases in other regions such as the CA3 region of the hippocampus and dendritic spine density increases or decreases in line with these changes in BDNF. Given the powerful influence that BDNF has on dendritic spine growth, these observations suggest that the fundamental reason for the direction and extent of changes in dendritic spine density in a particular region of the brain under stress is due to the changes in BDNF there. The most likely cause of these changes is provided by the stress initiated release of steroids, which readily enter neurons and alter gene expression, for example that of BDNF. Of particular interest is how glucocorticoids and mineralocorticoids tend to have opposite effects on BDNF gene expression offering the possibility that differences in the distribution of their receptors and of their downstream effects might provide a basis for the differential transcription of the BDNF genes. Alternatively, differences in the extent of methylation and acetylation in the epigenetic control of BDNF transcription are possible in different parts of the brain following stress. Although present evidence points to changes in BDNF transcription being the major causal agent for the changes in spine density in different parts of the brain following stress, steroids have significant effects on downstream pathways from the TrkB receptor once it is acted upon by BDNF, including those that modulate the density of dendritic spines. Finally, although glucocorticoids play a canonical role in determining BDNF modulation of dendritic spines, recent studies have shown a role for corticotrophin releasing factor (CRF) in this regard. There is considerable improvement in the extent of changes in spine size and density in rodents with forebrain specific knockout of CRF receptor 1 (CRFR1) even when

  12. 电针上调慢性抑郁大鼠血清E2和BDNF及影响海马区BDNF表达的抗抑郁效果%Anti-depression effects of electroacupuncture through up-regulating serum E2 and BDNF and expression of BDNF in hippocampus in chronic depression rats

    Institute of Scientific and Technical Information of China (English)

    穆道周; 黄熙

    2015-01-01

    目的:探讨电针百会、内关和三阴交穴对慢性抑郁模型大鼠血清雌二醇(estradiol, E2)和脑源性神经营养因子(brain-derived neurotrophic factor, BDNF)水平及海马区BDNF表达的影响。方法:将30只雌性Wistar大鼠随机分为三组,包括正常对照组,模型组和电针组,每组10只。采用慢性中等程度不可预见性刺激(chronic unpredicted mild stress, CUMS,如冷水游泳、夹尾、电击足底等)结合孤养21 d造模。模型组和电针组大鼠每天随机应用9种不同的刺激结合孤养。造模结束后,电针组给予电针百会、内关、三阴交治疗,每天一次,共14 d;模型组给予同等程度束缚。血清 E2用放免法检测,血清 BDNF 用酶联免疫吸附试验法(enzyme-linked immunosorbent assay, ELISA)检测,海马BDNF的表达用免疫组化法。结果:应激结束后,与正常对照组比较,模型组和电针组糖水偏爱率显著下降(P<0.01),强迫游泳不动时间显著增加(P<0.01)。此外,电针显著减少了大鼠的抑郁样行为(P<0.01)。与正常对照组比较,模型组血清E2、BDNF水平及海马区BDNF的表达显著下降(P<0.01, P<0.01, P<0.05)。与模型组比较,电针组血清BDNF和海马区BDNF表达显著增加(P<0.05),血清E2水平增加但差异无显著性(P>0.05)。结论:E2和BDNF可能与慢性轻度不可预见性应激大鼠抑郁样行为有关。电针可能通过增加血清和海马BDNF的表达发挥抗抑郁作用。%Objective:To investigate the effects of electroacupuncture (EA) at acupoints Baihui (GV 20), Neiguan (PC 6) and Sanyinjiao (SP 6) on the levels of estradiol (E2) and brain-derived neurotrophic factor (BDNF) in serum, as well as the expression of BDNF in hippocampus in chronic depression rat models. Methods:Thirty female Wistar rats were randomly divided into three groups, including a normal control (NC) group, a model group and an EA group, 10 rats in each group. The depression

  13. BDNF-induced synaptic delivery of AMPAR subunits is differentially dependent on NMDA receptors and requires ERK.

    Science.gov (United States)

    Li, Wei; Keifer, Joyce

    2009-03-01

    Previous studies using an in vitro model of eyeblink classical conditioning in turtles suggest that increased numbers of synaptic AMPARs supports the acquisition and expression of conditioned responses (CRs). Brain-derived neurotrophic factor (BDNF) and its associated receptor tyrosine kinase, TrkB, is also required for acquisition of CRs. Bath application of BDNF alone induces synaptic delivery of GluR1- and GluR4-containing AMPARs that is blocked by coapplication of the receptor tyrosine kinase inhibitor K252a. The molecular mechanisms involved in BDNF-induced AMPAR trafficking remain largely unknown. The aim of this study was to determine whether BDNF-induced synaptic AMPAR incorporation utilizes similar cellular mechanisms as AMPAR trafficking that occurs during in vitro classical conditioning. Using pharmacological blockade and confocal imaging, the results show that synaptic delivery of GluR1 subunits during conditioning or BDNF application does not require activity of NMDARs but is mediated by extracellular signal-regulated kinase (ERK). In contrast, synaptic delivery of GluR4-containing AMPARs during both conditioning and BDNF application is NMDAR- as well as ERK-dependent. These findings indicate that BDNF application mimics AMPAR trafficking observed during conditioning by activation of some of the same intracellular signaling pathways and suggest that BDNF is a key signal transduction element in postsynaptic events that mediate conditioning.

