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Sample records for huntingtin-mediated bdnf gene

  1. DNA Methylation of BDNF Gene in Schizophrenia

    PubMed Central

    Çöpoğlu, Ümit Sertan; İğci, Mehri; Bozgeyik, Esra; Kokaçya, M. Hanifi; İğci, Yusuf Ziya; Dokuyucu, Recep; Arı, Mustafa; Savaş, Haluk A.

    2016-01-01

    Background Although genetic factors are risk factors for schizophrenia, some environmental factors are thought to be required for the manifestation of disease. Epigenetic mechanisms regulate gene functions without causing a change in the nucleotide sequence of DNA. Brain-derived neurotrophic factor (BDNF) is a neurotrophin that regulates synaptic transmission and plasticity. It has been suggested that BDNF may play a role in the pathophysiology of schizophrenia. It is established that methylation status of the BDNF gene is associated with fear learning, memory, and stressful social interactions. In this study, we aimed to investigate the DNA methylation status of BDNF gene in patients with schizophrenia. Material/Methods The study included 49 patients (33 male and 16 female) with schizophrenia and 65 unrelated healthy controls (46 male and 19 female). Determination of methylation pattern of CpG islands was based on the principle that bisulfite treatment of DNA results in conversion of unmethylated cytosine residues into uracil, whereas methylated cytosine residues remain unmodified. Methylation-specific PCR was performed with primers specific for either methylated or unmethylated DNA. Results There was no significant difference in methylated or un-methylated status for BDNF promoters between schizophrenia patients and controls. The mean duration of illness was significantly lower in the hemi-methylated group compared to the non-methylated group for BDNF gene CpG island-1 in schizophrenia patients. Conclusions Although there were no differences in BDNF gene methylation status between schizophrenia patients and healthy controls, there was an association between duration of illness and DNA methylation. PMID:26851233

  2. DNA Methylation of BDNF Gene in Schizophrenia.

    PubMed

    Çöpoğlu, Ümit Sertan; Igci, Mehri; Bozgeyik, Esra; Kokaçya, M Hanifi; İğci, Yusuf Ziya; Dokuyucu, Recep; Ari, Mustafa; Savaş, Haluk A

    2016-02-06

    BACKGROUND Although genetic factors are risk factors for schizophrenia, some environmental factors are thought to be required for the manifestation of disease. Epigenetic mechanisms regulate gene functions without causing a change in the nucleotide sequence of DNA. Brain-derived neurotrophic factor (BDNF) is a neurotrophin that regulates synaptic transmission and plasticity. It has been suggested that BDNF may play a role in the pathophysiology of schizophrenia. It is established that methylation status of the BDNF gene is associated with fear learning, memory, and stressful social interactions. In this study, we aimed to investigate the DNA methylation status of BDNF gene in patients with schizophrenia. MATERIAL AND METHODS The study included 49 patients (33 male and 16 female) with schizophrenia and 65 unrelated healthy controls (46 male and 19 female). Determination of methylation pattern of CpG islands was based on the principle that bisulfite treatment of DNA results in conversion of unmethylated cytosine residues into uracil, whereas methylated cytosine residues remain unmodified. Methylation-specific PCR was performed with primers specific for either methylated or unmethylated DNA. RESULTS There was no significant difference in methylated or un-methylated status for BDNF promoters between schizophrenia patients and controls. The mean duration of illness was significantly lower in the hemi-methylated group compared to the non-methylated group for BDNF gene CpG island-1 in schizophrenia patients. CONCLUSIONS Although there were no differences in BDNF gene methylation status between schizophrenia patients and healthy controls, there was an association between duration of illness and DNA methylation.

  3. Epigenetic Regulation of BDNF Gene during Development and Diseases

    PubMed Central

    Chen, Kuan-Wei; Chen, Linyi

    2017-01-01

    Brain-derived neurotrophic factor (BDNF) is required for the development of the nervous system, proper cognitive function and memory formation. While aberrant expression of BDNF has been implicated in neurological disorders, the transcriptional regulation of BDNF remains to be elucidated. In response to different stimuli, BDNF expression can be initiated from different promoters. Several studies have suggested that the expression of BDNF is regulated by promoter methylation. An emerging theme points to the possibility that histone modifications at the BDNF promoters may link to the neurological pathology. Thus, understanding the epigenetic regulation at the BDNF promoters will shed light on future therapies for neurological disorders. The present review summarizes the current knowledge of histone modifications of the BDNF gene in neuronal diseases, as well as the developmental regulation of the BDNF gene based on data from the Encyclopedia of DNA Elements (ENCODE). PMID:28272318

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

    PubMed

    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.

  5. Systemic delivery of recombinant brain derived neurotrophic factor (BDNF) in the R6/2 mouse model of Huntington's disease.

    PubMed

    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.

  6. Systemic Delivery of Recombinant Brain Derived Neurotrophic Factor (BDNF) in the R6/2 Mouse Model of Huntington’s Disease

    PubMed Central

    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. PMID:23700454

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

    PubMed Central

    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

  8. BDNF gene effects on brain circuitry replicated in 455 twins.

    PubMed

    Chiang, Ming-Chang; Barysheva, Marina; Toga, Arthur W; Medland, Sarah E; Hansell, Narelle K; James, Michael R; McMahon, Katie L; de Zubicaray, Greig I; Martin, Nicholas G; Wright, Margaret J; Thompson, Paul M

    2011-03-15

    Brain-derived neurotrophic factor (BDNF) plays a key role in learning and memory, but its effects on the fiber architecture of the living brain are unknown. We genotyped 455 healthy adult twins and their non-twin siblings (188 males/267 females; age: 23.7±2.1 years, mean±SD) and scanned them with high angular resolution diffusion tensor imaging (DTI), to assess how the BDNF Val66Met polymorphism affects white matter microstructure. By applying genetic association analysis to every 3D point in the brain images, we found that the Val-BDNF genetic variant was associated with lower white matter integrity in the splenium of the corpus callosum, left optic radiation, inferior fronto-occipital fasciculus, and superior corona radiata. Normal BDNF variation influenced the association between subjects' performance intellectual ability (as measured by Object Assembly subtest) and fiber integrity (as measured by fractional anisotropy; FA) in the callosal splenium, and pons. BDNF gene may affect the intellectual performance by modulating the white matter development. This combination of genetic association analysis and large-scale diffusion imaging directly relates a specific gene to the fiber microstructure of the living brain and to human intelligence. Copyright © 2010 Elsevier Inc. All rights reserved.

  9. [Research on association of BDNF gene Val66Met polymorphism with efficacy of antidepressants and plasma BDNF level].

    PubMed

    Shen, Xinhua; Qian, Mincai; Yuan, Yonggui; Sun, Jushui; Zhong, Hua; Yang, Jianhong; Lin, Min; Li, Liang; Guan, Tiefeng; Shen, Zhongxia

    2014-04-01

    To assess the association of BDNF gene Val66Met polymorphism with efficacy of antidepressant treatment and plasma BDNF level. Two hundred and forty-nine ethnic Han Chinese patients with depression(study group), who have met the diagnostic criteria of DSM-IV, were prescribed with venlafaxine or paroxetine. Two hundred and two healthy individuals were recruited as the control group. General demographic information such as gender, age, educational status, occupation, and marriage status were collected. HAMD-17 was adopted as the primary rating tool to evaluate the severity of depression on the baseline and at the end of 1st, 2nd, 4th, 6th week of treatment. PCR-restriction fragment length polymorphism was applied to determine the Val66Met polymorphism of the BDNF gene in the two groups. Plasma BDNF concentration was measured with ELISA before and after 6 weeks of treatment. No significant differences have been found in HAMD scores and reduction of HAMD scores on the baseline and at the end of 1 st, 2nd, 4th, 6th weeks of treatment for each genotype. Nor were significant differences found in the Val66Met genotypes and allelic frequency between patients who achieved remission or not after 6 weeks' treatment as well as the healthy volunteers. The plasma BDNF level in depression patients was lower than that in healthy controls. The BDNF level has increased significantly after 6 weeks' treatment with both venlafaxine and paroxetine, but was still lower than the healthy controls. The BDNF level in the patients achieved remission who were treated with venlafaxine was similar to the normal controls, while those treated with paroxetine was still lower than normal controls. The BDNF level in patients who have not achieved remission was lower than normal controls. The BDNF level was not associated with the Val66Met polymorphism on the baseline and the end of 6th week. No association has been found between the efficacy of venlafaxine or paroxetine and the BDNF Val66Met

  10. An Intrastriatal Brain-Derived Neurotrophic Factor Infusion Restores Striatal Gene Expression in Bdnf Heterozygous Mice

    PubMed Central

    Saylor, Alicia J.; McGinty, Jacqueline F.

    2011-01-01

    Reduction in the amount of brain-derived neurotrophic factor (BDNF) in corticostriatal afferents is thought to contribute to the vulnerability of medium spiny striatal neurons in Huntington’s disease. In young Bdnf heterozygous (+/−) mice, striatal medium spiny neurons express less preprodynorphin, preproenkephalin, and D3 receptor mRNA than wildtype mice. Further, in aged Bdnf+/− mice, opioid, trkB receptor, and glutamic acid decarboxylase gene expression, and the number of dendritic spines on medium spiny neurons are more affected than in wildtype or younger Bdnf+/− mice. In this study, the possibility that intrastriatal infusions of BDNF would elevate gene expression in the striatum of Bdnf+/− mice was investigated. Wildtype and Bdnf+/− mice received a single, bilateral microinjection of BDNF or PBS into the dorsal striatum. Mice were sacrificed 24 hours later and semi-quantitative in situ hybridization histochemical analysis confirmed that preprodynorphin, preproenkephalin and D3 receptor mRNA was less in the caudate-putamen and nucleus accumbens core of Bdnf+/− mice than in wildtype mice. A BDNF infusion increased preprodynorphin mRNA in the caudate-putamen and NAc core of wildtype mice and restored preprodynorphin mRNA levels in the nucleus accumbens core of Bdnf+/− mice. BDNF also restored the gene expression of preproenkephalin in the caudate-putamen of Bdnf+/− mice to wildtype levels; however, preproenkephalin mRNA in the nucleus accumbens did not differ among groups. Furthermore, BDNF increased D3 receptor mRNA in the nucleus accumbens core of wildtype and Bdnf+/− mice. These results demonstrate that exogenous BDNF restores striatal opioid and D3R gene expression in mice with genetically reduced levels of endogenous BDNF. PMID:20938680

  11. Amphetamine-induced locomotion and gene expression are altered in BDNF heterozygous mice

    PubMed Central

    Saylor, Alicia J.; McGinty, Jacqueline F.

    2008-01-01

    Administration of amphetamine over-stimulates medium spiny neurons by releasing dopamine and glutamate from afferents in the striatum. However, these afferents also release brain-derived neurotrophic factor (BDNF) that protects striatal medium spiny neurons from over-stimulation. Intriguingly, all three neurochemicals increase opioid gene expression in medium spiny neurons. In contrast, striatal opioid expression is less in naïve BDNF heterozygous (BDNF+/-) versus wildtype mice. This study was designed to determine whether partial genetic depletion of BDNF influences the behavioral and molecular response to an acute amphetamine injection. An acute injection of amphetamine (5 mg/kg, i.p.) or saline was administered to wildtype and BDNF+/- mice. Wildtype and BDNF+/- mice exhibited similar locomotor activity during habituation whereas BDNF+/- mice exhibited more prolonged locomotor activation during the third hour after injection of amphetamine. Three hours after amphetamine injection, there was an increase of preprodynorphin mRNA in the caudate putamen and nucleus accumbens and D3R mRNA levels were increased in the nucleus accumbens of BDNF+/- and wildtype mice. Striatal/cortical trkB and BDNF, and mesencephalic TH mRNA levels were only increased in wildtype mice. These results indicate that BDNF modifies the locomotor responses of mice to acute amphetamine and differentially regulates amphetamine-induced gene expression. PMID:18681898

  12. Tyrosine triple mutated AAV2-BDNF gene therapy in a rat model of transient IOP elevation

    PubMed Central

    Igarashi, Tsutomu; Kobayashi, Maika; Kameya, Shuhei; Fujimoto, Chiaki; Nakamoto, Kenji; Takahashi, Hisatomo; Igarashi, Toru; Miyake, Noriko; Iijima, Osamu; Hirai, Yukihiko; Shimada, Takashi; Okada, Takashi; Takahashi, Hiroshi

    2016-01-01

    Purpose We examined the neuroprotective effects of exogenous brain-derived neurotrophic factor (BDNF), which provides protection to retinal ganglion cells (RGCs) in rodents, in a model of transient intraocular pressure (IOP) elevation using a mutant (triple Y-F) self-complementary adeno-associated virus type 2 vector encoding BDNF (tm-scAAV2-BDNF). Methods The tm-scAAV2-BDNF or control vector encoding green fluorescent protein (GFP; tm-scAAV2-GFP) was intravitreally administered to rats, which were then divided into four groups: control, ischemia/reperfusion (I/R) injury only, I/R injury with tm-scAAV2-GFP, and tm-scAAV2-BDNF. I/R injury was then induced by transiently increasing IOP, after which the rats were euthanized to measure the inner retinal thickness and cell counts in the RGC layer. Results Intravitreous injection of tm-scAAV2-BDNF resulted in high levels of BDNF expression in the neural retina. Histological analysis showed that the inner retinal thickness and cell numbers in the RGC layer were preserved after transient IOP elevation in eyes treated with tm-scAAV2-BDNF but not in the other I/R groups. Significantly reduced glial fibrillary acidic protein (GFAP) immunostaining after I/R injury in the rats that received tm-scAAV2-BDNF indicated reduced retinal stress, and electroretinogram (ERG) analysis confirmed preservation of retinal function in the tm-scAAV2-BDNF group. Conclusions These results demonstrate the feasibility and effectiveness of neuroprotective gene therapy using tm-scAAV2-BDNF to protect the inner retina from transiently high intraocular pressure. An in vivo gene therapeutic approach to the clinical management of retinal diseases in conditions such as glaucoma, retinal artery occlusion, hypertensive retinopathy, and diabetic retinopathy thus appears feasible. PMID:27440998

  13. Higher brain BDNF gene expression is associated with slower cognitive decline in older adults

    PubMed Central

    Yu, Lei; Boyle, Patricia A.; Schneider, Julie A.; De Jager, Philip L.; Bennett, David A.

    2016-01-01

    Objectives: We tested whether brain-derived neurotrophic factor (BDNF) gene expression levels are associated with cognitive decline in older adults. Methods: Five hundred thirty-five older participants underwent annual cognitive assessments and brain autopsy at death. BDNF gene expression was measured in the dorsolateral prefrontal cortex. Linear mixed models were used to examine whether BDNF expression was associated with cognitive decline adjusting for age, sex, and education. An interaction term was added to determine whether this association varied with clinical diagnosis proximate to death (no cognitive impairment, mild cognitive impairment, or dementia). Finally, we examined the extent to which the association of Alzheimer disease (AD) pathology with cognitive decline varied by BDNF expression. Results: Higher brain BDNF expression was associated with slower cognitive decline (p < 0.001); cognitive decline was about 50% slower with the 90th percentile BDNF expression vs 10th. This association was strongest in individuals with dementia. The level of BDNF expression was lower in individuals with pathologic AD (p = 0.006), but was not associated with macroscopic infarcts, Lewy body disease, or hippocampal sclerosis. BDNF expression remained associated with cognitive decline in a model adjusting for age, sex, education, and neuropathologies (p < 0.001). Furthermore, the effect of AD pathology on cognitive decline varied by BDNF expression such that the effect was strongest for high levels of AD pathology (p = 0.015); thus, in individuals with high AD pathology (90th percentile), cognitive decline was about 40% slower with the 90th percentile BDNF expression vs 10th. Conclusions: Higher brain BDNF expression is associated with slower cognitive decline and may also reduce the deleterious effects of AD pathology on cognitive decline. PMID:26819457

  14. Higher brain BDNF gene expression is associated with slower cognitive decline in older adults.

    PubMed

    Buchman, Aron S; Yu, Lei; Boyle, Patricia A; Schneider, Julie A; De Jager, Philip L; Bennett, David A

    2016-02-23

    We tested whether brain-derived neurotrophic factor (BDNF) gene expression levels are associated with cognitive decline in older adults. Five hundred thirty-five older participants underwent annual cognitive assessments and brain autopsy at death. BDNF gene expression was measured in the dorsolateral prefrontal cortex. Linear mixed models were used to examine whether BDNF expression was associated with cognitive decline adjusting for age, sex, and education. An interaction term was added to determine whether this association varied with clinical diagnosis proximate to death (no cognitive impairment, mild cognitive impairment, or dementia). Finally, we examined the extent to which the association of Alzheimer disease (AD) pathology with cognitive decline varied by BDNF expression. Higher brain BDNF expression was associated with slower cognitive decline (p < 0.001); cognitive decline was about 50% slower with the 90th percentile BDNF expression vs 10th. This association was strongest in individuals with dementia. The level of BDNF expression was lower in individuals with pathologic AD (p = 0.006), but was not associated with macroscopic infarcts, Lewy body disease, or hippocampal sclerosis. BDNF expression remained associated with cognitive decline in a model adjusting for age, sex, education, and neuropathologies (p < 0.001). Furthermore, the effect of AD pathology on cognitive decline varied by BDNF expression such that the effect was strongest for high levels of AD pathology (p = 0.015); thus, in individuals with high AD pathology (90th percentile), cognitive decline was about 40% slower with the 90th percentile BDNF expression vs 10th. Higher brain BDNF expression is associated with slower cognitive decline and may also reduce the deleterious effects of AD pathology on cognitive decline. © 2016 American Academy of Neurology.

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

    PubMed

    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.

  16. The Effects of BDNF Val66Met Gene Polymorphism on Serum BDNF and Cognitive Function in Methamphetamine-Dependent Patients and Normal Controls: A Case-Control Study.

    PubMed

    Su, Hang; Tao, Jingyan; Zhang, Jie; Xie, Ying; Wang, Yue; Zhang, Yu; Han, Bin; Lu, Yuling; Sun, Haiwei; Wei, Youdan; Zou, Shengzhen; Wu, Wenxiu; Zhang, Jiajia; Xu, Ke; Zhang, Xiangyang; He, Jincai

    2015-10-01

    Studies suggest that a functional polymorphism of the brain-derived neurotrophic factor gene (BDNF Val66Met) may contribute to methamphetamine dependence. We hypothesized that this polymorphism had a role in cognitive deficits in methamphetamine-dependent patients and in the relationship of serum BDNF with cognitive impairments. We conducted a case-control study by assessing 194 methamphetamine-dependent patients and 378 healthy volunteers without history of drug use on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the presence of the BDNF Val66Met polymorphism and serum BDNF levels. We showed no significant differences in genotype and allele distributions between the methamphetamine-dependent patients and controls. Some aspects of cognitive function significantly differed in the 2 groups. The serum BDNF levels in methamphetamine-dependent patients were significantly higher than those of the healthy controls. In the patients, partial correlation analysis showed a significant positive correlation between serum BDNF and the delayed memory index score. The RBANS scores showed statistically significant BDNF level × genotype interaction. Further regression analyses showed a significant positive association between BDNF levels and the RBANS total score, immediate memory or attention index among Val homozygote patients, whereas a significant negative association of BDNF levels with the RBANS total score, visuospatial/constructional, or language index was found among Met/Val heterozygous patients. We demonstrated significant impairment on some aspects of cognitive function and increased BDNF levels in methamphetamine-dependent patients as well as genotypic differences in the relationships between BDNF levels and RBANS scores on the BDNF Val66Met polymorphism only in these patients.

  17. Cochlear implants and ex vivo BDNF gene therapy protect spiral ganglion neurons.

    PubMed

    Rejali, Darius; Lee, Valerie A; Abrashkin, Karen A; Humayun, Nousheen; Swiderski, Donald L; Raphael, Yehoash

    2007-06-01

    Spiral ganglion neurons often degenerate in the deaf ear, compromising the function of cochlear implants. Cochlear implant function can be improved by good preservation of the spiral ganglion neurons, which are the target of electrical stimulation by the implant. Brain derived neurotrophic factor (BDNF) has previously been shown to enhance spiral ganglion survival in experimentally deafened ears. Providing enhanced levels of BDNF in human ears may be accomplished by one of several different methods. The goal of these experiments was to test a modified design of the cochlear implant electrode that includes a coating of fibroblast cells transduced by a viral vector with a BDNF gene insert. To accomplish this type of ex vivo gene transfer, we transduced guinea pig fibroblasts with an adenovirus with a BDNF gene cassette insert, and determined that these cells secreted BDNF. We then attached BDNF-secreting cells to the cochlear implant electrode via an agarose gel, and implanted the electrode in the scala tympani. We determined that the BDNF expressing electrodes were able to preserve significantly more spiral ganglion neurons in the basal turns of the cochlea after 48 days of implantation when compared to control electrodes. This protective effect decreased in the higher cochlear turns. The data demonstrate the feasibility of combining cochlear implant therapy with ex vivo gene transfer for enhancing spiral ganglion neuron survival.

  18. Epigenetic alterations of the BDNF gene in combat-related post-traumatic stress disorder.

    PubMed

    Kim, T Y; Kim, S J; Chung, H G; Choi, J H; Kim, S H; Kang, J I

    2017-02-01

    Brain-derived neurotrophic factor (BDNF) plays a crucial role in modulating resilience and vulnerability to stress. The aim of this study was to investigate whether epigenetic regulation of the BDNF gene is a biomarker of post-traumatic stress disorder (PTSD) development among veterans exposed to combat in the Vietnam War. Using the Clinician-Administered PTSD Scale, combat veterans were grouped into those with (n = 126) and without (n = 122) PTSD. DNA methylation levels at four CpG sites within the BDNF promoter I region were quantified in the peripheral blood using pyrosequencing. The effects of BDNF DNA methylation levels and clinical variables on the diagnosis of PTSD were tested using binary logistic regression analysis. Subjects with PTSD showed a higher DNA methylation of four CpG sites at the BDNF promoter compared with those without PTSD. High methylation levels at the BDNF promoter CpG site, high combat exposure, and alcohol problems were significantly associated with PTSD diagnosis. This study demonstrated an association between higher DNA methylation of the BDNF promoter and PTSD diagnosis in combat-exposed individuals. Our findings suggest that altered BDNF methylation may be a valuable biomarker of PTSD after trauma exposure. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. The interaction of BDNF and NTRK2 gene increases the susceptibility of paranoid schizophrenia.

    PubMed

    Lin, Zheng; Su, Yousong; Zhang, Chengfang; Xing, Mengjuan; Ding, Wenhua; Liao, Liwei; Guan, Yangtai; Li, Zezhi; Cui, Donghong

    2013-01-01

    The association between BDNF gene functional Val66Met polymorphism rs6265 and the schizophrenia is far from being consistent. In addition to the heterogeneous in schizophrenia per se leading to the inconsistent results, the interaction among multi-genes is probably playing the main role in the pathogenesis of schizophrenia, but not a single gene. Neurotrophic tyrosine kinase receptor 2 (NTRK2) is the high-affinity receptor of BDNF, and was reported to be associated with mood disorders, though no literature reported the association with schizophrenia. Thus, in the present study, total 402 patients with paranoid schizophrenia (the most common subtype of schizophrenia) and matched 406 healthy controls were recruited to investigate the role of rs6265 in BDNF, three polymorphisms in NTRK2 gene (rs1387923, rs2769605 and rs1565445) and their interaction in the susceptibility to paranoid schizophrenia in a Chinese Han population. We did not observe significant differences in allele and genotype frequencies between patients and healthy controls for all four polymorphisms separately. The haplotype analysis also showed no association between haplotype of NTRK2 genes (rs1387923, rs2769605, and rs1565445) and paranoid schizophrenia. However, we found the association between the interaction of BDNF and NTRK2 with paranoid schizophrenia by using the MDR method followed by conventional statistical analysis. The best gene-gene interaction model was a three-locus model (BDNF rs6265, NTRK2 rs1387923 and NTRK2 rs2769605), in which one low-risk and three high-risk four-locus genotype combinations were identified. Our findings implied that single polymorphism of rs6265 rs1387923, rs2769605, and rs1565445 in BDNF and NTRK2 were not associated with the development of paranoid schizophrenia in a Han population, however, the interaction of BDNF and NTRK2 genes polymorphisms (BDNF-rs6265, NTRK2-rs1387923 and NTRK2-rs2769605) may be involved in the susceptibility to paranoid schizophrenia.

  20. AAV1/2-mediated BDNF gene therapy in a transgenic rat model of Huntington's disease.

    PubMed

    Connor, B; Sun, Y; von Hieber, D; Tang, S K; Jones, K S; Maucksch, C

    2016-03-01

    Reduced expression and disrupted corticostriatal transportation of brain-derived neurotrophic factor (BDNF) is proposed to contribute to the selective vulnerability of medium spiny striatal projection neurons (MSNs) in Huntington's disease (HD). We have previously demonstrated that BDNF overexpression in the quinolinic acid lesioned rat striatum attenuates motor impairment and reduces the extent of MSN cell loss. To further investigate the potential therapeutic properties of BDNF for HD, the current study examines the effect of bilateral AAV1/2-mediated BDNF expression in the striatum of a transgenic rat model of HD. Transfer of the BDNF gene to striatal neurons using an AAV1/2 serotype vector enhanced BDNF protein levels in the striatum. Bilateral BDNF expression attenuated the impairment of both motor and cognitive function when compared with AAV1/2-vehicle- or YFP-treated transgenic HD rats. Interestingly, a gender effect was apparent with female transgenic HD rats exhibiting less functional impairment than males. Quantification of NeuN and DARRP32 immunoreactivity and striatal volume revealed limited disease phenotype between wild type and transgenic HD animals. However, AAV1/2-BDNF-treated transgenic HD rats showed evidence of greater striatal volume and increased NeuN+ cell numbers compared with wild-type vehicle- and AAV1/2-vehicle- or YFP-treated transgenic HD rats. We propose BDNF holds considerable therapeutic potential for alleviating behavioral dysfunction and neuronal degeneration in HD, with further work required to examine the role of BDNF-TrkB signaling and the preservation of axonal and synaptic function.

  1. Long-lasting regulation of hippocampal Bdnf gene transcription after contextual fear conditioning

    PubMed Central

    Mizuno, K.; Dempster, E.; Mill, J.; Giese, K.P.

    2014-01-01

    Long-term memory formation requires de novo protein synthesis and gene transcription. During contextual long-term memory formation brain-derived neurotrophic factor (BDNF) gene expression changes in conjunction with alterations of DNA methylation in the Bdnf gene. However, little is known about the molecular mechanisms underlying the maintenance and persistence of contextual long-term memory. Here, we examined the transcription of specific Bdnf exons in the hippocampus for long periods after contextual fear conditioning. We found changes in transcription lasting for at least 24 hours after contextual fear conditioning, with some sex-specific effects. In addition, hypomethylation at a CpG site in CpG island 2 located at the end of Bdnf exon III sequence was detected at 0.5 h and maintained for up to 24 h after contextual fear conditioning. The identification of these long-lasting changes in transcription and DNA methylation at the Bdnf gene suggests that BDNF might have a role for storage of contextual long-term memory in the hippocampus. PMID:22574690

  2. Response to psychotherapy in borderline personality disorder and methylation status of the BDNF gene

    PubMed Central

    Perroud, N; Salzmann, A; Prada, P; Nicastro, R; Hoeppli, M-E; Furrer, S; Ardu, S; Krejci, I; Karege, F; Malafosse, A

    2013-01-01

    Downregulation of brain-derived neurotrophic factor (BDNF) gene expression with corresponding increased methylation at specific promoters has been associated with stressful experiences in early life and may explain later adulthood psychopathology. We measured the percentage of methylation at BDNF CpG exons I and IV as well as plasma BDNF protein levels in 115 subjects with borderline personality disorder (BPD) and 52 controls. BPD subjects then underwent a 4-week course of intensive dialectical behavior therapy (I-DBT). BDNF methylation status and protein levels were re-assessed at the end of treatment. BPD subjects had significantly higher methylation status in both CpG regions than controls. In addition, the higher the number of childhood trauma, the higher was the methylation status. In BPD subjects, BDNF methylation significantly increased after I-DBT. Nonresponders accounted for the majority of this increase, whereas responders showed a decrease in methylation status over time. Accordingly, the changes in methylation status over time were significantly associated with changes in depression scores, hopelessness scores and impulsivity. No association was found between protein levels and BDNF methylation status. We here found a relationship between child maltreatment and higher DNA methylation of BDNF. These results moreover support the idea that these epigenetic marks may be changed through psychotherapeutic approaches and that these changes underline changes in cognitive functions. PMID:23422958

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

    PubMed

    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.

  4. Promoter Methylation and BDNF and DAT1 Gene Expression Profiles in Patients with Drug Addiction.

    PubMed

    Kordi-Tamandani, Dor Mohammad; Tajoddini, Shahrad; Salimi, Farzaneh

    2015-01-01

    Drug addiction is a brain disorder that has negative consequences for individuals and society. Addictions are chronic relapsing diseases of the brain that are caused by direct drug-induced effects and persevering neuroadaptations at the epigenetic, neuropeptide and neurotransmitter levels. Because the dopaminergic system has a significant role in drug abuse, the purpose of this study was to analyze the methylation and expression profile of brain-derived neurotrophic factor (BDNF) and dopamine transporter (DAT1) genes in individuals with drug addiction. BDNF and DAT1 promoter methylation were investigated with a methylation-specific polymerase chain reaction (PCR) technique in blood samples from 75 individuals with drug addiction and 65 healthy controls. The expression levels of BDNF and DAT1 were assessed in 12 mRNA samples from the blood of patients and compared to the samples of healthy controls (n = 12) with real-time quantitative reverse transcription PCR. No significant differences were found in the methylation of BDNF and DAT1 between patients and controls, but the relative levels of expression of BDNF and DAT1 mRNA differed significantly in the patients compared to controls (p < 0.0001). These results showed that the methylation status of the BDNF and DAT1 genes had no significant function in the processes of drug addiction.

  5. A Jacob/Nsmf Gene Knockout Results in Hippocampal Dysplasia and Impaired BDNF Signaling in Dendritogenesis

    PubMed Central

    Schumacher, Anne; Butnaru, Ioana; Macharadze, Tamar; Gomes, Guilherme M.; Yuanxiang, PingAn; Bayraktar, Gonca; Rodenstein, Carolin; Geiseler, Carolin; Kolodziej, Angela; Lopez-Rojas, Jeffrey; Montag, Dirk; Angenstein, Frank; Bär, Julia; D’Hanis, Wolfgang; Roskoden, Thomas; Mikhaylova, Marina; Budinger, Eike; Ohl, Frank W.; Stork, Oliver; Zenclussen, Ana C.; Karpova, Anna; Schwegler, Herbert; Kreutz, Michael R.

    2016-01-01

    Jacob, the protein encoded by the Nsmf gene, is involved in synapto-nuclear signaling and docks an N-Methyl-D-Aspartate receptor (NMDAR)-derived signalosome to nuclear target sites like the transcription factor cAMP-response-element-binding protein (CREB). Several reports indicate that mutations in NSMF are related to Kallmann syndrome (KS), a neurodevelopmental disorder characterized by idiopathic hypogonadotropic hypogonadism (IHH) associated with anosmia or hyposmia. It has also been reported that a protein knockdown results in migration deficits of Gonadotropin-releasing hormone (GnRH) positive neurons from the olfactory bulb to the hypothalamus during early neuronal development. Here we show that mice that are constitutively deficient for the Nsmf gene do not present phenotypic characteristics related to KS. Instead, these mice exhibit hippocampal dysplasia with a reduced number of synapses and simplification of dendrites, reduced hippocampal long-term potentiation (LTP) at CA1 synapses and deficits in hippocampus-dependent learning. Brain-derived neurotrophic factor (BDNF) activation of CREB-activated gene expression plays a documented role in hippocampal CA1 synapse and dendrite formation. We found that BDNF induces the nuclear translocation of Jacob in an NMDAR-dependent manner in early development, which results in increased phosphorylation of CREB and enhanced CREB-dependent Bdnf gene transcription. Nsmf knockout (ko) mice show reduced hippocampal Bdnf mRNA and protein levels as well as reduced pCREB levels during dendritogenesis. Moreover, BDNF application can rescue the morphological deficits in hippocampal pyramidal neurons devoid of Jacob. Taken together, the data suggest that the absence of Jacob in early development interrupts a positive feedback loop between BDNF signaling, subsequent nuclear import of Jacob, activation of CREB and enhanced Bdnf gene transcription, ultimately leading to hippocampal dysplasia. PMID:26977770

  6. A Jacob/Nsmf Gene Knockout Results in Hippocampal Dysplasia and Impaired BDNF Signaling in Dendritogenesis.

    PubMed

    Spilker, Christina; Nullmeier, Sven; Grochowska, Katarzyna M; Schumacher, Anne; Butnaru, Ioana; Macharadze, Tamar; Gomes, Guilherme M; Yuanxiang, PingAn; Bayraktar, Gonca; Rodenstein, Carolin; Geiseler, Carolin; Kolodziej, Angela; Lopez-Rojas, Jeffrey; Montag, Dirk; Angenstein, Frank; Bär, Julia; D'Hanis, Wolfgang; Roskoden, Thomas; Mikhaylova, Marina; Budinger, Eike; Ohl, Frank W; Stork, Oliver; Zenclussen, Ana C; Karpova, Anna; Schwegler, Herbert; Kreutz, Michael R

    2016-03-01

    Jacob, the protein encoded by the Nsmf gene, is involved in synapto-nuclear signaling and docks an N-Methyl-D-Aspartate receptor (NMDAR)-derived signalosome to nuclear target sites like the transcription factor cAMP-response-element-binding protein (CREB). Several reports indicate that mutations in NSMF are related to Kallmann syndrome (KS), a neurodevelopmental disorder characterized by idiopathic hypogonadotropic hypogonadism (IHH) associated with anosmia or hyposmia. It has also been reported that a protein knockdown results in migration deficits of Gonadotropin-releasing hormone (GnRH) positive neurons from the olfactory bulb to the hypothalamus during early neuronal development. Here we show that mice that are constitutively deficient for the Nsmf gene do not present phenotypic characteristics related to KS. Instead, these mice exhibit hippocampal dysplasia with a reduced number of synapses and simplification of dendrites, reduced hippocampal long-term potentiation (LTP) at CA1 synapses and deficits in hippocampus-dependent learning. Brain-derived neurotrophic factor (BDNF) activation of CREB-activated gene expression plays a documented role in hippocampal CA1 synapse and dendrite formation. We found that BDNF induces the nuclear translocation of Jacob in an NMDAR-dependent manner in early development, which results in increased phosphorylation of CREB and enhanced CREB-dependent Bdnf gene transcription. Nsmf knockout (ko) mice show reduced hippocampal Bdnf mRNA and protein levels as well as reduced pCREB levels during dendritogenesis. Moreover, BDNF application can rescue the morphological deficits in hippocampal pyramidal neurons devoid of Jacob. Taken together, the data suggest that the absence of Jacob in early development interrupts a positive feedback loop between BDNF signaling, subsequent nuclear import of Jacob, activation of CREB and enhanced Bdnf gene transcription, ultimately leading to hippocampal dysplasia.

  7. Genomic Organization and Identification of Promoter Regions for the BDNF Gene in the Pond Turtle Trachemys scripta elegans

    PubMed Central

    Zheng, Zhaoqing; Keifer, Joyce

    2014-01-01

    Brain-derived neurotrophic factor (BDNF) is an important regulator of neuronal development and synaptic function. The BDNF gene undergoes significant activity-dependent regulation during learning. Here, we identified the BDNF promoter regions, transcription start sites, and potential regulatory sequences for BDNF exons I–III that may contribute to activity-dependent gene and protein expression in the pond turtle Trachemys scripta elegans (tBDNF). By using transfection of BDNF promoter/luciferase plasmid constructs into human neuroblastoma SHSY5Y cells and mouse embryonic fibroblast NIH3T3 cells, we identified the basal regulatory activity of promoter sequences located upstream of each tBDNF exon, designated as pBDNFI–III. Further, through chromatin immunoprecipitation (ChIP) assays, we detected CREB binding directly to exon I and exon III promoters, while BHLHB2, but not CREB, binds within the exon II promoter. Elucidation of the promoter regions and regulatory protein binding sites in the tBDNF gene is essential for understanding the regulatory mechanisms that control tBDNF gene expression. PMID:24443176

  8. Interaction Effects of BDNF and COMT Genes on Resting-State Brain Activity and Working Memory

    PubMed Central

    Chen, Wen; Chen, Chunhui; Xia, Mingrui; Wu, Karen; Chen, Chuansheng; He, Qinghua; Xue, Gui; Wang, Wenjing; He, Yong; Dong, Qi

    2016-01-01

    Catechol-O-methyltransferase (COMT) and brain-derived neurotrophic factor (BDNF) genes have been found to interactively influence working memory (WM) as well as brain activation during WM tasks. However, whether the two genes have interactive effects on resting-state activities of the brain and whether these spontaneous activations correlate with WM are still unknown. This study included behavioral data from WM tasks and genetic data (COMT rs4680 and BDNF Val66Met) from 417 healthy Chinese adults and resting-state fMRI data from 298 of them. Significant interactive effects of BDNF and COMT were found for WM performance as well as for resting-state regional homogeneity (ReHo) in WM-related brain areas, including the left medial frontal gyrus (lMeFG), left superior frontal gyrus (lSFG), right superior and medial frontal gyrus (rSMFG), right medial orbitofrontal gyrus (rMOFG), right middle frontal gyrus (rMFG), precuneus, bilateral superior temporal gyrus, left superior occipital gyrus, right middle occipital gyrus, and right inferior parietal lobule. Simple effects analyses showed that compared to other genotypes, subjects with COMT-VV/BDNF-VV had higher WM and lower ReHo in all five frontal brain areas. The results supported the hypothesis that COMT and BDNF polymorphisms influence WM performance and spontaneous brain activity (i.e., ReHo). PMID:27853425

  9. MicroRNA-322 protects hypoxia-induced apoptosis in cardiomyocytes via BDNF gene

    PubMed Central

    Yang, Liguo; Song, Shigang; Lv, Hang

    2016-01-01

    Background: Cardiomyocytes apoptosis under hypoxia condition contributes significantly to various cardiovascular diseases. In this study, we investigated the role of microRNA-322 (miR-322) in regulating hypoxia-induced apoptosis in neonatal murine cardiomyocytes in vitro. Method: Cardiomyocytes of C57BL/6J mice were treated with hypoxia condition in vitro. Cardiomyocyte apoptosis was measured by TUNEL assay. Gene expression pattern of miR-322 was measured by qRT-PCR. Stable downregulation of miR-322 in cardiomyocytes were achieved by lentiviral transduction, and the effect of miR-322 downregulation on hypoxia-induced cardiomyocyte apoptosis was investigated. Possible regulation of miR-322 on its downstream target gene, brain derived neurotrophic factor (BDNF) was investigated in cardiomyocytes. BDNF was then genetically silenced by siRNA to evaluate its role in miR-137 mediated cardiomyocyte apoptosis protection under hypoxia condition. Results: Under hypoxia condition, significant apoptosis was induced and miR-322 was significantly upregulated in cardiomyocytes in vitro. Through lentiviral transduction, miR-322 was efficiently knocked down in cardiomyocytes. Downregulation of miR-322 protected hypoxia-induced cardiomyocyte apoptosis. Luciferase assay showed BDNF was the target gene of miR-322. QRT-PCR showed BDNF expression was associated with miR-322 regulation on hypoxia-induced cardiomyocyte apoptosis. Silencing BDNF in cardiomyocyte through siRNA transfection reversed the protective effect of miR-322 downregulation on hypoxia-induced apoptosis. Conclusion: Our study revealed that miR-322, in association with BDNF, played important role in regulating hypoxia-induced apoptosis in cardiomyocyte. PMID:27398164

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

    PubMed

    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.

  11. Ethanol-induced epigenetic regulations at the Bdnf gene in C57BL/6J mice.

    PubMed

    Stragier, E; Massart, R; Salery, M; Hamon, M; Geny, D; Martin, V; Boulle, F; Lanfumey, L

    2015-03-01

    High ethanol intake is well known to induce both anxiolytic and anxiogenic effects, in correlation with chromatin remodeling in the amygdaloid brain region and deficits in cell proliferation and survival in the hippocampus of rodents. Whether only moderate but chronic ethanol intake in C57BL/6J mice could also have an impact on chromatin remodeling and neuroplasticity was addressed here. Chronic ethanol consumption in a free choice paradigm was found to induce marked changes in the expression of genes implicated in neural development and histone post-translational modifications in the mouse hippocampus. Transcripts encoding neural bHLH activators and those from Bdnf exons II, III and VI were upregulated, whereas those from Bdnf exon VIII and Hdacs were downregulated by ethanol compared with water consumption. These ethanol-induced changes were associated with enrichment in both acetylated H3 at Bdnf promoter PVI and trimethylated H3 at PII and PIII. Conversely, acetylated H3 at PIII and PVIII and trimethylated H3 at PVIII were decreased in ethanol-exposed mice. In parallel, hippocampal brain-derived neurotrophic factor (BDNF) levels and TrkB-mediated neurogenesis in the dentate gyrus were significantly enhanced by ethanol consumption. These results suggest that, in C57BL/6J mice, chronic and moderate ethanol intake produces marked epigenetic changes underlying BDNF overexpression and downstream hippocampal neurogenesis.

  12. Integrating Epigenomic Elements and GWASs Identifies BDNF Gene Affecting Bone Mineral Density and Osteoporotic Fracture Risk

    PubMed Central

    Guo, Yan; Dong, Shan-Shan; Chen, Xiao-Feng; Jing, Ying-Aisha; Yang, Man; Yan, Han; Shen, Hui; Chen, Xiang-Ding; Tan, Li-Jun; Tian, Qing; Deng, Hong-Wen; Yang, Tie-Lin

    2016-01-01

    To identify susceptibility genes for osteoporosis, we conducted an integrative analysis that combined epigenomic elements and previous genome-wide association studies (GWASs) data, followed by validation at population and functional levels, which could identify common regulatory elements and predict new susceptibility genes that are biologically meaningful to osteoporosis. By this approach, we found a set of distinct epigenomic elements significantly enriched or depleted in the promoters of osteoporosis-associated genes, including 4 transcription factor binding sites, 27 histone marks, and 21 chromatin states segmentation types. Using these epigenomic marks, we performed reverse prediction analysis to prioritize the discovery of new candidate genes. Functional enrichment analysis of all the prioritized genes revealed several key osteoporosis related pathways, including Wnt signaling. Genes with high priority were further subjected to validation using available GWASs datasets. Three genes were significantly associated with spine bone mineral density, including BDNF, PDE4D, and SATB2, which all closely related to bone metabolism. The most significant gene BDNF was also associated with osteoporotic fractures. RNA interference revealed that BDNF knockdown can suppress osteoblast differentiation. Our results demonstrated that epigenomic data could be used to indicate common epigenomic marks to discover additional loci with biological functions for osteoporosis. PMID:27465306

  13. Integrating Epigenomic Elements and GWASs Identifies BDNF Gene Affecting Bone Mineral Density and Osteoporotic Fracture Risk.

    PubMed

    Guo, Yan; Dong, Shan-Shan; Chen, Xiao-Feng; Jing, Ying-Aisha; Yang, Man; Yan, Han; Shen, Hui; Chen, Xiang-Ding; Tan, Li-Jun; Tian, Qing; Deng, Hong-Wen; Yang, Tie-Lin

    2016-07-28

    To identify susceptibility genes for osteoporosis, we conducted an integrative analysis that combined epigenomic elements and previous genome-wide association studies (GWASs) data, followed by validation at population and functional levels, which could identify common regulatory elements and predict new susceptibility genes that are biologically meaningful to osteoporosis. By this approach, we found a set of distinct epigenomic elements significantly enriched or depleted in the promoters of osteoporosis-associated genes, including 4 transcription factor binding sites, 27 histone marks, and 21 chromatin states segmentation types. Using these epigenomic marks, we performed reverse prediction analysis to prioritize the discovery of new candidate genes. Functional enrichment analysis of all the prioritized genes revealed several key osteoporosis related pathways, including Wnt signaling. Genes with high priority were further subjected to validation using available GWASs datasets. Three genes were significantly associated with spine bone mineral density, including BDNF, PDE4D, and SATB2, which all closely related to bone metabolism. The most significant gene BDNF was also associated with osteoporotic fractures. RNA interference revealed that BDNF knockdown can suppress osteoblast differentiation. Our results demonstrated that epigenomic data could be used to indicate common epigenomic marks to discover additional loci with biological functions for osteoporosis.

  14. Specificity and timing of neocortical transcriptome changes in response to BDNF gene ablation during embryogenesis or adulthood.

    PubMed

    Glorioso, C; Sabatini, M; Unger, T; Hashimoto, T; Monteggia, L M; Lewis, D A; Mirnics, K

    2006-07-01

    Brain-derived neurotrophic factor (BDNF) has been reported to be critical for the development of cortical inhibitory neurons. However, the effect of BDNF on the expression of transcripts whose protein products are involved in gamma amino butric acid (GABA) neurotransmission has not been assessed. In this study, gene expression profiling using oligonucleotide microarrays was performed in prefrontal cortical tissue from mice with inducible deletions of BDNF. Both embryonic and adulthood ablation of BDNF gave rise to many shared transcriptome changes. BDNF appeared to be required to maintain gene expression in the SST-NPY-TAC1 subclass of GABA neurons, although the absence of BDNF did not alter their general phenotype as inhibitory neurons. Furthermore, we observed expression alterations in genes encoding early-immediate genes (ARC, EGR1, EGR2, FOS, DUSP1, DUSP6) and critical cellular signaling systems (CDKN1c, CCND2, CAMK1g, RGS4). These BDNF-dependent gene expression changes may illuminate the biological basis for transcriptome changes observed in certain human brain disorders.