  14. Epigenetic modification of hippocampal Bdnf DNA in adult rats in an animal model of post-traumatic stress disorder.

    Science.gov (United States)

    Roth, Tania L; Zoladz, Phillip R; Sweatt, J David; Diamond, David M

    2011-07-01

    Epigenetic alterations of the brain-derived neurotrophic factor (Bdnf) gene have been linked with memory, stress, and neuropsychiatric disorders. Here we examined whether there was a link between an established rat model of post-traumatic stress disorder (PTSD) and Bdnf DNA methylation. Adult male Sprague-Dawley rats were given psychosocial stress composed of two acute cat exposures in conjunction with 31 days of daily social instability. These manipulations have been shown previously to produce physiological and behavioral sequelae in rats that are comparable to symptoms observed in traumatized people with PTSD. We then assessed Bdnf DNA methylation patterns (at exon IV) and gene expression. We have found here that the psychosocial stress regimen significantly increased Bdnf DNA methylation in the dorsal hippocampus, with the most robust hypermethylation detected in the dorsal CA1 subregion. Conversely, the psychosocial stress regimen significantly decreased methylation in the ventral hippocampus (CA3). No changes in Bdnf DNA methylation were detected in the medial prefrontal cortex or basolateral amygdala. In addition, there were decreased levels of Bdnf mRNA in both the dorsal and ventral CA1. These results provide evidence that traumatic stress occurring in adulthood can induce CNS gene methylation, and specifically, support the hypothesis that epigenetic marking of the Bdnf gene may underlie hippocampal dysfunction in response to traumatic stress. Furthermore, this work provides support for the speculative notion that altered hippocampal Bdnf DNA methylation is a cellular mechanism underlying the persistent cognitive deficits which are prominent features of the pathophysiology of PTSD.

  15. The Influence of Exercise to the Brain - drived Neurotrophic Factor%运动对脑源性神经营养因子(BDNF)的影响

    Institute of Scientific and Technical Information of China (English)

    高自军; 秦爱华; 侯天德; 许世岩

    2006-01-01

    运动刺激可诱导脑源性神经营养因子(brain-drived neurotrophic factor BDNF)的基因表达上调,合成分泌增多;可促进脑损伤后的恢复、提高抑郁症的治疗效果、预防老年痴呆和增强记忆;对脑的健康有良好影响.

  16. Repeated Exposure to Sublethal Doses of the Organophosphorus Compound VX Activates BDNF Expression in Mouse Brain

    Science.gov (United States)

    2012-01-01

    cresyl/-4 H-1: 3: 2-benzodioxa- phosphorin-2-oxide (CBDP) on organophosphate poisoning and its therapy. Arch. Toxicol. 42, 207–216. French, S. J... organophosphates or other environmental insults, have a greater FIG. 4. Mice that received repeated exposure to low levels of VX (0.2 LD50 and 0.4 LD50...to neuro- behavioral deficits and neuropathology. Although exposure to organophosphates such as pesticides has been shown to affect the expression of

  17. Brain-Derived Neurotrophic Factor in Chronic Periodontitis

    Directory of Open Access Journals (Sweden)

    Jôice Dias Corrêa

    2014-01-01

    Full Text Available Brain-derived neurotrophic factor (BDNF is a member of the neurotrophic factor family. Outside the nervous system, BDNF has been shown to be expressed in various nonneural tissues, such as periodontal ligament, dental pulp, and odontoblasts. Although a role for BDNF in periodontal regeneration has been suggested, a function for BDNF in periodontal disease has not yet been studied. The aim of this study was to analyze the BDNF levels in periodontal tissues of patients with chronic periodontitis (CP and periodontally healthy controls (HC. All subjects were genotyped for the rs4923463 and rs6265 BDNF polymorphisms. Periodontal tissues were collected for ELISA, myeloperoxidase (MPO, and microscopic analysis from 28 CP patients and 29 HC subjects. BDNF levels were increased in CP patients compared to HC subjects. A negative correlation was observed when analyzing concentration of BDNF and IL-10 in inflamed periodontium. No differences in frequencies of BDNF genotypes between CP and HC subjects were observed. However, BDNF genotype GG was associated with increased levels of BDNF, TNF-α, and CXCL10 in CP patients. In conclusion, BDNF seems to be associated with periodontal disease process, but the specific role of BDNF still needs to be clarified.