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

    PubMed Central

    Yoshimura, Yuko; Kudo, Takashi; Shirakawa, Masaki; Shiba, Dai; Takahashi, Satoru; Morita, Hironobu

    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. PMID:28591153

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

    PubMed

    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.

  17. The modifier effect of the BDNF gene in the phenotype of the WAGRO syndrome.

    PubMed

    Rodríguez-López, Raquel; Pérez, José M Carbonell; Balsera, Aránzazu Margallo; Rodríguez, Guillermo Gervasini; Moreno, Trinidad Herrera; García de Cáceres, Mayte; Serrano, Marta González-Carpio; Freijo, Felipe Casanueva; Ruiz, Juan Ramón González; Angueira, Francisco Barros; Pérez, Pilar Méndez; Estévez, Manuela Núñez; Gómez, Enrique Galán

    2013-03-10

    Individuals who are carriers of deletions of various sizes that cause haploinsufficiency in the contiguous WT1 and PAX6 genes, located on chromosome 11p13 approximately 4 Mb centromeric to the BDNF gene, are susceptible to Wilms tumor, aniridia, mental retardation, genitourinary anomalies and obesity (WAGRO syndrome). The molecular characterization of the wide deletion 11p15.1p12 arr (18676926-36576388) x1 dn in a child with 3 years and 4 months of age only affected by aniridia, predicts not only other serious associated diseases, but also allows us to hypothesize a specific phenotype of mental impairment, conduct alterations and childhood obesity, possibly added to the onset of metabolic alterations. The variable appearance and/or description of haploinsufficiency for obesity susceptibility in the WAGR syndrome mainly depends on the critical region located within 80 kb of exon 1 of BDNF. The relationship between genetic variation based on the genotype combinations of the 4 gene SNPs tagging the BDNF gene and the body mass index (BMI) was studied. The polymorphic variability was similarly distributed in 218 children suffering a severe and non-syndromic obesity from families at high risk for obesity, as compared with 198 controls. The corroborated role of the BDNF gene as highly susceptible to severe syndromic obesity has not already been evidenced in the molecular basis of overweight attributed to the common polygenic principles. Its potential role as risk modifier variant to provoke more severe phenotype has not yet been demonstrated. Some genetic variants of brain-derived neurotrophic factor (BDNF) have resulted in important disorders of energy balance, but it is essential to know exactly their deleterious human capacity because they play a fundamental role in the development and plasticity of the central nervous system in regulating food intake. The existence of polymorphic amino acid changes of unknown functional significance in patients carrying the

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

    PubMed Central

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

    2015-01-01

    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 <42 years) and 22 older individuals (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, p<0.05; r=−0.40, p<0.05; r=−0.24, p=0.07), and DNAm in SST 5′ UTR and first exon/intron negatively correlated with SST expression (r=−0.48, p<0.01; r=−0.63, p<0.001), respectively. An expanded set of BDNF- and GABA-related genes 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. PMID:25881116

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

    PubMed

    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 <42 years) and 22 older individuals (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, p<0.05; r=-0.40, p<0.05; r=-0.24, p=0.07), and DNAm in SST 5' UTR and first exon/intron negatively correlated with SST expression (r=-0.48, p<0.01; r=-0.63, p<0.001), respectively. An expanded set of BDNF- and GABA-related genes 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.

  20. BDNF gene delivery mediated by neuron-targeted nanoparticles is neuroprotective in peripheral nerve injury.

    PubMed

    Lopes, Cátia D F; Gonçalves, Nádia P; Gomes, Carla P; Saraiva, Maria J; Pêgo, Ana P

    2017-03-01

    Neuron-targeted gene delivery is a promising strategy to treat peripheral neuropathies. Here we propose the use of polymeric nanoparticles based on thiolated trimethyl chitosan (TMCSH) to mediate targeted gene delivery to peripheral neurons upon a peripheral and minimally invasive intramuscular administration. Nanoparticles were grafted with the non-toxic carboxylic fragment of the tetanus neurotoxin (HC) to allow neuron targeting and were explored to deliver a plasmid DNA encoding for the brain-derived neurotrophic factor (BDNF) in a peripheral nerve injury model. The TMCSH-HC/BDNF nanoparticle treatment promoted the release and significant expression of BDNF in neural tissues, which resulted in an enhanced functional recovery after injury as compared to control treatments (vehicle and non-targeted nanoparticles), associated with an improvement in key pro-regenerative events, namely, the increased expression of neurofilament and growth-associated protein GAP-43 in the injured nerves. Moreover, the targeted nanoparticle treatment was correlated with a significantly higher density of myelinated axons in the distal stump of injured nerves, as well as with preservation of unmyelinated axon density as compared with controls and a protective role in injury-denervated muscles, preventing them from denervation. These results highlight the potential of TMCSH-HC nanoparticles as non-viral gene carriers to deliver therapeutic genes into the peripheral neurons and thus, pave the way for their use as an effective therapeutic intervention for peripheral neuropathies.

  1. Fermented Brown Rice Extract Stimulates BDNF Gene Transcription in C6 Glioma Cells: Possible Connection with HO-1 Expression.

    PubMed

    Morita, Kyoji; Nishibori, Naoyoshi; Kishibuchi, Reina; Itoh, Mari; Horie, Yukiko; Nemoto, Hideyuki

    2017-03-04

    Fermented brown rice with Aspergillus oryzae, designated as FBRA, is known to be commercially available dietary fiber-rich food, which is appreciated as prebiotics to improve intestinal microflora, and also shown to contain various biologically active substances including polyphenolic compounds. On the other hand, polyphenolic compounds have been suggested to stimulate the expression of brain-derived neurotrophic factor (BDNF) gene in connection with the expression of heme oxidase-1 (HO-1) gene in glial cells, thus resulting in the augmentation of BDNF production in the brain, thereby being anticipated to have a putative effect on the brain function. Then, the effect of FBRA extract on HO-1 and BDNF messenger ribonucleic acid (mRNA) levels in C6 glioma cells was examined, and the extract was shown to stimulate both HO-1 and BDNF gene transcription in the glioma cells. Further studies showed that the stimulatory effect of FBRA extract on BDNF gene transcription was almost completely suppressed by silencing HO-1 gene expression with an HO-1 antisense oligodeoxynucleotide and also inhibiting HO-1 activity with an inhibitor zinc protoporphyrin, thus suggesting that FBRA might have a potential ability to induce BDNF gene expression through HO-1 activity in glial cells.

  2. Association study between BDNF gene variants and Mexican patients with obsessive-compulsive disorder.

    PubMed

    Márquez, Lidia; Camarena, Beatriz; Hernández, Sandra; Lóyzaga, Cristina; Vargas, Luis; Nicolini, Humberto

    2013-11-01

    Obsessive-compulsive disorder (OCD) is a psychiatric disorder whose etiology is not yet known. We investigate the role of three variants of the BDNF gene (rs6265, rs1519480 and rs7124442) by single SNP and haplotype analysis in OCD Mexican patients using a case-control and family-based association design. BDNF gene variants were genotyped in 283 control subjects, 232 OCD patients and first degree relatives of 111 OCD subjects. Single SNP analysis in case-control study showed an association between rs6265 and OCD with a high frequency of Val/Val genotype and Val allele (p=0.0001 and p=0.0001, respectively). Also, genotype and allele analysis of rs1519480 showed significant differences (p=0.0001, p=0.0001; respectively) between OCD and control groups. Haplotype analysis showed a high frequency of A-T (rs6265-rs1519480) in OCD patients compared with the control group (OR=2.06 [1.18-3.59], p=0.0093) and a low frequency of haplotype A-C in the OCD patients (OR=0.04 [0.01-0.16], p=0.000002). The family-based association study showed no significant differences in the transmission of any variant. Our study replicated the association between BDNF Val66Met gene polymorphism and OCD. Also, we found a significant association of rs1519480 in OCD patients compared with a control group, region that has never been analyzed in OCD. In conclusion, our findings suggest that BDNF gene could be related to the development of OCD. © 2013 Elsevier B.V. and ECNP. All rights reserved.

  3. Connexin 26 null mice exhibit spiral ganglion degeneration that can be blocked by BDNF gene therapy

    PubMed Central

    Takada, Yohei; Beyer, Lisa A.; Swiderski, Donald L.; O’Neal, Aubrey L.; Prieskorn, Diane M.; Shivatzki, Shaked; Avraham, Karen B.; Raphael, Yehoash

    2014-01-01

    Mutations in the connexin 26 gene (GJB2) are the most common genetic cause of deafness, leading to congenital bilateral non-syndromic sensorineural hearing loss. Here we report the generation of a mouse model for a connexin 26 (C×26) mutation, in which cre-Sox10 drives excision of the C×26 gene from non-sensory cells flanking the auditory epithelium. We determined that these conditional knockout mice, designated Gjb2-CKO, have a severe hearing loss. Immunocytochemistry of the auditory epithelium confirmed absence of C×26 in the non-sensory cells. Histology of the organ of Corti and the spiral ganglion neurons (SGNs) performed at ages 1, 3, or 6 months revealed that in Gjb2-CKO mice, the organ of Corti began to degenerate in the basal cochlear turn at an early stage, and the degeneration rapidly spread to the apex. In addition, the density of SGNs in Rosenthal’s canal decreased rapidly along a gradient from the base of the cochlea to the apex, where some SGNs survived until at least 6 months of age. Surviving neurons often clustered together and formed clumps of cells in the canal. We then assessed the influence of brain derived neurotrophic factor (BDNF) gene therapy on the SGNs of Gjb2-CKO mice by inoculating Adenovirus BDNF (Ad.BDNF) into the base of the cochlea via the scala tympani or scala media. We determined that over-expression of BDNF beginning around 1 month of age resulted in a significant rescue of neurons in Rosenthal’s canal of the cochlear basal turn but not in the middle or apical portions. This data may be used to design therapies for enhancing the SGN physiological status in all GJB2 patients and to a sub-group of GJB2 patients where the hearing loss progresses due to ongoing degeneration of the auditory nerve, thereby improving the outcome of cochlear implant therapy in these ears. PMID:24333301

  4. Hyperglycemia and hypercapnia suppress BDNF gene expression in vulnerable regions after transient forebrain ischemia in the rat.

    PubMed

    Uchino, H; Lindvall, O; Siesjö, B K; Kokaia, Z

    1997-12-01

    Preischemic hyperglycemia or superimposed hypercapnia exaggerates brain damage caused by transient forebrain ischemia. Because high regional levels of brain-derived neurotrophic factor (BDNF) protein correlate with resistance to ischemic damage, we studied the expression of BDNF mRNA using in situ hybridization in rats subjected to 10 minutes of forebrain ischemia under normoglycemic, hyperglycemic, or hypercapnic conditions. Compared with normoglycemic animals, the increase of BDNF mRNA using in situ hybridization in rats subjected to 10 minutes of forebrain ischemia under normoglycemic, or hypercapnic conditions. Compared with normoglycemic animals, the increase of BDNF mRNA in dentate granule cells was attenuated and that in CA3 pyramidal neurons completely prevented in hyperglycemic rats. No ischemia-induced increases of BDNF mRNA levels in the hippocampal formation were detected in hypercapnic animals. Hyperglycemic and hypercapnic rats showed transiently decreased expression of BDNF mRNA levels in the cingulate cortex, which was not observed in normoglycemic animals. The results suggest that suppression of the BDNF gene might contribute to the increased vulnerability of the CA3 region and cingulate cortex in hyperglycemic and hypercapnic animals.

  5. Variation in the BDNF gene interacts with age to predict mortality in a prospective, longitudinal cohort with severe TBI

    PubMed Central

    Failla, Michelle D.; Kumar, Raj; Peitzman, Andrew; Conley, Yvette P.; Ferrell, Robert E.; Wagner, Amy K.

    2014-01-01

    Background Mortality predictions following traumatic brain injury (TBI) may be improved by including genetic risk in addition to traditional prognostic variables. One promising target is the gene coding for brain-derived neurotrophic factor (BDNF), a ubiquitous neurotrophin important for neuronal survival and neurogenesis. Objective We hypothesized the addition of BDNF genetic variation would improve mortality prediction models and that BDNF Met-carriers (rs6265) and C-carriers (rs7124442) would have the highest mortality rates post-TBI. Methods This study examined BDNF functional single nucleotide polymorphisms (SNPs) rs6265r (val66met) and rs7124442 (T>C) in relation to mortality in a prospective, longitudinal cohort with severe TBI. We examined 315 individuals receiving care for a closed head injury within the University of Pittsburgh Medical Center, aged 16–79. Mortality was examined acutely (0–7 days post-injury) and post-acutely (8–365 days post-injury). A gene risk score (GRS) was developed to examine both BDNF loci. Cox proportional hazards models were used to calculate hazard ratios for survivability post-TBI while controlling for covariates. Results BDNF GRS was significantly associated with acute mortality, regardless of age. Interestingly, subjects in the hypothesized no-risk allele group had the lowest survival probability. Post-acutely, BDNF-GRS interacted with age such that younger participants in the no-risk group had the highest survival probability, while older participants in the hypothesized no-risk group had the lowest probability of survival. Conclusions These data suggest complex relationships between BDNF and TBI mortality that interact with age to influence survival predictions beyond clinical variables alone. Evidence supporting dynamic, temporal balances of pro-survival/pro-apoptotic target receptors may explain injury and age-related gene associations. PMID:25063686

  6. Association of Polymorphisms in BDNF, MTHFR, and Genes Involved in the Dopaminergic Pathway with Memory in a Healthy Chinese Population

    ERIC Educational Resources Information Center

    Yeh, Ting-Kuang; Hu, Chung-Yi; Yeh, Ting-Chi; Lin, Pei-Jung; Wu, Chung-Hsin; Lee, Po-Lei; Chang, Chun-Yen

    2012-01-01

    The contribution of genetic factors to the memory is widely acknowledged. Research suggests that these factors include genes involved in the dopaminergic pathway, as well as the genes for brain-derived neurotrophic factor (BDNF) and methylenetetrahydrofolate reductase (MTHFR). The activity of the products of these genes is affected by single…

  7. Association of Polymorphisms in BDNF, MTHFR, and Genes Involved in the Dopaminergic Pathway with Memory in a Healthy Chinese Population

    ERIC Educational Resources Information Center

    Yeh, Ting-Kuang; Hu, Chung-Yi; Yeh, Ting-Chi; Lin, Pei-Jung; Wu, Chung-Hsin; Lee, Po-Lei; Chang, Chun-Yen

    2012-01-01

    The contribution of genetic factors to the memory is widely acknowledged. Research suggests that these factors include genes involved in the dopaminergic pathway, as well as the genes for brain-derived neurotrophic factor (BDNF) and methylenetetrahydrofolate reductase (MTHFR). The activity of the products of these genes is affected by single…

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

    PubMed

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

    PubMed

    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. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Polymorphisms of BDNF Gene and Autism Spectrum Disorders: Family Based Association Study with Korean Trios

    PubMed Central

    Yoo, Hee Jeong; Yang, So Young; Cho, In Hee; Park, Mira

    2014-01-01

    Objective Autism spectrum disorders (ASDs) are a group of early childhood-onset neurodevelopmental disorders characterized by deficits in social interaction and language skills, and repetitive behaviors. Brain-derived neurotrophic factor (BDNF) plays a critical role in the differentiation of normal neuronal cells during embryonic and postnatal neuronal development through its neurotrophic effects. Methods In this study, we performed a family-based association test (FBAT) between single nucleotide polymorphisms (SNPs; rs6265, rs11030101, rs7103411, and rs7103873) or haplotypes in the BDNF gene and affection status or several quantitative traits characterized by ADI-R with151 Korean trios, including a child diagnosed as ASDs. Results While no significant association was found between SNPs or haplotypes and the ASDs disease status, a quantitative transmission disequilibrium test (QTDT) by using quantitative traits identified associations of the SNPs (rs6265 and rs11030101) with a domain score for "Restricted, Repetitive and Stereotyped patterns of behavior" (C domain), especially at the subdomain scores for "encompassing preoccupation or circumscribed pattern of interest" (C1) (rs6265A allele, dominant model, p-value=0.019; rs11030101 A allele, additive model, p-value=0.015) and "preoccupations with part of objects or non-functional elements of material" (C4) (rs11030101 A allele, additive model, p-value=0.015) within the ADI-R diagnostic algorithm. In addition, significant associations were also identified between the haplotypes and these quantitative traits (C1, p-value=0.016; C4, p-value=0.012). Conclusion We conclude that BDNF gene polymorphisms have a possible role in the pathogenesis of ASDs. PMID:25110506

  11. Genetic association between BDNF gene polymorphisms and phobic disorders: a case-control study among mainland Han Chinese.

    PubMed

    Xie, Bing; Wang, Binbin; Suo, Peisu; Kou, Changgui; Wang, Jing; Meng, Xiangfei; Cheng, Longfei; Ma, Xu; Yu, Yaqin

    2011-07-01

    Phobic disorders are a common group of syndromes comprising persistently recurring, irrational severe anxiety of specific objects, activities, or situations with avoidance behavior of the phobic stimulus. The present study investigated the association between whole region polymorphisms, (including the Val66Met variant), in the BDNF gene and phobic disorders among Han Chinese young adults. We conducted a case-control study to investigate the genetic association between BDNF polymorphisms and phobic disorders among mainland Chinese. One hundred and twenty young adults with phobic disorders and 267 matched controls were recruited. Three tag SNPs of BDNF were successfully genotyped by using PCR-based ligase detection reaction (PCR-LDR). We found significant differences in allele distributions of SNP rs10835210 (P<0.001) between the experimental and the control groups. In the haplotype analysis based on linkage-disequilibrium across this gene locus, we demonstrated significant association between phobic disorders and BDNF haplotype CAC (P=0.004). Association was significant after 10(4) permutation tests (P<0.001). To the best of our knowledge, this is the first study showing that the BDNF gene may play a significant role in the etiology of phobic disorders in the Han Chinese population. Copyright © 2010. Published by Elsevier B.V.

  12. AAV-mediated gene delivery of BDNF or GDNF is neuroprotective in a model of Huntington disease.

    PubMed

    Kells, Adrian P; Fong, Dahna M; Dragunow, Mike; During, Matthew J; Young, Deborah; Connor, Bronwen

    2004-05-01

    Huntington disease (HD) is a neurodegenerative disorder that results in the progressive loss of GABAergic medium spiny projection neurons in the striatum. Neurotrophic factors have demonstrated neuroprotective actions on striatal neurons, suggesting that increased neurotrophic factor expression may prevent or reduce neuronal loss in the HD brain. We investigated whether enhanced expression of brain-derived neurotrophic factor (BDNF) or glial cell line-derived neurotrophic factor (GDNF), achieved by adeno-associated viral (AAV) vector-mediated gene delivery, could protect striatal neurons in the quinolinic acid (QA) rodent model of HD. Adult Wistar rats received unilateral intrastriatal injections of AAV-BDNF, AAV-GDNF, AAV-GFP, or PBS. Three weeks later, the rats were lesioned with QA, a toxin that induces striatal neuron death by an excitotoxic process. Both AAV-BDNF and AAV-GDNF significantly reduced the loss of both NeuN- and calbindin-immunopositive striatal neurons 2 weeks after lesion compared to controls. AAV-BDNF also provided significant neurotrophic support to NOS-immunopositive striatal interneurons, while AAV-GDNF-treated rats demonstrated significant protection of parvalbumin-immunopositive striatal interneurons compared to controls. These results indicate that AAV-mediated gene transfer of BDNF or GDNF into the striatum provides neuronal protection in a rodent model of HD.

  13. The impact of Bdnf gene deficiency to the memory impairment and brain pathology of APPswe/PS1dE9 mouse model of Alzheimer's disease.

    PubMed

    Rantamäki, Tomi; Kemppainen, Susanna; Autio, Henri; Stavén, Saara; Koivisto, Hennariikka; Kojima, Masami; Antila, Hanna; Miettinen, Pasi O; Kärkkäinen, Elisa; Karpova, Nina; Vesa, Liisa; Lindemann, Lothar; Hoener, Marius C; Tanila, Heikki; Castrén, Eero

    2013-01-01

    Brain-derived neurotrophic factor (BDNF) importantly regulates learning and memory and supports the survival of injured neurons. Reduced BDNF levels have been detected in the brains of Alzheimer's disease (AD) patients but the exact role of BDNF in the pathophysiology of the disorder remains obscure. We have recently shown that reduced signaling of BDNF receptor TrkB aggravates memory impairment in APPswe/PS1dE9 (APdE9) mice, a model of AD. The present study examined the influence of Bdnf gene deficiency (heterozygous knockout) on spatial learning, spontaneous exploratory activity and motor coordination/balance in middle-aged male and female APdE9 mice. We also studied brain BDNF protein levels in APdE9 mice in different ages showing progressive amyloid pathology. Both APdE9 and Bdnf mutations impaired spatial learning in males and showed a similar trend in females. Importantly, the effect was additive, so that double mutant mice performed the worst. However, APdE9 and Bdnf mutations influenced spontaneous locomotion in contrasting ways, such that locomotor hyperactivity observed in APdE9 mice was normalized by Bdnf deficiency. Obesity associated with Bdnf deficiency did not account for the reduced hyperactivity in double mutant mice. Bdnf deficiency did not alter amyloid plaque formation in APdE9 mice. Before plaque formation (3 months), BDNF protein levels where either reduced (female) or unaltered (male) in the APdE9 mouse cortex. Unexpectedly, this was followed by an age-dependent increase in mature BDNF protein. Bdnf mRNA and phospho-TrkB levels remained unaltered in the cortical tissue samples of middle-aged APdE9 mice. Immunohistological studies revealed increased BDNF immunoreactivity around amyloid plaques indicating that the plaques may sequester BDNF protein and prevent it from activating TrkB. If similar BDNF accumulation happens in human AD brains, it would suggest that functional BDNF levels in the AD brains are even lower than reported, which could

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

    PubMed

    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.

  15. BDNF Gene Polymorphism (Val66Met) Predicts Amygdala and Anterior Hippocampus Responses to Emotional Faces in Anxious and Depressed Adolescents

    PubMed Central

    Lau, Jennifer Y.F.; Goldman, David; Buzas, Beata; Hodgkinson, Colin; Leibenluft, Ellen; Nelson, Eric; Sankin, Lindsey; Pine, Daniel S.; Ernst, Monique

    2009-01-01

    A polymorphism of the human Brain Derived Neurotrophic Factor (BDNF) gene that produces a valine-to-methionine substitution at codon 66 (Val66Met), is linked to adult anxiety and mood disorders, possibly through effects on brain circuitry function. Associations between BDNF gene variants and brain activity have not been explored in anxious and depressed adolescents. The current study investigated the association between BDNF genotype and amygdala-hippocampal responses to emotional stimuli in adolescents with anxiety disorders and/or major depressive disorder (MDD) and in healthy adolescents. Twenty-seven unmedicated patients with acutely-impairing current anxiety disorders and/or MDD and 31 healthy adolescents, matched on age, gender and IQ, rated their fear of fearful, angry, neutral and happy facial expressions during collection of fMRI data on the amygdala and hippocampus. Left and right amygdala and hippocampal responses were analyzed using Repeated-measures Analyses of Variance models, with Diagnosis (patients, healthy) and Genotype (Met-carriers, Val/Val homozygotes) as between-group factors and facial expression (fearful, angry, neutral, happy) as a within-subject factor. Significant effects of Diagnosis and Diagnosis-by-Genotype interactions (F’s>4, p’s<.05) characterized activations in amygdala and anterior hippocampal regions. Greater activations in patients than healthy adolescents were found. Critically, these hyperactivations were modulated by BDNF genotype: Met-carriers showed greater neural responses of emotional faces than Val/Val homozygotes in patients only. These data are first to demonstrate the contribution of BDNF gene variants to the neural correlates of adolescent anxiety and depression. Early “gene-brain” linkages may lay the foundation for longer-term patterns of neural dysfunction in affective disorders. PMID:19931400

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

    PubMed

    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.

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

    PubMed Central

    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

    2008-01-01

    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 5′ end of the BDNF gene. The patient’s genomic DNA was heterozygous for a common coding polymorphism in BDNF, but monoallelic expression was seen in peripheral lymphocytes. Serum concentration of BDNF protein was reduced compared with age- and BMI-matched subjects. Haploinsufficiency for BDNF was associated with increased ad libitum food intake, severe early-onset obesity, hyper-activity, and cognitive impairment. These findings provide direct evidence for the role of the neurotrophin BDNF in human energy homeostasis, as well as in cognitive function, memory, and behavior. PMID:17130481

  18. Impact of variation in the BDNF gene on social stress sensitivity and the buffering impact of positive emotions: replication and extension of a gene-environment interaction.

    PubMed

    van Winkel, Mark; Peeters, Frenk; van Winkel, Ruud; Kenis, Gunter; Collip, Dina; Geschwind, Nicole; Jacobs, Nele; Derom, Catherine; Thiery, Evert; van Os, Jim; Myin-Germeys, Inez; Wichers, Marieke

    2014-06-01

    A previous study reported that social stress sensitivity is moderated by the brain-derived-neurotrophic-factor(Val66Met) (BDNF rs6265) genotype. Additionally, positive emotions partially neutralize this moderating effect. The current study aimed to: (i) replicate in a new independent sample of subjects with residual depressive symptoms the moderating effect of BDNF(Val66Met) genotype on social stress sensitivity, (ii) replicate the neutralizing impact of positive emotions, (iii) extend these analyses to other variations in the BDNF gene in the new independent sample and the original sample of non-depressed individuals. Previous findings were replicated in an experience sampling method (ESM) study. Negative Affect (NA) responses to social stress were stronger in "Val/Met" carriers of BDNF(Val66Met) compared to "Val/Val" carriers. Positive emotions neutralized the moderating effect of BDNF(Val66Met) genotype on social stress sensitivity in a dose-response fashion. Finally, two of four additional BDNF SNPs (rs11030101, rs2049046) showed similar moderating effects on social stress-sensitivity across both samples. The neutralizing effect of positive emotions on the moderating effects of these two additional SNPs was found in one sample. In conclusion, ESM has important advantages in gene-environment (GxE) research and may attribute to more consistent findings in future GxE research. This study shows how the impact of BDNF genetic variation on depressive symptoms may be explained by its impact on subtle daily life responses to social stress. Further, it shows that the generation of positive affect (PA) can buffer social stress sensitivity and partially undo the genetic susceptibility.

  19. Laser Acupuncture Exerts Neuroprotective Effects via Regulation of Creb, Bdnf, Bcl-2, and Bax Gene Expressions in the Hippocampus

    PubMed Central

    Yun, Yeong-Chan; Yoon, Sun-Bee; Kim, Dohyeong; Choi, Dong-Hee; Lee, Yu-Mi

    2017-01-01

    Acupuncture has a positive effect on cognitive deficits. However, the effects of laser acupuncture (LA) on cognitive function and its mechanisms of action are unclear. The present study aimed to evaluate the effects of LA on middle cerebral artery occlusion- (MCAO-) induced cognitive impairment and its mechanisms of action. Transient focal cerebral ischemia was modeled in adult Sprague-Dawley rats by MCAO. After LA or manual-acupuncture (MA) treatment at the GV20 and HT7 for 2 weeks, hippocampal-dependent memory was evaluated using the Morris water maze (MWM) test. The hippocampus was dissected to analyze choline acetyltransferase (ChAT) immunoreactivity and Creb, Bdnf, Bcl-2, and Bax gene expressions. MWM test demonstrated a significant improvement in hippocampal-dependent memory in the MCAO rats after LA treatment. LA treatment significantly reversed the postischemic decrease in ChAT immunoreactivity in the hippocampal CA1 region. LA treatment significantly normalized gene expression in the hippocampus which had been altered by MCAO, especially upregulating gene expression of Creb, Bdnf, and Bcl-2 and downregulating gene expression of Bax. This study suggests that LA treatment could improve cognitive impairment in MCAO rats to enhance the cholinergic system in the hippocampal CA1 region and to exert a neuroprotective effect by regulating Creb, Bdnf, Bcl-2, and Bax gene expressions. PMID:28408940

  20. Laser Acupuncture Exerts Neuroprotective Effects via Regulation of Creb, Bdnf, Bcl-2, and Bax Gene Expressions in the Hippocampus.

    PubMed

    Yun, Yeong-Chan; Jang, Dongyeop; Yoon, Sun-Bee; Kim, Dohyeong; Choi, Dong-Hee; Kwon, O-Sang; Lee, Yu-Mi; Youn, Daehwan

    2017-01-01

    Acupuncture has a positive effect on cognitive deficits. However, the effects of laser acupuncture (LA) on cognitive function and its mechanisms of action are unclear. The present study aimed to evaluate the effects of LA on middle cerebral artery occlusion- (MCAO-) induced cognitive impairment and its mechanisms of action. Transient focal cerebral ischemia was modeled in adult Sprague-Dawley rats by MCAO. After LA or manual-acupuncture (MA) treatment at the GV20 and HT7 for 2 weeks, hippocampal-dependent memory was evaluated using the Morris water maze (MWM) test. The hippocampus was dissected to analyze choline acetyltransferase (ChAT) immunoreactivity and Creb, Bdnf, Bcl-2, and Bax gene expressions. MWM test demonstrated a significant improvement in hippocampal-dependent memory in the MCAO rats after LA treatment. LA treatment significantly reversed the postischemic decrease in ChAT immunoreactivity in the hippocampal CA1 region. LA treatment significantly normalized gene expression in the hippocampus which had been altered by MCAO, especially upregulating gene expression of Creb, Bdnf, and Bcl-2 and downregulating gene expression of Bax. This study suggests that LA treatment could improve cognitive impairment in MCAO rats to enhance the cholinergic system in the hippocampal CA1 region and to exert a neuroprotective effect by regulating Creb, Bdnf, Bcl-2, and Bax gene expressions.

  1. Predicting Response Trajectories during Cognitive-Behavioural Therapy for Panic Disorder: No Association with the BDNF Gene or Childhood Maltreatment

    PubMed Central

    Santacana, Martí; Arias, Bárbara; Mitjans, Marina; Bonillo, Albert; Montoro, María; Rosado, Sílvia; Guillamat, Roser; Vallès, Vicenç; Pérez, Víctor; Forero, Carlos G.; Fullana, Miquel A.

    2016-01-01

    Background Anxiety disorders are highly prevalent and result in low quality of life and a high social and economic cost. The efficacy of cognitive-behavioural therapy (CBT) for anxiety disorders is well established, but a substantial proportion of patients do not respond to this treatment. Understanding which genetic and environmental factors are responsible for this differential response to treatment is a key step towards “personalized medicine”. Based on previous research, our objective was to test whether the BDNF Val66Met polymorphism and/or childhood maltreatment are associated with response trajectories during exposure-based CBT for panic disorder (PD). Method We used Growth Mixture Modeling to identify latent classes of change (response trajectories) in patients with PD (N = 97) who underwent group manualized exposure-based CBT. We conducted logistic regression to investigate the effect on these trajectories of the BDNF Val66Met polymorphism and two different types of childhood maltreatment, abuse and neglect. Results We identified two response trajectories (“high response” and “low response”), and found that they were not significantly associated with either the genetic (BDNF Val66Met polymorphism) or childhood trauma-related variables of interest, nor with an interaction between these variables. Conclusions We found no evidence to support an effect of the BDNF gene or childhood trauma-related variables on CBT outcome in PD. Future studies in this field may benefit from looking at other genotypes or using different (e.g. whole-genome) approaches. PMID:27355213

  2. BDNF gene delivery within and beyond templated agarose multi-channel guidance scaffolds enhances peripheral nerve regeneration

    NASA Astrophysics Data System (ADS)

    Gao, Mingyong; Lu, Paul; Lynam, Dan; Bednark, Bridget; Campana, W. Marie; Sakamoto, Jeff; Tuszynski, Mark

    2016-12-01

    Objective. We combined implantation of multi-channel templated agarose scaffolds with growth factor gene delivery to examine whether this combinatorial treatment can enhance peripheral axonal regeneration through long sciatic nerve gaps. Approach. 15 mm long scaffolds were templated into highly organized, strictly linear channels, mimicking the linear organization of natural nerves into fascicles of related function. Scaffolds were filled with syngeneic bone marrow stromal cells (MSCs) secreting the growth factor brain derived neurotrophic factor (BDNF), and lentiviral vectors expressing BDNF were injected into the sciatic nerve segment distal to the scaffold implantation site. Main results. Twelve weeks after injury, scaffolds supported highly linear regeneration of host axons across the 15 mm lesion gap. The incorporation of BDNF-secreting cells into scaffolds significantly increased axonal regeneration, and additional injection of viral vectors expressing BDNF into the distal segment of the transected nerve significantly enhanced axonal regeneration beyond the lesion. Significance. Combinatorial treatment with multichannel bioengineered scaffolds and distal growth factor delivery significantly improves peripheral nerve repair, rivaling the gold standard of autografts.

  3. The antidepressive effect of the physical exercise correlates with increased levels of mature BDNF, and proBDNF proteolytic cleavage-related genes, p11 and tPA.

    PubMed

    Sartori, C R; Vieira, A S; Ferrari, E M; Langone, F; Tongiorgi, E; Parada, C A

    2011-04-28

    Clinical studies show an evident antidepressive effect of physical exercise and animal research corroborate such evidence. However, the neurobiological mechanisms underlying the antidepressive effect of exercise are not completely understood. Notwithstanding, it is known that exercise increases brain-derived neurotrophic factor (BDNF) expression in the hippocampus similarly to antidepressant drugs. BDNF is synthesized as a precursor molecule that undergoes a proteolytic cleavage to generate either a mature or a truncated isoform. Precursor and mature BDNF are assumed to elicit opposing biological effects in neuroplasticity. In the present study we investigated the effect of voluntary physical activity on precursor and mature brain-derived neurotrophic factor levels and on proBDNF cleavage related genes, p11 and tissue plasminogen activator (tPA), as well as the antidepressive and cognitive effects of voluntary physical activity. Mice had access to mobile or locked running wheels for 28 days and were submitted to forced-swim, tail suspension and water maze tests. Their hippocampi were dissected and analyzed by Western blot and real time RT-PCR. Voluntary physical activity, but not locked wheel exposure, induced a robust increase in hippocampal mature BDNF protein levels, as well as in p11 and tPA mRNA expression; and also promoted antidepressive effects and improved learning, when compared with sedentary mice. On the other hand, there were no significant differences between any groups in the expression of precursor or truncated isoforms of BDNF. Our data suggest that the antidepressive effect of the physical exercise may depend, at least in part, on changes in BDNF post-translational processing. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

  4. BDNF — EDRN Public Portal

    Cancer.gov

    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.

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

    PubMed Central

    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

  6. Association between Val66Met polymorphism of Brain-Derived Neurotrophic Factor (BDNF) gene and a deficiency of colour vision in alcohol-dependent male patients.

    PubMed

    Serý, Omar; Sťastný, František; Zvolský, Petr; Hlinomazová, Zuzana; Balcar, Vladimir J

    2011-07-25

    Brain-derived neurotrophic factor (BDNF) is a protein encoded, in humans, by BDNF gene on chromosome 11. BDNF protects adult neurons and promotes growth and differentiation during ontogenetic development but the nature and magnitude of its effects could be influenced by functional polymorphisms. The BDNF polymorphism Val66Met (rs6265) has been studied in the context of etiology of mental diseases including alcoholism. Alcoholism - a complex disorder known to be linked to several genes - has multiple manifestations, including sensory deficits such as those affecting vision. In the present study we examined a relationship between the Val66Met polymorphism, alcohol dependence and colour vision deficiency (CVD) in 167 alcohol-dependent men and 289 control male subjects. Statistical analysis revealed that almost half (about 48%) of the alcohol dependent men had a CVD. In addition we found that CVD was significantly associated (P=0.005) with the Val66Met polymorphism. The A allele containing 66Met promotes BDNF expression and this may protect humans against CVD induced by long-term excessive alcohol intake. The present findings indicate that alcohol-induced CVD does not depend solely on excessive alcohol consumption but is significantly influenced by genetic predisposition in the form of a specific BDNF polymorphism.

  7. Methamphetamine blocks exercise effects on Bdnf and Drd2 gene expression in frontal cortex and striatum

    PubMed Central

    Thompson, Andrew B.; Stolyarova, Alexandra; Ying, Zhe; Zhuang, Yumei; Gómez-Pinilla, Fernando; Izquierdo, Alicia

    2017-01-01

    Exposure to drugs of abuse can produce many neurobiological changes which may lead to increased valuation of rewards and decreased sensitivity to their costs. Many of these behavioral alterations are associated with activity of D2-expressing medium spiny neurons in the striatum. Additionally, Bdnf in the striatum has been shown to play a role in flexible reward-seeking behavior. Given that voluntary aerobic exercise can affect the expression of these proteins in healthy subjects, and that exercise has shown promise as an anti-addictive therapy, we set out to quantify changes in D2 and Bdnf expression in methamphetamine-exposed rats given access to running wheels. Sixty-four rats were treated for two weeks with an escalating dose of methamphetamine or saline, then either sacrificed, housed in standard cages, or given free access to a running wheel for 6 weeks prior to sacrifice. Rats treated with methamphetamine ran significantly greater distances than saline-treated rats, suggesting an augmentation in the reinforcement value of voluntary wheel running. Transcription of Drd2 and Bdnf was assessed via RT-qPCR. Protein expression levels of D2 and phosphorylation of the TrkB receptor were measured via western blot. Drd2 and Bdnf mRNA levels were impacted independently by exercise and methamphetamine, but exposure to methamphetamine prior to the initiation of exercise blocked the exercise-induced changes seen in rats treated with saline. Expression levels of both proteins were elevated immediately after methamphetamine, but returned to baseline after six weeks, regardless of exercise status. PMID:26334786

  8. Methamphetamine blocks exercise effects on Bdnf and Drd2 gene expression in frontal cortex and striatum.

    PubMed

    Thompson, Andrew B; Stolyarova, Alexandra; Ying, Zhe; Zhuang, Yumei; Gómez-Pinilla, Fernando; Izquierdo, Alicia

    2015-12-01

    Exposure to drugs of abuse can produce many neurobiological changes which may lead to increased valuation of rewards and decreased sensitivity to their costs. Many of these behavioral alterations are associated with activity of D2-expressing medium spiny neurons in the striatum. Additionally, Bdnf in the striatum has been shown to play a role in flexible reward-seeking behavior. Given that voluntary aerobic exercise can affect the expression of these proteins in healthy subjects, and that exercise has shown promise as an anti-addictive therapy, we set out to quantify changes in D2 and Bdnf expression in methamphetamine-exposed rats given access to running wheels. Sixty-four rats were treated for two weeks with an escalating dose of methamphetamine or saline, then either sacrificed, housed in standard cages, or given free access to a running wheel for 6 weeks prior to sacrifice. Rats treated with methamphetamine ran significantly greater distances than saline-treated rats, suggesting an augmentation in the reinforcement value of voluntary wheel running. Transcription of Drd2 and Bdnf was assessed via RT-qPCR. Protein expression levels of D2 and phosphorylation of the TrkB receptor were measured via western blot. Drd2 and Bdnf mRNA levels were impacted independently by exercise and methamphetamine, but exposure to methamphetamine prior to the initiation of exercise blocked the exercise-induced changes seen in rats treated with saline. Expression levels of both proteins were elevated immediately after methamphetamine, but returned to baseline after six weeks, regardless of exercise status.

  9. The presence of a single nucleotide polymorphism in the BDNF gene affects the rate of locomotor adaptation after stroke

    PubMed Central

    Helm, Erin E.; Tyrell, Christine M.; Pohlig, Ryan T.; Brady, Lucas D.; Reisman, Darcy S.

    2015-01-01

    Induction of neural plasticity through motor learning has been demonstrated in animals and humans. Brain derived neurotrophic factor (BDNF), a member of the neurotrophin family of growth factors, is thought to play an integral role in modulation of central nervous system plasticity during learning and motor skill recovery. Thirty percent of humans possess a single nucleotide polymorphism on the BDNF gene (Val66Met), which has been linked to decreased activity dependent release of BDNF. Presence of the polymorphism has been associated with altered cortical activation, short term plasticity and altered skill acquisition, and learning in healthy humans. The impact of the Val66Met polymorphism on motor learning post-stroke has not been explored. The purpose of this study was to examine the impact of the Val66Met polymorphism in learning of a novel locomotor task in subjects with chronic stroke. It was hypothesized that subjects with the polymorphism would have an altered rate and magnitude of adaptation to a novel locomotor walking paradigm (the split-belt treadmill), compared to those without the polymorphism. The rate of adaptation was evaluated as the reduction in gait asymmetry during the first 30 (early adaptation) and last 100 (late adaptation) strides. Twenty-seven individuals with chronic stroke participated in a single session of split-belt treadmill walking and tested for the polymorphism. Step length and limb phase were measured to assess adaptation of spatial and temporal parameters of walking. The rate of adaptation of step length asymmetry differed significantly between those with and without the polymorphism, while the amount of total adaptation did not. These results suggest that chronic stroke survivors, regardless of presence or absence of the polymorphism, are able to adapt their walking pattern over a period of trial and error practice, however the presence of the polymorphism influences the rate at which this is achieved. PMID:26487176

  10. The presence of a single-nucleotide polymorphism in the BDNF gene affects the rate of locomotor adaptation after stroke.

    PubMed

    Helm, Erin E; Tyrell, Christine M; Pohlig, Ryan T; Brady, Lucas D; Reisman, Darcy S

    2016-02-01

    Induction of neural plasticity through motor learning has been demonstrated in animals and humans. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family of growth factors, is thought to play an integral role in modulation of central nervous system plasticity during learning and motor skill recovery. Thirty percent of humans possess a single-nucleotide polymorphism on the BDNF gene (Val66Met), which has been linked to decreased activity-dependent release of BDNF. Presence of the polymorphism has been associated with altered cortical activation, short-term plasticity and altered skill acquisition, and learning in healthy humans. The impact of the Val66Met polymorphism on motor learning post-stroke has not been explored. The purpose of this study was to examine the impact of the Val66Met polymorphism in learning of a novel locomotor task in subjects with chronic stroke. It was hypothesized that subjects with the polymorphism would have an altered rate and magnitude of adaptation to a novel locomotor walking paradigm (the split-belt treadmill), compared to those without the polymorphism. The rate of adaptation was evaluated as the reduction in gait asymmetry during the first 30 (early adaptation) and last 100 (late adaptation) strides. Twenty-seven individuals with chronic stroke participated in a single session of split-belt treadmill walking and tested for the polymorphism. Step length and limb phase were measured to assess adaptation of spatial and temporal parameters of walking. The rate of adaptation of step length asymmetry differed significantly between those with and without the polymorphism, while the amount of total adaptation did not. These results suggest that chronic stroke survivors, regardless of presence or absence of the polymorphism, are able to adapt their walking pattern over a period of trial-and-error practice; however, the presence of the polymorphism influences the rate at which this is achieved.

  11. A 1.7-Mb YAC contig around the human BDNF gene (11p13): integration of the physical, genetic, and cytogenetic maps in relation to WAGR syndrome

    SciTech Connect

    Rosier, M.F.; Martin, A.; Houlgatte, R.

    1994-11-01

    WAGR (Wilms tumor, aniridia, genito-urinary abnormalities, mental retardation) syndrome in humans is associated with deletions of the 11p13 region. The brain-derived neurotrophic factor (BDNF) gene maps to this region, and its deletion seems to contribute to the severity of the patient`s mental retardation. Yeast artificial chromosomes (YACs) carrying the BDNF gene have been isolated and characterized. Localization of two known exons of this gene leads to a minimal estimation of its size of about 40 kb. Chimerism of the BDNF YACs has been investigated by fluorescence in situ hybridization and chromosome assignment on somatic cell hybrids. Using the BDNF gene, YAC end sequence tagged sites (STS), and Genethon microsatellite markers, the authors constructed a 1.7-Mb contig and refined the cytogenetic map at 11p13. The resulting integrated physical, genetic, and cytogenetic map constitutes a resource for the characterization of genes that may be involved in the WAGR syndrome. 42 refs., 2 figs., 3 tabs.

  12. BDNF gene therapy induces auditory nerve survival and fiber sprouting in deaf Pou4f3 mutant mice.

    PubMed

    Fukui, H; Wong, H T; Beyer, L A; Case, B G; Swiderski, D L; Di Polo, A; Ryan, A F; Raphael, Y

    2012-01-01

    Current therapy for patients with hereditary absence of cochlear hair cells, who have severe or profound deafness, is restricted to cochlear implantation, a procedure that requires survival of the auditory nerve. Mouse mutations that serve as models for genetic deafness can be utilized for developing and enhancing therapies for hereditary deafness. A mouse with Pou4f3 loss of function has no hair cells and a subsequent, progressive degeneration of auditory neurons. Here we tested the influence of neurotrophin gene therapy on auditory nerve survival and peripheral sprouting in Pou4f3 mouse ears. BDNF gene transfer enhanced preservation of auditory neurons compared to control ears, in which nearly all neurons degenerated. Surviving neurons in treated ears exhibited pronounced sprouting of nerve fibers into the auditory epithelium, despite the absence of hair cells. This enhanced nerve survival and regenerative sprouting may improve the outcome of cochlear implant therapy in patients with hereditary deafness.