  18. NPY modulates miR-30a-5p and BDNF in opposite direction in an in vitro model of Alzheimer disease: a possible role in neuroprotection?

    Science.gov (United States)

    Croce, Nicoletta; Gelfo, Francesca; Ciotti, Maria Teresa; Federici, Giorgio; Caltagirone, Carlo; Bernardini, Sergio; Angelucci, Francesco

    2013-04-01

    Using in vitro models of Alzheimer's disease (AD), we found that the toxic effects of amyloid beta 25-35 (Aβ(25-35)) on the neurotrophin brain-derived neurotrophic factor (BDNF) were counteracted by pre-incubation with neuropeptide Y (NPY), a neuropeptide expressed within the central nervous system. Nonetheless, the mechanism of action of NPY on BDNF neuronal production in the presence of Aβ is not known. BDNF expression might be directly regulated by microRNA (miRs), small non-coding DNA fragments that regulate the expression of target genes. Thus, there is the possibility that miRs alterations are present in AD-affected neurons and that NPY influences miR expression. To test this hypothesis, we exposed NPY-pretreated primary rat cortical neurons to Aβ(25-35) and measured miR-30a-5p (a member of the miR-30a family involved in BDNF tuning expression) and BDNF mRNA and protein expression after 24 and 48 h. Our results demonstrated that pre-treatment with NPY decreased miR-30a-5p expression and increased BDNF mRNA and protein expression at 24 and 48 h of incubation with Aβ. Therefore, this study demonstrates that NPY modulates BDNF and its regulating microRNA miR-30a-5p in opposite direction with a mechanism that possibly contributes to the neuroprotective effect of NPY in rat cortical neurons exposed to Aβ.

  19. Influence of Exercise on BDNF Expression in Rats Hippocampus%有氧运动对大鼠海马神经元BDNF表达的影响

    Institute of Scientific and Technical Information of China (English)

    杨尚明; 李红

    2012-01-01

    The purpose of this paper is to investigate the changes of brain-derived neurotropic factor(BDNF) expression in rats hippocampus after swimming and discussed the neurobiology mechanism of aerobic exercise promoting the brain healthy.And this investigation divided the rats into CG and SG(3SG,7SG,12SG),the expression of BDNF positivistic numbers in hippocampus CA1 in rats were observed with the dyeing method of SABC immunity organization chemistry.The result showed that there was BDNF expression at hippocampus,and the expression was mainly in the neuron.Compared with CG,BDNF expression in hippocampus of 7SG was increased significantly(P0.05),12SG was significantly increased individually(P0.01).In conclusion,the aerobic swimming could increase the BDNF expression and promote the brain nerve plasticity.%本文意在通过观察适宜游泳运动后大鼠海马脑源性神经营养因子(BDNF)表达的变化,探讨有氧运动促进大脑健康的神经生物学机制。研究将24只SD大鼠随机分为对照组和运动组,运动组又分为3,7,12天三个亚组。采用SABC免疫组化染色法观察分析海马CA1区神经元BDNF阳性表达的数量。结果表明CG大鼠海马有BDNF阳性细胞的蛋白表达,并以神经元表达为主。与CG相比,7SG大鼠海马CA1区BDNF阳性细胞数量增加达显著水平(P〈0.05),12SG大鼠海马CA1区BDNF阳性细胞数量增加达极显著水平(P〈0.01)。因此,适量的有氧运动可增加BDNF的表达,促进大脑神经可塑性。

  20. Effect of FK506 and cyclosporine A on the expression of BDNF, tyrosine kinase B and p75 neurotrophin receptors in astrocytes exposed to simulated ischemia in vitro.

    Science.gov (United States)

    Gabryel, Bozena; Bernacki, Jacek

    2009-07-01

    We investigated whether the immunosuppressive drugs, FK506 and cyclosporine A, increase BDNF protein and/or mRNA expression in ischemic astrocytes and if an increase could be related to changes in the nuclear expression of p-CREB, p-Erk1/2 and p-Akt. The influence of these immunosuppressants on protein and mRNA levels of TrkB and p75(NTR) receptors was also examined. On day 21, cultures of rat astrocytes were subjected to ischemic conditions simulated in vitro (combined oxygen glucose deprivation, OGD) for 8h and exposed to FK506 (10-1000nM) and cyclosporine A (0.25-10microM). FK506 and cyclosporine A (at 1000nM and 0.25microM, respectively) stimulated the expression and release of BDNF in cultured rat cerebral cortical astrocytes exposed to OGD. The immunosuppressants at these doses simultaneously increased p-CREB and p-Erk1/2 expression in the nuclear fraction of astrocytes. The results RT-PCR and Western blot analysis provided further evidence of a modulating influence of the drugs on the expression of trkB and p75(NTR) genes and their protein products in ischemic astrocytes.