  13. Significant changes in endogenous retinal gene expression assessed 1 year after a single intraocular injection of AAV-CNTF or AAV-BDNF

    PubMed Central

    LeVaillant, Chrisna J; Sharma, Anil; Muhling, Jill; Wheeler, Lachlan PG; Cozens, Greg S; Hellström, Mats; Rodger, Jennifer; Harvey, Alan R

    2016-01-01

    Use of viral vectors to deliver therapeutic genes to the central nervous system holds promise for the treatment of neurodegenerative diseases and neurotrauma. Adeno-associated viral (AAV) vectors encoding brain-derived neurotrophic factor (BDNF) or ciliary derived neurotrophic factor (CNTF) promote the viability and regeneration of injured adult rat retinal ganglion cells. However, these growth-inducing transgenes are driven by a constitutively active promoter, thus we examined whether long-term AAV-mediated secretion of BDNF or CNTF affected endogenous retinal gene expression. One year after the intravitreal injection of AAV-green fluorescent protein (GFP), bi-cistronic AAV-BDNF-GFP or AAV-CNTF-GFP, mRNA was extracted and analyzed using custom 96 well polymerase chain reaction arrays. Of 93 test genes, 56% showed significantly altered expression in AAV-BDNF-GFP and/or AAV-CNTF-GFP retinas compared with AAV-GFP controls. Of these genes, 73% showed differential expression in AAV-BDNF versus AAV-CNTF injected eyes. To focus on retinal ganglion cell changes, quantitative polymerase chain reaction was undertaken on mRNA (16 genes) obtained from fixed retinal sections in which the ganglion cell layer was enriched. The sign and extent of fold changes in ganglion cell layer gene expression differed markedly from whole retinal samples. Sustained and global alteration in endogenous mRNA expression after gene therapy should be factored into any interpretation of experimental/clinical outcomes, particularly when introducing factors into the central nervous system that require secretion to evoke functionality. PMID:27933306

  14. Significant changes in endogenous retinal gene expression assessed 1 year after a single intraocular injection of AAV-CNTF or AAV-BDNF.

    PubMed

    LeVaillant, Chrisna J; Sharma, Anil; Muhling, Jill; Wheeler, Lachlan Pg; Cozens, Greg S; Hellström, Mats; Rodger, Jennifer; Harvey, Alan R

    2016-01-01

    Use of viral vectors to deliver therapeutic genes to the central nervous system holds promise for the treatment of neurodegenerative diseases and neurotrauma. Adeno-associated viral (AAV) vectors encoding brain-derived neurotrophic factor (BDNF) or ciliary derived neurotrophic factor (CNTF) promote the viability and regeneration of injured adult rat retinal ganglion cells. However, these growth-inducing transgenes are driven by a constitutively active promoter, thus we examined whether long-term AAV-mediated secretion of BDNF or CNTF affected endogenous retinal gene expression. One year after the intravitreal injection of AAV-green fluorescent protein (GFP), bi-cistronic AAV-BDNF-GFP or AAV-CNTF-GFP, mRNA was extracted and analyzed using custom 96 well polymerase chain reaction arrays. Of 93 test genes, 56% showed significantly altered expression in AAV-BDNF-GFP and/or AAV-CNTF-GFP retinas compared with AAV-GFP controls. Of these genes, 73% showed differential expression in AAV-BDNF versus AAV-CNTF injected eyes. To focus on retinal ganglion cell changes, quantitative polymerase chain reaction was undertaken on mRNA (16 genes) obtained from fixed retinal sections in which the ganglion cell layer was enriched. The sign and extent of fold changes in ganglion cell layer gene expression differed markedly from whole retinal samples. Sustained and global alteration in endogenous mRNA expression after gene therapy should be factored into any interpretation of experimental/clinical outcomes, particularly when introducing factors into the central nervous system that require secretion to evoke functionality.

  15. Functional coupling analysis suggests link between the obesity gene FTO and the BDNF-NTRK2 signaling pathway

    PubMed Central

    2011-01-01

    Background The Fat mass and obesity gene (FTO) has been identified through genome wide association studies as an important genetic factor contributing to a higher body mass index (BMI). However, the molecular context in which this effect is mediated has yet to be determined. We investigated the potential molecular network for FTO by analyzing co-expression and protein-protein interaction databases, Coxpresdb and IntAct, as well as the functional coupling predicting multi-source database, FunCoup. Hypothalamic expression of FTO-linked genes defined with this bioinformatics approach was subsequently studied using quantitative real time-PCR in mouse feeding models known to affect FTO expression. Results We identified several candidate genes for functional coupling to FTO through database studies and selected nine for further study in animal models. We observed hypothalamic expression of Profilin 2 (Pfn2), cAMP-dependent protein kinase catalytic subunit beta (Prkacb), Brain derived neurotrophic factor (Bdnf), neurotrophic tyrosine kinase, receptor, type 2 (Ntrk2), Signal transducer and activator of transcription 3 (Stat3), and Btbd12 to be co-regulated in concert with Fto. Pfn2 and Prkacb have previously not been linked to feeding regulation. Conclusions Gene expression studies validate several candidates generated through database studies of possible FTO-interactors. We speculate about a wider functional role for FTO in the context of current and recent findings, such as in extracellular ligand-induced neuronal plasticity via NTRK2/BDNF, possibly via interaction with the transcription factor CCAAT/enhancer binding protein β (C/EBPβ). PMID:22087873

  16. Evidence of association between Val66Met polymorphism at BDNF gene and anxiety disorders in a community sample of children and adolescents.

    PubMed

    Tocchetto, Andréa; Salum, Giovanni A; Blaya, Carolina; Teche, Stefania; Isolan, Luciano; Bortoluzzi, Andressa; Rebelo E Silva, Rafael; Becker, Juliana A; Bianchin, Marino M; Rohde, Luis Augusto; Leistner-Segal, Sandra; Manfro, Gisele G

    2011-09-20

    Different lines of evidence support BDNF as a candidate gene in mood and anxiety modulation. More recently, the Met allele of the BDNF Val66Met polymorphism has been implicated in anxiety in animal models and anxiety-traits in humans. The aim of this study is to evaluate the a priori hypothesis that the association between anxiety disorders and Val66Met polymorphism at the BDNF gene would be replicated in a community sample of children and adolescents. 240 subjects from a total sample of 2457 children and adolescents aged 10-17 years from the public schools in the catchment area of the primary care unit of a university hospital participated in this case-control study and were assessed for psychopathology using the K-SADS-PL. A sample of saliva was collected for DNA analysis of Val66Met polymorphism. BDNF was the single gene evaluated in this sample. We found a significant association between carrying one copy of the Met allele and higher chance of anxiety disorders in children and adolescents. The association remained positive even after the adjustment for potential confounders (228 subjects; OR=3.53 (CI95% 1.77-7.06; p<0.001)). Our results support the a priori hypothesis of an association between anxiety and the polymorphism Val66Met. To our knowledge, this is the first study documenting a potential role of this polymorphism in a community sample of anxious children and adolescents.

  17. Opposing roles of synaptic and extrasynaptic NMDA receptors in neuronal calcium signalling and BDNF gene regulation.

    PubMed

    Vanhoutte, Peter; Bading, Hilmar

    2003-06-01

    Neuronal responses to electrical activity-induced calcium signals are specified by the localization of the calcium entry site and the spatial properties of the calcium transient. Calcium flux through NMDA receptors located in the synapse initiates changes in synaptic efficacy and promotes pro-survival events, whereas calcium flux through extrasynaptic NMDA receptors is coupled to cell death pathways. The dialogue between the synaptic NMDA receptors and the nucleus is also modulated by extrasynaptic NMDA receptors, which shut down activity of CRE-binding protein (CREB) and antagonize the increase in brain-derived neurotrophic factor (BDNF) expression induced by synaptic NMDA receptors. The specification of the biological response by the localization of the receptor activated is a new concept in neuronal calcium signalling that can explain many of the opposing roles of NMDA receptors.

  18. 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.

    PubMed

    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.

  19. Association Between Smoking, Nicotine Dependence, and BDNF Val66Met Polymorphism with BDNF Concentrations in Serum

    PubMed Central

    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 Val66Met polymorphism has also been found. The aim of this study is to examine the levels of serum BDNF in never-smokers, former smokers, and current smokers—with and without nicotine dependence—and to examine the interaction of the polymorphism and smoking status with serum BDNF. Methods: We used baseline serum and gene data of BDNF on 2,088 participants from the Netherlands Study of Depression and Anxiety (NESDA) to investigate smoking-BDNF association while controlling for potential confounding variables. Nicotine dependence was assessed with the Fagerstrom Test for Nicotine Dependence (FTND). Results: Smokers with and without nicotine dependence had higher levels of serum BDNF than former and never-smokers. Nicotine dependence and number of cigarettes smoked per day did not add to the prediction of serum BDNF; however, total number of smoking years was a significant predictor of serum BDNF. There was no association of BDNF Val66Met, nor an interaction of this polymorphism and smoking status, with serum BDNF. Conclusions: Current smoking and higher number of smoking years are associated with higher levels of serum BDNF, and this is independent of the BDNF genotype. Nicotine dependence itself is not associated with a further increase or decrease of serum BDNF. Longitudinal investigations that address changes in serum BDNF in incident smokers and/or in quitters may be useful to understand the association of smoking with BDNF. PMID:25183693

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

    PubMed

    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.

  1. Implication of the env Gene of the Human Endogenous Retrovirus W Family in the Expression of BDNF and DRD3 and Development of Recent-Onset Schizophrenia

    PubMed Central

    Huang, WenJie; Li, Shan; Hu, YuanMing; Yu, Honglian; Luo, Feng; Zhang, Qi; Zhu, Fan

    2011-01-01

    Objective: Retrovirus has been suggested as one of agents involved in the development of schizophrenia. In the present study, we examined the role of the human endogenous retrovirus W family (HERV-W) env gene in the etiopathogenesis of recent-onset schizophrenia, using molecular and epidemiological approaches. Methods: Nested RT-PCR was used to detect the messenger RNA (mRNA) of the HERV-w env gene in plasmas. Quantitative real-time polymerase chain reaction (PCR) was employed to detect the viral reverse transcriptase activity in human sera. Human U251 glioma cells were used to study the potential role of the HERV-W env gene in the etiopathogenesis of recent-onset schizophrenia. Results: We identified genes with mRNA sequences homologous to HERV-W env gene from plasmas of 42 out of 118 individuals with recent-onset schizophrenia but not from any of 106 normal persons (P < .01, t test). Quantitative real-time PCR showed a significantly increase in the reverse transcriptase activity in the sera of patients (by 35.59%) compared with controls (by 2.83%) (P < .05, t test). Overexpression of HERV-w env in human U251 glioma cells upregulated brain-derived neurotrophic factor (BDNF), an important schizophrenia-associated gene, neurotrophic tyrosine kinase receptor type 2 (NTRK2, also called TrkB), and dopamine receptor D3 and increased the phosphorylation of cyclic adenosine monophosphate response element–binding (CREB) protein. BDNF promoter reporter gene assays showed that the HERV-W env triggers BDNF production in human U251 glioma cells. Using gene knockdown, we found that CREB is required for the expression of BDNF that is regulated by env. Conclusion: Our data revealed that the transcriptional activation of HERV is associated with the development of schizophrenia in some patients and indicated that HERV-W env regulates the expression of schizophrenia-associated genes. This report is the first to elucidate the signaling pathway responsible for the upregulation of

  2. Impact of exercise and a complex environment on hippocampal dendritic morphology, Bdnf gene expression, and DNA methylation in male rat pups neonatally exposed to alcohol.

    PubMed

    Boschen, K E; McKeown, S E; Roth, T L; Klintsova, A Y

    2016-09-06

    Alcohol exposure in utero can result in Fetal Alcohol Spectrums Disorders (FASD). Measures of hippocampal neuroplasticity, including long-term potentiation, synaptic and dendritic organization, and adult neurogenesis, are consistently disrupted in rodent models of FASD. The current study investigated whether third trimester-equivalent binge-like alcohol exposure (AE) [postnatal days (PD) 4-9] affects dendritic morphology of immature dentate gyrus granule cells, and brain-derived neurotrophic factor (Bdnf) gene expression and DNA methylation in hippocampal tissue in adult male rats. To understand immediate impact of alcohol, DNA methylation was measured in the PD10 hippocampus. In addition, two behavioral interventions, wheel running (WR) and environmental complexity (EC), were utilized as rehabilitative therapies for alcohol-induced deficits. AE significantly decreased dendritic complexity of the immature neurons, demonstrating the long-lasting impact of neonatal alcohol exposure on dendritic morphology of immature neurons in the hippocampus. Both housing conditions robustly enhanced dendritic complexity in the AE animals. While Bdnf exon I DNA methylation was lower in the AE and sham-intubated animals compared with suckle controls on PD10, alterations to Bdnf DNA methylation and gene expression levels were not present at PD72. In control animals, exercise, but not exercise followed by housing in EC, resulted in higher levels of hippocampal Bdnf gene expression and lower DNA methylation. These studies demonstrate the long-lasting negative impact of developmental alcohol exposure on hippocampal dendritic morphology and support the implementation of exercise and complex environments as therapeutic interventions for individuals with FASD. © 2016 Wiley Periodicals, Inc. Develop Neurobiol, 2016.

  3. MeCP2 regulates Tet1-catalyzed demethylation, CTCF binding, and learning-dependent alternative splicing of the BDNF gene in Turtle

    PubMed Central

    Zheng, Zhaoqing; Ambigapathy, Ganesh; Keifer, Joyce

    2017-01-01

    MECP2 mutations underlying Rett syndrome cause widespread misregulation of gene expression. Functions for MeCP2 other than transcriptional are not well understood. In an ex vivo brain preparation from the pond turtle Trachemys scripta elegans, an intraexonic splicing event in the brain-derived neurotrophic factor (BDNF) gene generates a truncated mRNA transcript in naïve brain that is suppressed upon classical conditioning. MeCP2 and its partners, splicing factor Y-box binding protein 1 (YB-1) and methylcytosine dioxygenase 1 (Tet1), bind to BDNF chromatin in naïve but dissociate during conditioning; the dissociation correlating with decreased DNA methylation. Surprisingly, conditioning results in new occupancy of BDNF chromatin by DNA insulator protein CCCTC-binding factor (CTCF), which is associated with suppression of splicing in conditioning. Knockdown of MeCP2 shows it is instrumental for splicing and inhibits Tet1 and CTCF binding thereby negatively impacting DNA methylation and conditioning-dependent splicing regulation. Thus, mutations in MECP2 can have secondary effects on DNA methylation and alternative splicing. DOI: http://dx.doi.org/10.7554/eLife.25384.001 PMID:28594324

  4. A common polymorphism in the brain-derived neurotrophic factor gene (BDNF) modulates human cortical plasticity and the response to rTMS.

    PubMed

    Cheeran, Binith; Talelli, Penelope; Mori, Francesco; Koch, Giacomo; Suppa, Antonio; Edwards, Mark; Houlden, Henry; Bhatia, Kailash; Greenwood, Richard; Rothwell, John C

    2008-12-01

    The brain-derived neurotrophic factor gene (BDNF) is one of many genes thought to influence synaptic plasticity in the adult brain and shows a common single nucleotide polymorphism (BDNF Val66Met) in the normal population that is associated with differences in hippocampal volume and episodic memory. It is also thought to influence possible synaptic changes in motor cortex following a simple motor learning task. Here we extend these studies by using new non-invasive transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (TDCS) techniques that directly test the excitability and plasticity of neuronal circuits in human motor cortex in subjects at rest. We investigated whether the susceptibility to TMS probes of plasticity is significantly influenced by the BDNF polymorphism. Val66Met carriers were matched with Val66Val individuals and tested on the following protocols: continuous and intermittent theta burst TMS; median nerve paired associative stimulation; and homeostatic plasticity in the TDCS/1 Hz rTMS model. The response of Met allele carriers differed significantly in all protocols compared with the response of Val66Val individuals. We suggest that this is due to the effect of BNDF on the susceptibility of synapses to undergo LTP/LTD. The circuits tested here are implicated in the pathophysiology of movement disorders such as dystonia and are being assessed as potential new targets in the treatment of stroke. Thus the polymorphism may be one factor that influences the natural response of the brain to injury and disease.

  5. Brain-derived neurotrophic factor (BDNF) gene: a gender-specific role in cognitive function during normal cognitive aging of the MEMO-Study?

    PubMed

    Laing, Katharine R; Mitchell, David; Wersching, Heike; Czira, Maria E; Berger, Klaus; Baune, Bernhard T

    2012-08-01

    Cognitive aging processes are underpinned by multiple processes including genetic factors. The brain-derived neurotrophic factor (BDNF) has been suggested to be involved in age-related cognitive decline in otherwise healthy individuals. The gender-specific role of the BDNF gene in cognitive aging remains unclear. The identification of genetic biomarkers might be a useful approach to identify individuals at risk of cognitive decline during healthy aging processes. The aim of this study was to investigate the associations between three single-nucleotide polymorphisms (SNPs) in the BDNF gene and domains of cognitive functioning in normal cognitive aging. The sample, comprising 369 participants (M = 72.7 years, SD = 4.45 years), completed an extensive neuropsychological test battery measuring memory, motor function, and perceptual speed. The relationships between the SNPs rs6265, rs7103411, and rs7124442 and cognitive domains were examined. While significant main effects of BDNF SNPs on cognitive function were found for the association between rs7103411 and memory performance, gender-specific analyses revealed for females significant main effects of rs7103411 for memory and of rs6265 for perceptual speed independent of the APOE*E4 status and education. The finding for the association between rs6265 and perceptual speed in females remained significant after Bonferroni correction for multiple comparisons. None of the analyses showed significant results for males. This study is the first to implicate that the SNPs rs6265 and rs7103411 affect cognitive function in the elderly in a gender-specific way.

  6. BDNF modulates contextual fear learning during adolescence.

    PubMed

    Dincheva, Iva; Pattwell, Siobhan S; Tessarollo, Lino; Bath, Kevin G; Lee, Francis S

    2014-01-01

    Brain-derived neurotrophic factor (BDNF) is a growth factor that plays key roles in regulating higher-order emotional and cognitive processes including fear learning and memory. A common single-nucleotide polymorphism (SNP) has been identified in the human BDNF gene (BDNF Val66Met) that leads to decreased BDNF secretion and impairments in specific forms of fear learning in adult humans and genetically modified mice containing this SNP. As the emergence of anxiety and other fear-related disorders peaks during adolescence, we sought to better understand the impact of this BDNF SNP on fear learning during the transition through adolescence in BDNF Val66Met knock-in mice. Previously, we have shown that contextual fear expression is temporarily suppressed in wild-type mice during a distinct period in adolescence, but re-emerges at later, postadolescent ages. Until recently, it was unclear whether BDNF-TrkB signaling is involved in the modulation of hippocampal-dependent contextual fear learning and memory during this adolescent period. Here we show that in BDNF Val66Met mice, the presence of the Met allele does not alter contextual fear expression during adolescence, but when previously conditioned BDNF(Met/Met) mice are tested in adulthood, they fail to display the delayed expression of contextual fear compared to wild-type BDNF(Val/Val) controls, indicating that the Met allele may permanently alter hippocampal function, leading to persistent functioning that is indistinguishable from the adolescent state. Conversely, truncated TrkB receptor (TrkB.T1)-deficient (TrkB.T1(-/-)) mice, a genetic mouse model with increased BDNF-TrkB signaling through full-length TrkB receptors, exhibit an accelerated expression of contextual fear during adolescence compared to wild-type controls. Our results point to a critical function for BDNF-TrkB signaling in fear regulation in vivo, particularly during a potentially sensitive period in adolescence. © 2014 S. Karger AG, Basel.

  7. Synaptic regulation of affective behaviors; role of BDNF

    PubMed Central

    Ninan, Ipe

    2013-01-01

    Brain derived neurotrophic factor (BDNF), a neurotrophin essential for nervous system development and synaptic plasticity, has been found to have a significant influence on affective behaviors. The notion that an impairment in BDNF signaling might be involved in affective disorders is originated primarily from the opposing effects of antidepressants and stress on BDNF signaling. Antidepressants enhance BDNF signaling and synaptic plasticity. On the other hand, negative environmental factors such as severe stress suppress BDNF signaling, impair synaptic activity and increase susceptibility to affective disorders. Postmortem studies provided strong support for decreased BDNF signaling in depressive disorders. Remarkably, studies in humans with a single nucleotide polymorphism in the BDNF gene, the BDNF Val66Met which affects regulated release of BDNF, showed profound deficits in hippocampal and prefrontal cortical (PFC) plasticity and cognitive behaviors. BDNF regulates synaptic mechanisms responsible for various cognitive processes including attenuation of aversive memories, a key process in the regulation of affective behaviors. The unique role of BDNF in cognitive and affective behaviors suggests that cognitive deficits due to altered BDNF signaling might underlie affective disorders. Understanding how BDNF modulates synapses in neural circuits relevant to affective behaviors, particularly the medial prefrontal cortical (mPFC)-hippocampus-amygdala pathway, and its interaction with development, sex, and environmental risk factors might shed light on potential therapeutic targets for affective disorders. PMID:23747574

  8. Genetic moderation of child maltreatment effects on depression and internalizing symptoms by 5-HTTLPR, BDNF, NET, and CRHR1 genes in African-American children

    PubMed Central

    Cicchetti, Dante; Rogosch, Fred A.

    2014-01-01

    Genetic moderation of the effects of child maltreatment on depression and internalizing symptoms was investigated in a sample of low-income maltreated and nonmaltreated African-American children (N = 1,096). Lifetime child maltreatment experiences were independently coded from Child Protective Services records and maternal report. Child depression and internalizing problems were assessed in the context of a summer research camp by self-report (Children’s Depression Inventory, CDI) and adult counselor-report (Teacher Report Form, TRF). DNA was obtained from buccal cell or saliva samples and genotyped for polymorphisms of the following genes: 5-HTTLPR, BDNF, NET, and CRHR1. ANCOVAs with age and gender as covariates were conducted, with maltreatment status and respective polymorphism as main effects and their GxE interactions. Maltreatment consistently was associated with higher CDI and TRF symptoms. Results for child self-report symptoms indicated a GxE interaction for BDNF and maltreatment. Additionally, BDNF and tri-allelic 5-HTTLPR interacted with child maltreatment in a GxGxE interaction. Analyses for counselor-report of child anxiety/depression symptoms on the TRF indicated moderation of child maltreatment effects by tri-allelic 5-HTTLPR. These effects were elaborated based on variation in developmental timing of maltreatment experiences. NET was found to further moderate the GxE interaction of 5-HTTLPR and maltreatment status revealing a GxGxE interaction. This GxGxE was extended by consideration of variation in maltreatment subtype experiences. Finally, GxGxE effects were observed for the co-action of BDNF and the CRHR1 haplotype. The findings illustrate the variable influence of specific genotypes in GxE interactions based on variation in maltreatment experiences and the importance of a multi-genic approach for understanding influences on depression and internalizing symptoms among African-American children. PMID:25422957

  9. Lack of an association of BDNF Val66Met polymorphism and plasma BDNF with hippocampal volume and memory

    PubMed Central

    Kim, Ana; Fagan, Anne M; Goate, Alison M; Benzinger, Tammie LS; Morris, John C; Head, Denise

    2015-01-01

    Brain-derived neurotrophic factor (BDNF) has been shown to be important for neuronal survival and synaptic plasticity in the hippocampus in non-human animals. The Val66Met polymorphism in the BDNF gene, involving a valine (Val) to methionine (Met) substitution at codon 66, has been associated with lower BDNF secretion in vitro. However, there have been mixed results regarding associations between either circulating BDNF or the BDNF Val66Met polymorphism with hippocampal volume and memory in humans. The current study examined the association of BDNF genotype and plasma BDNF with hippocampal volume and memory in two large independent cohorts of middle-aged and older adults (both cognitively normal and early-stage dementia). Sample sizes ranged from 123 to 649. Measures of the BDNF genotype, plasma BDNF, MRI-based hippocampal volume and memory performance were obtained from the Knight Alzheimer Disease Research Center (ADRC) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). There were no significant differences between BDNF Met+ and Met- groups on either hippocampal volume or memory in either cohort. In addition, plasma BDNF was not significantly associated with either hippocampal volume or memory in either cohort. Neither age, cognitive status nor gender moderated any of the relationships. Overall, current findings suggest that BDNF genotype and plasma BDNF may not be robust predictors for variance in hippocampal volume and memory in middle age and older adult cohorts. PMID:25784293

  10. Maternal supply of BDNF to mouse fetal brain through the placenta.

    PubMed

    Kodomari, Ikuko; Wada, Etsuko; Nakamura, Shun; Wada, Keiji

    2009-02-01

    Gastrointestinal peptides and hormones are known to penetrate through the utero-placental barrier and regulate fetal development. In the present study, we tested permeation of maternal brain-derived neurotrophic factor (BDNF) to fetuses, using BDNF-gene deficient mice and exogenous BDNF administration. At embryonic day 13.5 (E13.5)-14.5, BDNF protein concentrations in the fetal brain of BDNF homozygous null mutant (bdnf (-/-)) were comparable to the levels seen in wild-type fetuses. After E17.5, BDNF protein levels in bdnf (-/-) fetal brain were still detectable but its levels were significantly decreased below those in wild-type brain. When recombinant BDNF protein was injected into pregnant wild-type mice carrying E14.5 embryos, BDNF protein levels in fetal brain were elevated dose-dependently. These findings suggest that maternal BDNF reaches the fetal brain through utero-placental barrier and might contribute to its development.

  11. A Novel Interaction between Tryptophan Hydroxylase 2 (TPH2) Gene Polymorphism (rs4570625) and BDNF Val66Met Predicts a High-Risk Emotional Phenotype in Healthy Subjects

    PubMed Central

    Latsko, Maeson S.; Gilman, T. Lee; Matt, Lindsey M.; Nylocks, K. Maria; Coifman, Karin G.; Jasnow, Aaron M.

    2016-01-01

    Poor inhibitory processing of negative emotional content is central to many psychiatric disorders, including depression and anxiety. Moreover, increasing evidence suggests that core aspects of emotion-inhibitory processing are largely inherited and as such may represent a key intermediate or risk-related phenotype for common affective diseases (e.g., unipolar depressive, anxiety disorders). The current study employed a candidate-gene approach in order to most effectively examine this complex behavioral phenotype. We examined the novel interaction between BDNF (Val66Met) and TPH2 (rs4570625) polymorphisms and their influence on behavioral inhibition of negative emotion in two independent investigations of healthy adults. BDNF Met carriers consistently report greater symptoms of affective disease and display corresponding behavioral rigidity, while TPH2 T carriers display poor inhibitory processing. These genotypes are traditionally perceived as ‘risk’ genotypes when compared to their respective major Val and G homozygous genotypes, but evidence is mixed. Recent studies in humans and mutant mouse models suggest biological epistasis between BDNF and genes involved in serotonin regulation. Moreover, polymorphisms in the TPH2 gene may have greater influence on serotonergic function than other more commonly studied polymorphisms (e.g., 5-HTTLPR). We observed consistent evidence across two different emotion-inhibition paradigms, one with high internal validity (Study 1, n = 119) and one with high ecological validity (Study 2, n = 115) that the combination of Val/Val and G/G genotypes was clearly associated with impaired inhibition of negative emotional content. This was followed by individuals carrying the BDNF—Met allele (including Met/Val and Met/Met) when combined with the TPH2—T allele (including T/G and T/T combinations). The consistency of these results across tasks and studies suggests that these two groups may be particularly vulnerable to the most common

  12. Inhibition of BDNF-AS Provides Neuroprotection for Retinal Ganglion Cells against Ischemic Injury

    PubMed Central

    Xu, Lifang; Zhang, Ziyin; Xie, Tianhua; Zhang, Xiaoyang; Dai, Tu

    2016-01-01

    Background: Brain-derived neurotrophic factor (BDNF) protects retinal ganglion cells against ischemia in ocular degenerative diseases. We aimed to determine the effect of BDNF-AS on the ischemic injury of retinal ganglion cells. Methods: The levels of BDNF and BDNF-AS were measured in retinal ganglion cells subjected to oxygen and glucose deprivation. The lentiviral vectors were constructed to either overexpress or knock out BDNF-AS. The luciferase reporter gene assay was used to determine whether BDNF-AS could target its seed sequence on BDNF mRNA. The methyl thiazolyl tetrazolium assay was used to determine cell viability, and TUNEL staining was used for cell apoptosis. Results: The levels of BDNF-AS were negatively correlated with BDNF in ischemic retinal ganglion cells. BDNF-AS directly targeted its complementary sequences on BDNF mRNA. BDNF-AS regulated the expression of BDNF and its related genes in retinal ganglion cells. Down-regulation of BDNF-AS increased cell viability and decreased the number of TUNEL-positive retinal ganglion cells under oxygen and glucose deprivation conditions. Conclusion: Inhibition of BDNF-AS protected retinal ganglion cells against ischemia by increasing the levels of BDNF. PMID:27935942

  13. Comparison of the temporary dynamics of NGF and BDNF gene expression in rat hippocampus, frontal cortex, and retina under Semax action.

    PubMed

    Shadrina, Maria; Kolomin, Timur; Agapova, Tamara; Agniullin, Yan; Shram, Stanislav; Slominsky, Petr; Lymborska, Svetlana; Myasoedov, Nikolay

    2010-05-01

    Neurotrophins are a family of structurally related proteins that regulate the survival, differentiation, and maintenance of function of different neuron populations. Some peptides are able to affect the production and activity of neurotrophins. One of these synthetic peptides is heptapeptide Semax, an analog of the N-terminal adrenocorticotropic hormone fragment 4-10. It is known that Semax has effects on learning and memory formation and exerts some neuroprotective effects in rodents and humans. Male Wistar rats were treated for 20 min, 40 min, 90 min, 3 h, 8 h, and 24 h with Semax. Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) gene expression in rat brain and retina was analyzed by real-time polymerase chain reaction. It was revealed that after Semax administration the multidirectional activation of the expression of the genes under investigation in the hippocampus, frontal cortex, and retina was observed. The expression of both neurotrophin genes was decreased in rat hippocampus and retina 20 min after Semax administration and was increased in the frontal cortex. The expression levels of NGF remained practically constant in the retina at the initial stage, whereas the expression levels of BDNF were significantly increased 90 min after Semax administration.

  14. The Interacting Effect of the BDNF Val66Met Polymorphism and Stressful Life Events on Adolescent Depression Is Not an Artifact of Gene-Environment Correlation: Evidence from a Longitudinal Twin Study

    ERIC Educational Resources Information Center

    Chen, Jie; Li, Xinying; McGue, Matt

    2013-01-01

    Background: Confounding introduced by gene-environment correlation (rGE) may prevent one from observing a true gene-environment interaction (G × E) effect on psychopathology. The present study investigated the interacting effect of the BDNF Val66Met polymorphism and stressful life events (SLEs) on adolescent depression while controlling for the…

  15. The Interacting Effect of the BDNF Val66Met Polymorphism and Stressful Life Events on Adolescent Depression Is Not an Artifact of Gene-Environment Correlation: Evidence from a Longitudinal Twin Study

    ERIC Educational Resources Information Center

    Chen, Jie; Li, Xinying; McGue, Matt

    2013-01-01

    Background: Confounding introduced by gene-environment correlation (rGE) may prevent one from observing a true gene-environment interaction (G × E) effect on psychopathology. The present study investigated the interacting effect of the BDNF Val66Met polymorphism and stressful life events (SLEs) on adolescent depression while controlling for the…

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

    PubMed Central

    2010-01-01

    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. PMID:20074340

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

    PubMed

    Tognoli, Chiara; Rossi, Federica; Di Cola, Francesco; Baj, Gabriele; Tongiorgi, Enrico; Terova, Genciana; Saroglia, Marco; Bernardini, Giovanni; Gornati, Rosalba

    2010-01-14

    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. 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%. 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. 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

    PubMed Central

    Chagnon, Yvon C.; Potvin, Olivier; Hudon, Carol; Préville, Michel

    2015-01-01

    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 aging 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 ± 0.42; p= 0.0026). This difference was more pronounced in subjects carrying the BDNF rs6265 CT genotype (2.99 ± 0.41 vs. 2.27 ± 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 rs53576 SNV, more particularly at one out of the seven CpGs studied (7.01 ± 0.94 vs. 4.44 ± 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. PMID:26175754

  19. Meta-analysis of six genes (BDNF, DRD1, DRD3, DRD4, GRIN2B and MAOA) involved in neuroplasticity and the risk for alcohol dependence.

    PubMed

    Forero, Diego A; López-León, Sandra; Shin, Hyoung Doo; Park, Byung Lae; Kim, Dai-Jin

    2015-04-01

    Alcohol-related problems have a large impact on human health, accounting for around 4% of deaths and 4.5% of disability-adjusted life-years around the world. Genetic factors could explain a significant fraction of the risk for alcohol dependence (AD). Recent meta-analyses have found significant pooled odds ratios (ORs) for variants in the ADH1B, ADH1C, DRD2 and HTR2A genes. In the present study, we carried out a meta-analysis of common variants in 6 candidate genes involved in neurotransmission and neuroplasticity: BDNF, DRD1, DRD3, DRD4, GRIN2B and MAOA. We carried out a systematic search for published association studies that analyzed the genes of interest. Relevant articles were retrieved and demographic and genetic data were extracted. Pooled ORs were calculated using a random-effects model using the Meta-Analyst program. Dominant, recessive and allelic models were tested and analyses were also stratified by ethnicity. Forty two published studies were included in the current meta-analysis: BDNF-rs6265 (nine studies), DRD1-rs4532 (four studies), DRD3-rs6280 (eleven studies), DRD4-VNTR (seven studies), GRIN2B-rs1806201 (three studies) and MAOA-uVNTR (eight studies). We did not find significant pooled ORs for any of the six genes, under different models and stratifying for ethnicity. In terms of the number of candidate genes included, this is one of the most comprehensive meta-analyses for genetics of AD. Pooled ORs did not support consistent associations with any of the six candidate genes tested. Future studies of novel genes of functional relevance and meta-analyses of quantitative endophenotypes could identify further susceptibility molecular factors for AD. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  20. BDNF deregulation in Rett syndrome

    PubMed Central

    Li, Wei; Pozzo-Miller, Lucas

    2013-01-01

    BDNF is the best-characterized neurotrophin in terms of its gene structure and modulation, secretion processing, and signaling cascades following its release. In addition to diverse features at the genetic and molecular levels, the abundant expression in several regions of the central nervous system has implicated BDNF as a potent modulator in many aspects of neuronal development, as well as synaptic transmission and plasticity. Impairments in any of these critical functions likely contribute to a wide array of neurodevelopmental, neurodegenerative, and neuropsychiatric diseases. In this review, we focus on a prevalent neurodevelopmental disorder, Rett syndrome (RTT), which afflicts 1:15,000 women world-wide. We describe the consequences of loss-of-function mutations in the gene encoding the transcription factor methyl-CpG binding protein 2 (MeCP2) in RTT, and then elaborate on the current understanding of how MeCP2 controls BDNF expression. Finally, we discuss the literature regarding alterations in BDNF levels in RTT individuals and MeCP2-based mouse models, as well as recent progress in searching for rational therapeutic interventions. PMID:23597512

  1. Estimation of BDNF gene polymorphism and predisposition to dependence development for selected psychoactive compounds: genetic aspects of addiction with the selected drugs, amphetamine, tetrahydrocannabinol and opiates.

    PubMed

    Biskupska, J; Borowiak, K S; Karlin-Grazewicz, K; Janus, T; Waloszczyk, P; Potocka-Banas, B; Machoy-Mokrzynska, A; Ossowski, A; Ciechanowicz, A

    2013-03-01

    The etiology of drug addiction, a central nervous system (CNS) disease, is not fully known. This complex problem is believed to be connected with concurrently affecting genetic, psychological and environmental factors. The development of addiction is connected with CNS reinforcement system and dopaminergic neurotransmission. Molecular processes are postulated to be of universal character and allow to presume a similar mechanism of dependence for both ethanol and other substances. Therefore, elements of dopaminergic transmission become excellent candidates for the examination of genetic influence on the development of addiction. A relationship between alcoholic disease and the presence of TaqIA1 and DRD2 alleles permits to initiate another investigation of gene-coding DRD2 dopamine receptor. The latest results indicate the importance of brain-derived neurotrophic factor (BDNF) in the regulation of dopaminergic route. The purpose of this research was to reveal the relationship between the Val66Met BDNF gene polymorphism and dependence of psychoactive agent. The examinations were performed with the Local Research Ethics Committee approval and patient's consent. The study group consisted of 100 patients (88 men and 12 women) aged 18-52 years, qualified for research program according to the International Classification of Diseases, Tenth Revision (ICD-10) requirements, medical examination and detailed questionnaire.

  2. Asymmetrical expression of BDNF and NTRK3 genes in frontoparietal cortex of stress-resilient rats in an animal model of depression.

    PubMed

    Farhang, Sara; Barar, Jaleh; Fakhari, Ali; Mesgariabbasi, Mehran; Khani, Sajjad; Omidi, Yadollah; Farnam, Alireza

    2014-09-01

    The current study is based on the "approach-withdrawal" theory of emotional regulation and lateralization of brain function in rodents, which has little been studied. The aim was to indentify asymmetry in hemispheric genes expression during depression. Depressive-like symptoms were induced in rats using chronic mild stress protocol. The sucrose consumption test was performed to identify the anhedonic and stress-resilient rats. After decapitation, RNA was extracted from frontotemporal cortex of both hemispheres of anhedonic and stress-resilient rats. The pattern of gene expression in these samples was compared with controls by real-time polymerase chain reaction. A linear mixed model analysis of variance was fitted to the data to estimate the effect of rat line. From the total of 30 rats in the experimental group, five rats were identified to be anhedonic and five were stress-resilient, according to the result of sucrose-consumption test. BDNF and NTRK-3 were expressed at significantly lower levels in the right hemisphere of anhedonic rats compared with stress-resilient rats. No significant difference was found between left hemispheres. Hemispheric asymmetry in the level of gene expression was only observed for the BDNF gene in stress-resilient rats, upregulated in right hemisphere compared with the left. Expression of NTRK3, HTR2A, COMT, and SERT was not lateralized. There was no significant asymmetry between hemispheres of anhedonic rats. This study supports the evidence for the role of genes responsible for neural plasticity in pathophysiology of depression, emphasizing probable hemispheric asymmetry at level of gene expression. Copyright © 2014 Wiley Periodicals, Inc.

  3. Development of a cost-efficient novel method for rapid, concurrent genotyping of five common single nucleotide polymorphisms of the brain derived neurotrophic factor (BDNF) gene by tetra-primer amplification refractory mutation system.

    PubMed

    Wang, Cathy K; Xu, Michael S; Ross, Colin J; Lo, Ryan; Procyshyn, Ric M; Vila-Rodriguez, Fidel; White, Randall F; Honer, William G; Barr, Alasdair M

    2015-09-01

    Brain derived neurotrophic factor (BDNF) is a molecular trophic factor that plays a key role in neuronal survival and plasticity. Single nucleotide polymorphisms (SNPs) of the BDNF gene have been associated with specific phenotypic traits in a large number of neuropsychiatric disorders and the response to psychotherapeutic medications in patient populations. Nevertheless, due to study differences and occasionally contrasting findings, substantial further research is required to understand in better detail the association between specific BDNF SNPs and these psychiatric disorders. While considerable progress has been made recently in developing advanced genotyping platforms of SNPs, many high-throughput probe- or array-based detection methods currently available are limited by high costs, slow processing times or access to advanced instrumentation. The polymerase chain reaction (PCR)-based, tetra-primer amplification refractory mutation system (T-ARMS) method is a potential alternative technique for detecting SNP genotypes efficiently, quickly, easily, and cheaply. As a tool in psychopathology research, T-ARMS was shown to be capable of detecting five common SNPs in the BDNF gene (rs6265, rs988748, rs11030104, 11757G/C and rs7103411), which are all SNPs with previously demonstrated clinical relevance to schizophrenia and depression. The present technique therefore represents a suitable protocol for many research laboratories to study the genetic correlates of BDNF in psychiatric disorders. Copyright Copyright © 2015 John Wiley & Sons, Ltd.

  4. Antidepressant-like effect of sodium butyrate is associated with an increase in TET1 and in 5-hydroxymethylation levels in the Bdnf gene.

    PubMed

    Wei, Yabin; Melas, Philippe A; Wegener, Gregers; Mathé, Aleksander A; Lavebratt, Catharina

    2014-10-31

    Epigenetic drugs like sodium butyrate (NaB) show antidepressant-like effects in preclinical studies, but the exact molecular mechanisms of the antidepressant effects remain unknown. While research using NaB has mainly focused on its role as a histone deacetylase inhibitor (HDACi), there is also evidence that NaB affects DNA methylation. The purpose of this study was to examine NaB's putative antidepressant-like efficacy in relation to DNA methylation changes in the prefrontal cortex of an established genetic rat model of depression (the Flinders Sensitive Line [FSL]) and its controls (the Flinders Resistant Line). The FSL rats had lower levels of ten-eleven translocation methylcytosine dioxygenase 1 (TET1), which catalyzes the conversion of DNA methylation to hydroxymethylation. As indicated by the behavioral despair test, chronic administration of NaB had antidepressant-like effects in the FSL and was accompanied by increased levels of TET1. The TET1 upregulation was also associated with an increase of hydroxymethylation and a decrease of methylation in brain-derived neurotrophic factor (Bdnf), a gene associated with neurogenesis and synaptic plasticity. These epigenetic changes were associated with a corresponding BDNF overexpression. Our data support the antidepressant efficacy of HDACis and suggest that their epigenetic effects may also include DNA methylation changes that are mediated by demethylation-facilitating enzymes like TET1. © The Author 2015. Published by Oxford University Press on behalf of CINP.

  5. Antidepressant-Like Effect of Sodium Butyrate is Associated with an Increase in TET1 and in 5-Hydroxymethylation Levels in the Bdnf Gene

    PubMed Central

    Wei, Ya Bin; Melas, Philippe A.; Wegener, Gregers; Mathé, Aleksander A.; Lavebratt, Catharina

    2015-01-01

    Background: Epigenetic drugs like sodium butyrate (NaB) show antidepressant-like effects in preclinical studies, but the exact molecular mechanisms of the antidepressant effects remain unknown. While research using NaB has mainly focused on its role as a histone deacetylase inhibitor (HDACi), there is also evidence that NaB affects DNA methylation. Methods: The purpose of this study was to examine NaB’s putative antidepressant-like efficacy in relation to DNA methylation changes in the prefrontal cortex of an established genetic rat model of depression (the Flinders Sensitive Line [FSL]) and its controls (the Flinders Resistant Line). Results: The FSL rats had lower levels of ten-eleven translocation methylcytosine dioxygenase 1 (TET1), which catalyzes the conversion of DNA methylation to hydroxymethylation. As indicated by the behavioral despair test, chronic administration of NaB had antidepressant-like effects in the FSL and was accompanied by increased levels of TET1. The TET1 upregulation was also associated with an increase of hydroxymethylation and a decrease of methylation in brain-derived neurotrophic factor (Bdnf), a gene associated with neurogenesis and synaptic plasticity. These epigenetic changes were associated with a corresponding BDNF overexpression. Conclusions: Our data support the antidepressant efficacy of HDACis and suggest that their epigenetic effects may also include DNA methylation changes that are mediated by demethylation-facilitating enzymes like TET1. PMID:25618518

  6. Maternal micronutrient imbalance alters gene expression of BDNF, NGF, TrkB and CREB in the offspring brain at an adult age.

    PubMed

    Sable, Pratiksha; Kale, Anvita; Joshi, Asmita; Joshi, Sadhana

    2014-05-01

    Micronutrients like folate, vitamin B12, and fatty acids which are interlinked in the one carbon cycle play a vital role in mediating epigenetic processes leading to an increased risk for neurodevelopmental disorders in the offspring. Our earlier study demonstrates that a micronutrient imbalanced diet adversely affects docosahexaenoic acid (DHA) and protein levels of neurotrophins like brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the brain and cognition in the offspring by 3 months of age. In this study we attempt to analyze if these effects are a consequence of a change in gene expression of these molecules. Further, we also examined the effect of either a postnatal control diet or a prenatal omega-3 fatty acid supplementation on gene expression in the cortex of the offspring. Pregnant rats were divided into control and five treatment groups at two levels of folic acid (normal and excess folate) in the presence and absence of vitamin B12. Omega-3 fatty acid (eicosapentaenoic acid - EPA+DHA) supplementation was given to vitamin B12 deficient groups. Following delivery, 8 dams from each group were shifted to control diet and remaining continued on the same treatment diet. Our results demonstrate that the imbalanced diet caused a marked reduction in the mRNA levels of BDNF, NGF, TrkB, and cAMP response element-binding protein (CREB). Prenatal omega-3 fatty acid supplementation to the maternal imbalanced diet was able to normalize the mRNA levels of all the above genes. This study demonstrates that a maternal diet imbalanced in micronutrients (folic acid, vitamin B12) influences gene expression of neurotrophins and their signalling molecules and thereby adversely affects the brain of the offspring.

  7. Developmental fluoxetine exposure increases behavioral despair and alters epigenetic regulation of the hippocampal BDNF gene in adult female offspring.

    PubMed

    Boulle, Fabien; Pawluski, Jodi L; Homberg, Judith R; Machiels, Barbie; Kroeze, Yvet; Kumar, Neha; Steinbusch, Harry W M; Kenis, Gunter; van den Hove, Daniel L A

    2016-04-01

    A growing number of infants are exposed to selective serotonin reuptake inhibitor (SSRI) medications during the perinatal period. Perinatal exposure to SSRI medications alter neuroplasticity and increase depressive- and anxiety-related behaviors, particularly in male offspring as little work has been done in female offspring to date. The long-term effects of SSRI on development can also differ with previous exposure to prenatal stress, a model of maternal depression. Because of the limited work done on the role of developmental SSRI exposure on neurobehavioral outcomes in female offspring, the aim of the present study was to investigate how developmental fluoxetine exposure affects anxiety and depression-like behavior, as well as the regulation of hippocampal brain-derived neurotrophic factor (BDNF) signaling in the hippocampus of adult female offspring. To do this female Sprague-Dawley rat offspring were exposed to prenatal stress and fluoxetine via the dam, for a total of four groups of female offspring: 1) No Stress+Vehicle, 2) No Stress+Fluoxetine, 3) Prenatal Stress+Vehicle, and 4) Prenatal Stress+Fluoxetine. Primary results show that, in adult female offspring, developmental SSRI exposure significantly increases behavioral despair measures on the forced swim test, decreases hippocampal BDNF exon IV mRNA levels, and increases levels of the repressive histone 3 lysine 27 tri-methylated mark at the corresponding promoter. There was also a significant negative correlation between hippocampal BDNF exon IV mRNA levels and immobility in the forced swim test. No effects of prenatal stress or developmental fluoxetine exposure were seen on tests of anxiety-like behavior. This research provides important evidence for the long-term programming effects of early-life exposure to SSRIs on female offspring, particularily with regard to affect-related behaviors and their underlying molecular mechanisms.

  8. 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.

    PubMed

    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.

  9. Nicotinamide improves motor deficits and upregulates PGC-1α and BDNF gene expression in a mouse model of Huntington’s disease

    PubMed Central

    Hathorn, Tyisha; Snyder-Keller, Abigail; Messer, Anne

    2010-01-01

    Huntington’s disease (HD) is a fatal autosomal dominant neurodegenerative disorder caused by an expansion of the polyglutamine (polyQ) repeat in exon-1 in the Huntingtin gene (HTT). This results in misfolding and accumulation of the huntingtin (htt) protein, forming nuclear and cytoplasmic inclusions. HD is associated with dysregulation of gene expression as well as mitochondrial dysfunction. We hypothesized that by improving transcriptional regulation of genes necessary for energy metabolism, the HD motor phenotype would also improve. We therefore examined the protective effects of nicotinamide (NAM), a well-characterized water-soluble B vitamin that is an inhibitor of sirtuin1/class III NAD+-dependent histone deacetylase (HDAC). In this study, both mini-osmotic pumps and drinking water deliveries were tested at 250mg NAM/kg/day, using the B6.HDR6/1 transgenic mouse model. Results were similar for both modes of delivery, and there was no evidence of toxicity. We found that NAM treatment increased mRNA levels of brain-derived neurotrophic factor (BDNF), and Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), the master regulator of mitochondrial biogenesis. Protein levels of BDNF were also significantly increased. In addition, NAM treatment increased PGC-1α activation in HD mice, pointing to a possible mode of action as a therapeutic. Critically, NAM treatment was able to improve motor deficits associated with the HD phenotype, tested as time courses of open field, rotarod, and balance beam activities. These improvements were substantial, despite the fact that NAM did not appear to reduce htt aggregation, or to prevent late-stage weight loss. Our study therefore concludes that NAM or similar drugs may be beneficial in clinical treatment of the motor dysfunctions of HD, while additional therapeutic approaches must be added to combat the aggregation phenotype and overall physiological decline. PMID:20736066

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

    PubMed Central

    Baj, Gabriele; Ieraci, Alessandro; Corna, Stefano; Musazzi, Laura; Lee, Francis S.; Tongiorgi, Enrico; Popoli, Maurizio

    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 hallmarks of individuals carrying the BDNFMet allele, we measured expression levels, epigenetic changes at promoters, and dendritic trafficking of distinct BDNF transcripts using quantitative PCR, chromatin immunoprecipitation (ChIP), and in situ hybridization. Results: BDNF-4 and BDNF-6 transcripts were reduced in BDNFMet/Met mice, compared with BDNFVal/Val mice. ChIP for acetyl-histone H3, a marker of active gene transcription, and trimethyl-histone-H3-Lys27 (H3K27me3), a marker of gene repression, showed higher H3K27me3 binding to exon 5, 6, and 8 promoters in BDNFMet/Met. The H3K27 methyltransferase enhancer of zeste homolog 2 (EZH2) is involved in epigenetic regulation of BDNF expression, because in neuroblastoma cells BDNF expression was increased both by short interference RNA for EZH2 and incubation with 3-deazaneplanocin A, an inhibitor of EZH2. In situ hybridization for BDNF-2, BDNF-4, and BDNF-6 after pilocarpine treatment showed that BDNF-6 transcript was virtually absent from distal dendrites of the CA1 and CA3 regions in BDNFMet/Met mice, while no changes were found for BDNF-2 and BDNF-4. Conclusions: Impaired BDNF expression and dendritic targeting in BDNFMet/Met mice may contribute to reduced regulated secretion of BDNF at synapses, and may be a specific correlate of pathology in individuals carrying the Met allele. PMID:26108221

  11. Genotypes do not confer risk for delinquency but rather alter susceptibility to positive and negative environmental factors: gene-environmentinteractions of BDNF Val66Met, 5-HTTLPR, and MAOA-uVNTR [corrected].

    PubMed

    Nilsson, Kent W; Comasco, Erika; Hodgins, Sheilagh; Oreland, Lars; Åslund, Cecilia

    2014-12-10

    Previous evidence of gene-by-environment interactions associated with emotional and behavioral disorders is contradictory. Differences in findings may result from variation in valence and dose of the environmental factor, and/or failure to take account of gene-by-gene interactions. The present study investigated interactions between the brain-derived neurotrophic factor gene (BDNF Val66Met), the serotonin transporter gene-linked polymorphic region (5-HTTLPR), the monoamine oxidase A (MAOA-uVNTR) polymorphisms, family conflict, sexual abuse, the quality of the child-parent relationship, and teenage delinquency. In 2006, as part of the Survey of Adolescent Life in Västmanland, Sweden, 1 337 high-school students, aged 17-18 years, anonymously completed questionnaires and provided saliva samples for DNA analyses. Teenage delinquency was associated with two-, three-, and four-way interactions of each of the genotypes and the three environmental factors. Significant four-way interactions were found for BDNF Val66Met × 5-HTTLPR×MAOA-uVNTR × family conflicts and for BDNF Val66Met × 5-HTTLPR×MAOA-uVNTR × sexual abuse. Further, the two genotype combinations that differed the most in expression levels (BDNF Val66Met Val, 5-HTTLPR LL, MAOA-uVNTR LL [girls] and L [boys] vs BDNF Val66Met Val/Met, 5-HTTLPR S/LS, MAOA-uVNTR S/SS/LS) in interaction with family conflict and sexual abuse were associated with the highest delinquency scores. The genetic variants previously shown to confer vulnerability for delinquency (BDNF Val66Met Val/Met × 5-HTTLPR S × MAOA-uVNTR S) were associated with the lowest delinquency scores in interaction with a positive child-parent relationship. Functional variants of the MAOA-uVNTR, 5-HTTLPR, and BDNF Val66Met, either alone or in interaction with each other, may be best conceptualized as modifying sensitivity to environmental factors that confer either risk or protection for teenage delinquency. © The Author 2015. Published by Oxford University

  12. Genotypes Do Not Confer Risk For Delinquency ut Rather Alter Susceptibility to Positive and Negative Environmental Factors: Gene-Environment Interactions of BDNF Val66Met, 5-HTTLPR, and MAOA-uVNTR

    PubMed Central

    Comasco, Erika; Hodgins, Sheilagh; Oreland, Lars; Åslund, Cecilia

    2015-01-01

    Background: Previous evidence of gene-by-environment interactions associated with emotional and behavioral disorders is contradictory. Differences in findings may result from variation in valence and dose of the environmental factor, and/or failure to take account of gene-by-gene interactions. The present study investigated interactions between the brain-derived neurotrophic factor gene (BDNF Val66Met), the serotonin transporter gene-linked polymorphic region (5-HTTLPR), the monoamine oxidase A (MAOA-uVNTR) polymorphisms, family conflict, sexual abuse, the quality of the child-parent relationship, and teenage delinquency. Methods: In 2006, as part of the Survey of Adolescent Life in Västmanland, Sweden, 1 337 high-school students, aged 17–18 years, anonymously completed questionnaires and provided saliva samples for DNA analyses. Results: Teenage delinquency was associated with two-, three-, and four-way interactions of each of the genotypes and the three environmental factors. Significant four-way interactions were found for BDNF Val66Met × 5-HTTLPR×MAOA-uVNTR × family conflicts and for BDNF Val66Met × 5-HTTLPR×MAOA-uVNTR × sexual abuse. Further, the two genotype combinations that differed the most in expression levels (BDNF Val66Met Val, 5-HTTLPR LL, MAOA-uVNTR LL [girls] and L [boys] vs BDNF Val66Met Val/Met, 5-HTTLPR S/LS, MAOA-uVNTR S/SS/LS) in interaction with family conflict and sexual abuse were associated with the highest delinquency scores. The genetic variants previously shown to confer vulnerability for delinquency (BDNF Val66Met Val/Met × 5-HTTLPR S × MAOA-uVNTR S) were associated with the lowest delinquency scores in interaction with a positive child-parent relationship. Conclusions: Functional variants of the MAOA-uVNTR, 5-HTTLPR, and BDNF Val66Met, either alone or in interaction with each other, may be best conceptualized as modifying sensitivity to environmental factors that confer either risk or protection for teenage delinquency. PMID

  13. 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.

    PubMed

    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 (P<.05). Piglets in the high and low Lf group had 30% and 7% larger jejunal crypts compared with the control group (P<.05). Escherichia coli 16S rRNA copy number per gram of ascending colon contents was significantly reduced (P=.001), while the copy number of Bifidobacteria and Lactobacillus spp. was not affected. In addition, Lf increased intestinal alkaline phosphatase activity (P<.05) and delayed the onset of food transitional diarrhea, reducing its frequency and duration (P<.05). The incidence of diarrhea in the high and low Lf groups was decreased 54% and 15%, respectively, compared with the control group (P=.035). In summary, these findings provide new evidence that dietary Lf supplementation up-regulated gene expression of BDNF and UCHL1, decreased the colon microbiota of E. coli, improved gut maturation and reduced early weaning diarrhea in piglets. The molecular basis underlying these findings suggests that Lf may enhance gut development and immune function by providing new insight into the gut-brain-microbe axis that has not been previously reported. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. No Association of BDNF, COMT, MAOA, SLC6A3, and SLC6A4 Genes and Depressive Symptoms in a Sample of Healthy Colombian Subjects.

    PubMed

    González-Giraldo, Yeimy; Camargo, Andrés; López-León, Sandra; Forero, Diego A

    2015-01-01

    Background. Major depressive disorder (MDD) is the second cause of years lived with disability around the world. A large number of studies have been carried out to identify genetic risk factors for MDD and related endophenotypes, mainly in populations of European and Asian descent, with conflicting results. The main aim of the current study was to analyze the possible association of five candidate genes and depressive symptoms in a Colombian sample of healthy subjects. Methods and Materials. The Spanish adaptation of the Hospital Anxiety and Depression Scale (HADS) was applied to one hundred eighty-eight healthy Colombian subjects. Five functional polymorphisms were genotyped using PCR-based assays: BDNF-Val66Met (rs6265), COMT-Val158Met (rs4680), SLC6A4-HTTLPR (rs4795541), MAOA-uVNTR, and SLC6A3-VNTR (rs28363170). Result. We did not find significant associations with scores of depressive symptoms, derived from the HADS, for any of the five candidate genes (nominal p values >0.05). In addition, we did not find evidence of significant gene-gene interactions. Conclusion. This work is one of the first studies of candidate genes for depressive symptoms in a Latin American sample. Study of additional genetic and epigenetic variants, taking into account other pathophysiological theories, will help to identify novel candidates for MDD in populations around the world.

  15. No Association of BDNF, COMT, MAOA, SLC6A3, and SLC6A4 Genes and Depressive Symptoms in a Sample of Healthy Colombian Subjects

    PubMed Central

    González-Giraldo, Yeimy; Camargo, Andrés; López-León, Sandra; Forero, Diego A.

    2015-01-01

    Background. Major depressive disorder (MDD) is the second cause of years lived with disability around the world. A large number of studies have been carried out to identify genetic risk factors for MDD and related endophenotypes, mainly in populations of European and Asian descent, with conflicting results. The main aim of the current study was to analyze the possible association of five candidate genes and depressive symptoms in a Colombian sample of healthy subjects. Methods and Materials. The Spanish adaptation of the Hospital Anxiety and Depression Scale (HADS) was applied to one hundred eighty-eight healthy Colombian subjects. Five functional polymorphisms were genotyped using PCR-based assays: BDNF-Val66Met (rs6265), COMT-Val158Met (rs4680), SLC6A4-HTTLPR (rs4795541), MAOA-uVNTR, and SLC6A3-VNTR (rs28363170). Result. We did not find significant associations with scores of depressive symptoms, derived from the HADS, for any of the five candidate genes (nominal p values >0.05). In addition, we did not find evidence of significant gene-gene interactions. Conclusion. This work is one of the first studies of candidate genes for depressive symptoms in a Latin American sample. Study of additional genetic and epigenetic variants, taking into account other pathophysiological theories, will help to identify novel candidates for MDD in populations around the world. PMID:26557993

  16. [Influence of chronic alcohol treatment on the expression of the Bdnf, Bax, Bcl-xL, and CASP3 genes in the mouse brain: Role of the C1473G polymorphism in the gene encoding tryptophan hydroxylase 2].

    PubMed

    Bazovkina, D V; Tsybko, A S; Filimonova, E A; Ilchibaeva, T V; Naumenko, V S

    2016-01-01

    Tryptophan hydroxylase 2 (Tph-2) is the key enzyme in serotonin biosynthesis. Serotonin is one of the main neurotransmitters involved in the regulation of various physiological functions and behavior patterns. The influence of chronic ethanol consumption on the expression of the Bdnf, Bax, Bcl-xL, and CASP3 genes was studied in the brain structures of B6-1473C (C/C) and B6-1473G (G/G) mice that had been obtained on the base of the C57BL/6 strain. The strains differed in the genotype for the C1473G single nucleotide polymorphism in the Tph-2 gene and in Tph-2 enzyme activity. It was found that chronic alcohol treatment led to a significant increase in the expression of the Bdnf gene in the midbrain of B6-1473G mice, but not in B6-1473С. Chronic alcohol treatment considerably decreased the expression of the ultimate brain apoptosis effector, caspase 3, in the frontal cortex, but increased it in the hippocampus of B6-1473G mice. At the same time, chronic ethanol administration reduced the level of the antiapoptotic Bcl-xL mRNA in the midbrain of B6-1473C mice. Thus, the C1473G polymorphism in the Tph-2 gene considerably influenced the changes in the expression patterns of genes involved in the regulation of neurogenesis and neural apoptosis induced by chronic ethanol treatment.

  17. A conserved BDNF, glutamate- and GABA-enriched gene module related to human depression identified by coexpression meta-analysis and DNA variant genome-wide association studies.

    PubMed

    Chang, Lun-Ching; Jamain, Stephane; Lin, Chien-Wei; Rujescu, Dan; Tseng, George C; Sibille, Etienne

    2014-01-01

    Large scale gene expression (transcriptome) analysis and genome-wide association studies (GWAS) for single nucleotide polymorphisms have generated a considerable amount of gene- and disease-related information, but heterogeneity and various sources of noise have limited the discovery of disease mechanisms. As systematic dataset integration is becoming essential, we developed methods and performed meta-clustering of gene coexpression links in 11 transcriptome studies from postmortem brains of human subjects with major depressive disorder (MDD) and non-psychiatric control subjects. We next sought enrichment in the top 50 meta-analyzed coexpression modules for genes otherwise identified by GWAS for various sets of disorders. One coexpression module of 88 genes was consistently and significantly associated with GWAS for MDD, other neuropsychiatric disorders and brain functions, and for medical illnesses with elevated clinical risk of depression, but not for other diseases. In support of the superior discriminative power of this novel approach, we observed no significant enrichment for GWAS-related genes in coexpression modules extracted from single studies or in meta-modules using gene expression data from non-psychiatric control subjects. Genes in the identified module encode proteins implicated in neuronal signaling and structure, including glutamate metabotropic receptors (GRM1, GRM7), GABA receptors (GABRA2, GABRA4), and neurotrophic and development-related proteins [BDNF, reelin (RELN), Ephrin receptors (EPHA3, EPHA5)]. These results are consistent with the current understanding of molecular mechanisms of MDD and provide a set of putative interacting molecular partners, potentially reflecting components of a functional module across cells and biological pathways that are synchronously recruited in MDD, other brain disorders and MDD-related illnesses. Collectively, this study demonstrates the importance of integrating transcriptome data, gene coexpression modules

  18. The Antidepressant Agomelatine Improves Memory Deterioration and Upregulates CREB and BDNF Gene Expression Levels in Unpredictable Chronic Mild Stress (UCMS)-Exposed Mice

    PubMed Central

    Gumuslu, Esen; Mutlu, Oguz; Sunnetci, Deniz; Ulak, Guner; Celikyurt, Ipek K.; Cine, Naci; Akar, Furuzan; Savlı, Hakan; Erden, Faruk

    2014-01-01

    Agomelatine, a novel antidepressant with established clinical efficacy, acts as an agonist of melatonergic MT1 and MT2 receptors and as an antagonist of 5-HT2C receptors. The present study was undertaken to investigate whether chronic treatment with agomelatine would block unpredictable chronic mild stress (UCMS)-induced cognitive deterioration in mice in passive avoidance (PA), modified elevated plus maze (mEPM), novel object recognition (NOR), and Morris water maze (MWM) tests. Moreover, the effects of stress and agomelatine on brain-derived neurotrophic factor (BDNF) and cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) messenger ribonucleic acid (mRNA) levels in the hippocampus was also determined using quantitative real-time polymerase chain reaction (RT-PCR). Male inbred BALB/c mice were treated with agomelatine (10 mg/kg, i.p.), melatonin (10 mg/kg), or vehicle daily for five weeks. The results of this study revealed that UCMS-exposed animals exhibited memory deterioration in the PA, mEPM, NOR, and MWM tests. The chronic administration of melatonin had a positive effect in the PA and +mEPM tests, whereas agomelatine had a partial effect. Both agomelatine and melatonin blocked stress-induced impairment in visual memory in the NOR test and reversed spatial learning and memory impairment in the stressed group in the MWM test. Quantitative RT-PCR revealed that CREB and BDNF gene expression levels were downregulated in UCMS-exposed mice, and these alterations were reversed by chronic agomelatine or melatonin treatment. Thus, agomelatine plays an important role in blocking stress-induced hippocampal memory deterioration and activates molecular mechanisms of memory storage in response to a learning experience. PMID:24634580

  19. Association of COMT (Val158Met) and BDNF (Val66Met) Gene Polymorphisms with Anxiety, ADHD and Tics in Children with Autism Spectrum Disorder

    ERIC Educational Resources Information Center

    Gadow, Kenneth D.; Roohi, Jasmin; Devincent, Carla J.; Kirsch, Sarah; Hatchwell, Eli

    2009-01-01

    The aim of the study is to examine rs4680 ("COMT") and rs6265 ("BDNF") as genetic markers of anxiety, ADHD, and tics. Parents and teachers completed a DSM-IV-referenced rating scale for a total sample of 67 children with autism spectrum disorder (ASD). Both "COMT" (p = 0.06) and "BDNF" (p = 0.07) genotypes were marginally significant for teacher…

  20. Association of COMT (Val158Met) and BDNF (Val66Met) Gene Polymorphisms with Anxiety, ADHD and Tics in Children with Autism Spectrum Disorder

    ERIC Educational Resources Information Center

    Gadow, Kenneth D.; Roohi, Jasmin; Devincent, Carla J.; Kirsch, Sarah; Hatchwell, Eli

    2009-01-01

    The aim of the study is to examine rs4680 ("COMT") and rs6265 ("BDNF") as genetic markers of anxiety, ADHD, and tics. Parents and teachers completed a DSM-IV-referenced rating scale for a total sample of 67 children with autism spectrum disorder (ASD). Both "COMT" (p = 0.06) and "BDNF" (p = 0.07) genotypes were marginally significant for teacher…

  1. RACK1 affects morphine reward via BDNF.

    PubMed

    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.

  2. Steroid hormones and BDNF.

    PubMed

    Pluchino, N; Russo, M; Santoro, A N; Litta, P; Cela, V; Genazzani, A R

    2013-06-03

    Brain-derived neurotrophic factor (BDNF) is a neurotrophin abundantly expressed in several areas of the central nervous system (CNS) and is known to induce a lasting potentiation of synaptic efficacy, to enhance specific learning and memory processes. BDNF is one of the key molecules modulating brain plasticity and it affects cognitive deficit associated with aging and neurodegenerative disease. Several studies have shown an altered BDNF production and secretion in a variety of neurodegenerative diseases like Alzheimer's and Parkinson's diseases but also in mood disorders like depression, eating disorders and schizophrenia. Plasma BDNF is also a biomarker of impaired memory and general cognitive function in aging women. Gonadal steroids are involved in the regulation of several CNS processes, specifically mood, affective and cognitive functions during fertile life and reproductive aging. These observations lead many scientists to investigate a putative co-regulation between BDNF and gonadal and/or adrenal steroids and their relationship with gender difference in the incidence of mental diseases. This overview aims to summarize the current knowledge on the correlation between BDNF expression/function and both gonadal (progesterone, estrogens, and testosterone) and adrenal hormones (mainly cortisol and dehydroepiandrosterone (DHEA)) with relevance in clinical application.

  3. DREAM regulates BDNF-dependent spinal sensitization

    PubMed Central

    2010-01-01

    Background The transcriptional repressor DREAM (downstream regulatory element antagonist modulator) controls the expression of prodynorphin and has been involved in the modulation of endogenous responses to pain. To investigate the role of DREAM in central mechanisms of pain sensitization, we used a line of transgenic mice (L1) overexpressing a Ca2+- and cAMP-insensitive DREAM mutant in spinal cord and dorsal root ganglia. Results L1 DREAM transgenic mice showed reduced expression in the spinal cord of several genes related to pain, including prodynorphin and BDNF (brain-derived neurotrophic factor) and a state of basal hyperalgesia without change in A-type currents. Peripheral inflammation produced enhancement of spinal reflexes and increased expression of BDNF in wild type but not in DREAM transgenic mice. The enhancement of the spinal reflexes was reproduced in vitro by persistent electrical stimulation of C-fibers in wild type but not in transgenic mice. Exposure to exogenous BDNF produced a long-term enhancement of dorsal root-ventral root responses in transgenic mice. Conclusions Our results indicate that endogenous BDNF is involved in spinal sensitization following inflammation and that blockade of BDNF induction in DREAM transgenic mice underlies the failure to develop spinal sensitization. PMID:21167062

  4. DREAM regulates BDNF-dependent spinal sensitization.

    PubMed

    Rivera-Arconada, Ivan; Benedet, Tomaso; Roza, Carolina; Torres, Begoña; Barrio, Jorge; Krzyzanowska, Agnieszka; Avendaño, Carlos; Mellström, Britt; Lopez-Garcia, José A; Naranjo, José R

    2010-12-18

    The transcriptional repressor DREAM (downstream regulatory element antagonist modulator) controls the expression of prodynorphin and has been involved in the modulation of endogenous responses to pain. To investigate the role of DREAM in central mechanisms of pain sensitization, we used a line of transgenic mice (L1) overexpressing a Ca(2+)- and cAMP-insensitive DREAM mutant in spinal cord and dorsal root ganglia. L1 DREAM transgenic mice showed reduced expression in the spinal cord of several genes related to pain, including prodynorphin and BDNF (brain-derived neurotrophic factor) and a state of basal hyperalgesia without change in A-type currents. Peripheral inflammation produced enhancement of spinal reflexes and increased expression of BDNF in wild type but not in DREAM transgenic mice. The enhancement of the spinal reflexes was reproduced in vitro by persistent electrical stimulation of C-fibers in wild type but not in transgenic mice. Exposure to exogenous BDNF produced a long-term enhancement of dorsal root-ventral root responses in transgenic mice. Our results indicate that endogenous BDNF is involved in spinal sensitization following inflammation and that blockade of BDNF induction in DREAM transgenic mice underlies the failure to develop spinal sensitization.

  5. Age at onset of psychotic disorder: cannabis, BDNF Val66Met, and sex-specific models of gene-environment interaction.

    PubMed

    Decoster, Jeroen; van Os, Jim; Kenis, Gunter; Henquet, Cecile; Peuskens, Joseph; De Hert, Marc; van Winkel, Ruud

    2011-04-01

    Discovering modifiable predictors for age at onset may help to identify predictors of transition to psychotic disorder in the "at-risk mental state." Inconsistent effects of sex, BDNF Val66Met (rs6265), and cannabis use on age of onset were previously reported. BDNF Val66Met and cannabis use before illness onset were retrospectively assessed in a sample of 585 patients with schizophrenia and their association with age at onset was evaluated. Cannabis use was significantly associated with earlier age at onset of psychotic disorder (AOP; average difference 2.7 years, P < 0.001), showing dose-response effects with higher frequency and earlier age at first use. There was a weak association between BDNF Val66Met genotype and AOP (difference 1.2 years; P = 0.050). No evidence was found for BDNF × cannabis interaction (interaction χ(2) (1) = 0.65, P = 0.420). However, a significant BDNF × cannabis × sex interaction was found (interaction χ(2) (1) = 4.99, P = 0.026). In female patients, cannabis use was associated with earlier AOP in BDNF Met-carriers (difference 7 years), but not in Val/Val-genotypes. In male patients, cannabis use was associated with earlier AOP irrespective of BDNF Val66Met genotype (difference 1.3 years). BDNF Val66Met genotype in the absence of cannabis use did not influence AOP, neither in female or male patients with psychotic disorder. Complex interactions between cannabis and BDNF may shape age at onset in female individuals at risk of psychotic disorder. No compelling evidence was found that BDNF genotype is associated with age at onset of psychotic disorder in the absence of cannabis use.

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

    PubMed

    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.

  7. Candidate-gene approach in posttraumatic stress disorder after urban violence: association analysis of the genes encoding serotonin transporter, dopamine transporter, and BDNF.

    PubMed

    Valente, Nina Leão Marques; Vallada, Homero; Cordeiro, Quirino; Miguita, Karen; Bressan, Rodrigo Affonseca; Andreoli, Sergio Baxter; Mari, Jair Jesus; Mello, Marcelo Feijó

    2011-05-01

    Posttraumatic stress disorder (PTSD) is a prevalent, disabling anxiety disorder marked by behavioral and physiologic alterations which commonly follows a chronic course. Exposure to a traumatic event constitutes a necessary, but not sufficient, factor. There is evidence from twin studies supporting a significant genetic predisposition to PTSD. However, the precise genetic loci still remain unclear. The objective of the present study was to identify, in a case-control study, whether the brain-derived neurotrophic factor (BDNF) val66met polymorphism (rs6265), the dopamine transporter (DAT1) three prime untranslated region (3'UTR) variable number of tandem repeats (VNTR), and the serotonin transporter (5-HTTPRL) short/long variants are associated with the development of PTSD in a group of victims of urban violence. All polymorphisms were genotyped in 65 PTSD patients as well as in 34 victims of violence without PTSD and in a community control group (n = 335). We did not find a statistical significant difference between the BDNF val66met and 5-HTTPRL polymorphism and the traumatic phenotype. However, a statistical association was found between DAT1 3'UTR VNTR nine repeats and PTSD (OR = 1.82; 95% CI, 1.20-2.76). This preliminary result confirms previous reports supporting a susceptibility role for allele 9 and PTSD.

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

    PubMed Central

    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-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. PMID:18394710

  9. Histone Modifications around Individual BDNF Gene Promoters in Prefrontal Cortex Are Associated with Extinction of Conditioned Fear

    ERIC Educational Resources Information Center

    Bredy, Timothy W.; Wu, Hao; Crego, Cortney; Zellhoefer, Jessica; Sun, Yi E.; Barad, Mark

    2007-01-01

    Extinction of conditioned fear is an important model both of inhibitory learning and of behavior therapy for human anxiety disorders. Like other forms of learning, extinction learning is long-lasting and depends on regulated gene expression. Epigenetic mechanisms make an important contribution to persistent changes in gene expression; therefore,…

  10. Histone Modifications around Individual BDNF Gene Promoters in Prefrontal Cortex Are Associated with Extinction of Conditioned Fear

    ERIC Educational Resources Information Center

    Bredy, Timothy W.; Wu, Hao; Crego, Cortney; Zellhoefer, Jessica; Sun, Yi E.; Barad, Mark

    2007-01-01

    Extinction of conditioned fear is an important model both of inhibitory learning and of behavior therapy for human anxiety disorders. Like other forms of learning, extinction learning is long-lasting and depends on regulated gene expression. Epigenetic mechanisms make an important contribution to persistent changes in gene expression; therefore,…

  11. Depression, 5HTTLPR and BDNF Val66Met polymorphisms, and plasma BDNF levels in hemodialysis patients with chronic renal failure.

    PubMed

    Wang, Liang-Jen; Chen, Chih-Ken; Hsu, Heng-Jung; Wu, I-Wen; Sun, Chiao-Yin; Lee, Chin-Chan

    2014-01-01

    Depression is the most prevalent comorbid psychiatric disease among hemodialysis patients with end-stage renal disease. This cross-sectional study investigated whether depression in hemodialysis patients is associated with the polymorphism of the 5' flanking transcriptional region (5-HTTLPR) of the serotonin transporter gene, the valine (Val)-to-methionine (Met) substitution at codon 66 (Val66Met) polymorphism of the brain-derived neurotrophic factor (BDNF) gene, or plasma BDNF levels. A total of 188 participants (mean age: 58.5±14.0 years; 89 men and 99 women) receiving hemodialysis at the Chang Gung Memorial Hospital were recruited. The diagnosis of major depressive disorder (MDD) was confirmed using the Chinese version of the Mini International Neuropsychiatric Interview. The genotypes of 5-HTTLPR and BDNF Val66Met were conducted using polymerase chain reactions plus restriction fragment length polymorphism analysis. The plasma BDNF levels were measured using an enzyme-linked immunosorbent assay kit. Forty-five (23.9%) patients fulfilled the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV-TR) criteria for a MDD. There were no significant effects of the 5-HTTLPR or BDNF Val66Met gene polymorphism on MDD among the hemodialysis patients. The plasma BDNF levels correlated significantly with age (P=0.003) and sex (P=0.047) but not with depression, the genotypes of 5-HTTLPR and BDNF Val66Met, the current antidepressant treatment, or the duration under hemodialysis. Our results did not support the hypothesis of an involvement of the 5HTTLPR and BDNF Val66Met genotypes, or plasma BDNF levels in the pathogenesis of depression, in patients receiving hemodialysis. A study with a large sample size and homogenous patient group is warranted to confirm these findings.

  12. Depression, 5HTTLPR and BDNF Val66Met polymorphisms, and plasma BDNF levels in hemodialysis patients with chronic renal failure

    PubMed Central

    Wang, Liang-Jen; Chen, Chih-Ken; Hsu, Heng-Jung; Wu, I-Wen; Sun, Chiao-Yin; Lee, Chin-Chan

    2014-01-01

    Objective Depression is the most prevalent comorbid psychiatric disease among hemodialysis patients with end-stage renal disease. This cross-sectional study investigated whether depression in hemodialysis patients is associated with the polymorphism of the 5′ flanking transcriptional region (5-HTTLPR) of the serotonin transporter gene, the valine (Val)-to-methionine (Met) substitution at codon 66 (Val66Met) polymorphism of the brain-derived neurotrophic factor (BDNF) gene, or plasma BDNF levels. Methods A total of 188 participants (mean age: 58.5±14.0 years; 89 men and 99 women) receiving hemodialysis at the Chang Gung Memorial Hospital were recruited. The diagnosis of major depressive disorder (MDD) was confirmed using the Chinese version of the Mini International Neuropsychiatric Interview. The genotypes of 5-HTTLPR and BDNF Val66Met were conducted using polymerase chain reactions plus restriction fragment length polymorphism analysis. The plasma BDNF levels were measured using an enzyme-linked immunosorbent assay kit. Results Forty-five (23.9%) patients fulfilled the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV-TR) criteria for a MDD. There were no significant effects of the 5-HTTLPR or BDNF Val66Met gene polymorphism on MDD among the hemodialysis patients. The plasma BDNF levels correlated significantly with age (P=0.003) and sex (P=0.047) but not with depression, the genotypes of 5-HTTLPR and BDNF Val66Met, the current antidepressant treatment, or the duration under hemodialysis. Conclusion Our results did not support the hypothesis of an involvement of the 5HTTLPR and BDNF Val66Met genotypes, or plasma BDNF levels in the pathogenesis of depression, in patients receiving hemodialysis. A study with a large sample size and homogenous patient group is warranted to confirm these findings. PMID:25045267

  13. The lighter side of BDNF

    PubMed Central

    Noble, Emily E.; Billington, Charles J.; Kotz, Catherine M.

    2011-01-01

    Brain-derived neurotrophic factor (BDNF) mediates energy metabolism and feeding behavior. As a neurotrophin, BDNF promotes neuronal differentiation, survival during early development, adult neurogenesis, and neural plasticity; thus, there is the potential that BDNF could modify circuits important to eating behavior and energy expenditure. The possibility that “faulty” circuits could be remodeled by BDNF is an exciting concept for new therapies for obesity and eating disorders. In the hypothalamus, BDNF and its receptor, tropomyosin-related kinase B (TrkB), are extensively expressed in areas associated with feeding and metabolism. Hypothalamic BDNF and TrkB appear to inhibit food intake and increase energy expenditure, leading to negative energy balance. In the hippocampus, the involvement of BDNF in neural plasticity and neurogenesis is important to learning and memory, but less is known about how BDNF participates in energy homeostasis. We review current research about BDNF in specific brain locations related to energy balance, environmental, and behavioral influences on BDNF expression and the possibility that BDNF may influence energy homeostasis via its role in neurogenesis and neural plasticity. PMID:21346243

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

    PubMed

    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.

  15. BDNF Overexpression in the Forebrain Rescues Huntington’s Disease Phenotypes in YAC128 Mice

    PubMed Central

    Xie, Yuxiang; Hayden, Michael R.; Xu, Baoji

    2010-01-01

    Huntington’s disease (HD) is caused by an expansion of the polyglutamine tract at the amino-terminus of huntingtin. This mutation reduces levels of brain-derived neurotrophic factor (BDNF) in the striatum, likely by inhibiting cortical Bdnf gene expression and anterograde transport of BDNF from the cerebral cortex to the striatum. Substantial evidence suggests that this reduction of striatal BDNF plays a crucial role in HD pathogenesis. Here we report that overexpression of BDNF in the forebrain rescues many disease phenotypes in YAC128 mice that express a full-length human huntingtin mutant with a 128-glutamine tract. The Bdnf transgene, under the control of the promoter for α subunit of Ca2+/calmodulin-dependent protein kinase II, greatly increased BDNF levels in the cerebral cortex and striatum. BDNF overexpression in YAC128 mice prevented loss and atrophy of striatal neurons and motor dysfunction, normalized expression of the striatal dopamine receptor D2 and enkephalin, and improved procedural learning. Furthermore, quantitative analyses of Golgi-impregnated neurons revealed a decreased spine density and abnormal spine morphology in striatal neurons of YAC128 mice, which was also reversed by increasing BDNF levels in the striatum. These results demonstrate that reduced striatal BDNF plays a crucial role in the HD pathogenesis and suggest that attempts to restore striatal BDNF level may have therapeutic effects to the disease. PMID:21048129

  16. Childhood maternal care is associated with DNA methylation of the genes for brain-derived neurotrophic factor (BDNF) and oxytocin receptor (OXTR) in peripheral blood cells in adult men and women.

    PubMed

    Unternaehrer, Eva; Meyer, Andrea Hans; Burkhardt, Susan C A; Dempster, Emma; Staehli, Simon; Theill, Nathan; Lieb, Roselind; Meinlschmidt, Gunther

    2015-01-01

    In adults, reporting low and high maternal care in childhood, we compared DNA methylation in two stress-associated genes (two target sequences in the oxytocin receptor gene, OXTR; one in the brain-derived neurotrophic factor gene, BDNF) in peripheral whole blood, in a cross-sectional study (University of Basel, Switzerland) during 2007-2008. We recruited 89 participants scoring < 27 (n = 47, 36 women) or > 33 (n = 42, 35 women) on the maternal care subscale of the Parental Bonding Instrument (PBI) at a previous assessment of a larger group (N = 709, range PBI maternal care = 0-36, age range = 19-66 years; median 24 years). 85 participants gave blood for DNA methylation analyses (Sequenom(R) EpiTYPER, San Diego, CA) and cell count (Sysmex PocH-100i™, Kobe, Japan). Mixed model statistical analysis showed greater DNA methylation in the low versus high maternal care group, in the BDNF target sequence [Likelihood-Ratio (1) = 4.47; p = 0.035] and in one OXTR target sequence Likelihood-Ratio (1) = 4.33; p = 0.037], but not the second OXTR target sequence [Likelihood-Ratio (1) < 0.001; p = 0.995). Mediation analyses indicated that differential blood cell count did not explain associations between low maternal care and BDNF (estimate = -0.005, 95% CI = -0.025 to 0.015; p = 0.626) or OXTR DNA methylation (estimate = -0.015, 95% CI = -0.038 to 0.008; p = 0.192). Hence, low maternal care in childhood was associated with greater DNA methylation in an OXTR and a BDNF target sequence in blood cells in adulthood. Although the study has limitations (cross-sectional, a wide age range, only three target sequences in two genes studied, small effects, uncertain relevance of changes in blood cells to gene methylation in brain), the findings may indicate components of the epiphenotype from early life stress.

  17. Identification of a Functionally Distinct Truncated BDNF mRNA Splice Variant and Protein in Trachemys scripta elegans

    PubMed Central

    Ambigapathy, Ganesh; Zheng, Zhaoqing; Li, Wei; Keifer, Joyce

    2013-01-01

    Brain-derived neurotrophic factor (BDNF) has a diverse functional role and complex pattern of gene expression. Alternative splicing of mRNA transcripts leads to further diversity of mRNAs and protein isoforms. Here, we describe the regulation of BDNF mRNA transcripts in an in vitro model of eyeblink classical conditioning and a unique transcript that forms a functionally distinct truncated BDNF protein isoform. Nine different mRNA transcripts from the BDNF gene of the pond turtle Trachemys scripta elegans (tBDNF) are selectively regulated during classical conditioning: exon I mRNA transcripts show no change, exon II transcripts are downregulated, while exon III transcripts are upregulated. One unique transcript that codes from exon II, tBDNF2a, contains a 40 base pair deletion in the protein coding exon that generates a truncated tBDNF protein. The truncated transcript and protein are expressed in the naïve untrained state and are fully repressed during conditioning when full-length mature tBDNF is expressed, thereby having an alternate pattern of expression in conditioning. Truncated BDNF is not restricted to turtles as a truncated mRNA splice variant has been described for the human BDNF gene. Further studies are required to determine the ubiquity of truncated BDNF alternative splice variants across species and the mechanisms of regulation and function of this newly recognized BDNF protein. PMID:23825634

  18. Neuronal release of proBDNF

    PubMed Central

    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 TrkB. PMID:19136973

  19. Neuronal release of proBDNF.

    PubMed

    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

    2009-02-01

    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 TrkB.

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

    PubMed

    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.

  1. BDNF and TNF-α polymorphisms in memory.

    PubMed

    Yogeetha, B S; Haupt, L M; McKenzie, K; Sutherland, H G; Okolicsyani, R K; Lea, R A; Maher, B H; Chan, R C K; Shum, D H K; Griffiths, L R

    2013-09-01

    Here, we investigate the genetic basis of human memory in healthy individuals and the potential role of two polymorphisms, previously implicated in memory function. We have explored aspects of retrospective and prospective memory including semantic, short term, working and long-term memory in conjunction with brain derived neurotrophic factor (BDNF) and tumor necrosis factor-alpha (TNF-α). The memory scores for healthy individuals in the population were obtained for each memory type and the population was genotyped via restriction fragment length polymorphism for the BDNF rs6265 (Val66Met) SNP and via pyrosequencing for the TNF-α rs113325588 SNP. Using univariate ANOVA, a significant association of the BDNF polymorphism with visual and spatial memory retention and a significant association of the TNF-α polymorphism was observed with spatial memory retention. In addition, a significant interactive effect between BDNF and TNF-α polymorphisms was observed in spatial memory retention. In practice visual memory involves spatial information and the two memory systems work together, however our data demonstrate that individuals with the Val/Val BDNF genotype have poorer visual memory but higher spatial memory retention, indicating a level of interaction between TNF-α and BDNF in spatial memory retention. This is the first study to use genetic analysis to determine the interaction between BDNF and TNF-α in relation to memory in normal adults and provides important information regarding the effect of genetic determinants and gene interactions on human memory.

  2. Physiology of BDNF: focus on hypothalamic function.

    PubMed

    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.

  3. CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer's disease

    PubMed Central

    Caccamo, Antonella; Maldonado, Monica A.; Bokov, Alex F.; Majumder, Smita; Oddo, Salvatore

    2010-01-01

    Cognitive dysfunction and memory loss are common features of Alzheimer's disease (AD). Abnormalities in the expression profile of immediate early genes that play a critical role in memory formation, such as the cAMP-response element binding protein (CREB), have been reported in the brains of AD patients. Here we show that amyloid-β (Aβ) accumulation, which plays a primary role in the cognitive deficits of AD, interferes with CREB activity. We further show that restoring CREB function via brain viral delivery of the CREB-binding protein (CBP) improves learning and memory deficits in an animal model of AD. Notably, such improvements occur without changes in Aβ and tau pathology, and instead are linked to an increased level of brain-derived neurotrophic factor. The resulting data suggest that Aβ-induced learning and memory deficits are mediated by alterations in CREB function, based on the finding that restoring CREB activity by directly modulating CBP levels in the brains of adult mice is sufficient to ameliorate learning and memory. Therefore, increasing CBP expression in adult brains may be a valid therapeutic approach not only for AD, but also for various brain disorders characterized by alterations in immediate early genes, further supporting the concept that viral vector delivery may be a viable therapeutic approach in neurodegenerative diseases. PMID:21149712

  4. Additive genetic effect of APOE and BDNF on hippocampus activity.

    PubMed

    Kauppi, Karolina; Nilsson, Lars-Göran; Persson, Jonas; Nyberg, Lars

    2014-04-01

    Human memory is a highly heritable polygenic trait with complex inheritance patterns. To study the genetics of memory and memory-related diseases, hippocampal functioning has served as an intermediate phenotype. The importance of investigating gene-gene effects on complex phenotypes has been emphasized, but most imaging studies still focus on single polymorphisms. APOE ε4 and BDNF Met, two of the most studied gene variants for variability in memory performance and neuropsychiatric disorders, have both separately been related to poorer episodic memory and altered hippocampal functioning. Here, we investigated the combined effect of APOE and BDNF on hippocampal activation (N=151). No non-additive interaction effects were seen. Instead, the results revealed decreased activation in bilateral hippocampus and parahippocampus as a function of the number of APOE ε4 and BDNF Met alleles present (neither, one, or both). The combined effect was stronger than either of the individual effects, and both gene variables explained significant proportions of variance in BOLD signal change. Thus, there was an additive gene-gene effect of APOE and BDNF on medial temporal lobe (MTL) activation, showing that a larger proportion of variance in brain activation attributed to genetics can be explained by considering more than one gene variant. This effect might be relevant for the understanding of normal variability in memory function as well as memory-related disorders associated with APOE and BDNF. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. Differential regulation of Bdnf expression in cortical neurons by class-selective histone deacetylase inhibitors.

    PubMed

    Koppel, Indrek; Timmusk, Tõnis

    2013-12-01

    Histone deactylase (HDAC) inhibitors show promise as therapeutics for neurodegenerative and psychiatric diseases. Increased expression of brain-derived neurotrophic factor (BDNF) has been associated with memory-enhancing and neuroprotective properties of these drugs, but the mechanism of BDNF induction is not well understood. Here, we compared the effects of a class I/IIb selective HDAC inhibitor SAHA, a class I selective inhibitor MS-275, a class II selective inhibitor MC1568 and a HDAC6 selective inhibitor tubacin on Bdnf mRNA expression in rat primary neurons. We show that inhibition of class II HDACs resulted in rapid upregulation of Bdnf mRNA levels, whereas class I HDAC inhibition produced a markedly delayed Bdnf induction. In contrast to relatively slow upregulation of Bdnf transcripts, histone acetylation at BDNF promoters I and IV was rapidly induced by SAHA. Bdnf induction by SAHA and MS-275 at 24 h was sensitive to protein synthesis inhibition, suggesting that delayed Bdnf induction by HDAC inhibitors is secondary to changed expression of its regulators. HDAC4 and HDAC5 repressed Bdnf promoter IV activity, supporting the role of class II HDACs in regulation of Bdnf expression. In addition, we show a critical role for the cAMP/Ca2+ response element (CRE) in induction of Bdnf promoter IV by MS-275, MC1568, SAHA and sodium valproate. In contrast, MEF2-binding CaRE1 element was not necessary for promoter IV induction by HDAC inhibition. Finally, we show that similarly to Bdnf, the studied HDAC inhibitors differentially induced expression of neuronal activity-regulated genes c-fos and Arc. Together, our findings implicate class II HDACs in transcriptional regulation of Bdnf and indicate that class II selective HDAC inhibitors may have potential as therapeutics for nervous system disorders.

  6. [Research progress of BDNF and depression].

    PubMed

    Qiao, Hui; An, Shu-Cheng; Xu, Chang

    2011-06-01

    BDNF is widespread existed in CNS and PNS, because of its function in nerve regeneration and restoration, more and more researches focused on the effect of BDNF on neural plasticity in the development of depression and the mechanisms of antidepressant. This article review the basic results and the research trends on BDNF and depression at present, more researches about the interactions of BDNF and proBDNF, BDNF and other transmitters and their receptors should be expected.

  7. Methionine increases BDNF DNA methylation and improves memory in epilepsy

    PubMed Central

    Parrish, R Ryley; Buckingham, Susan C; Mascia, Katherine L; Johnson, Jarvis J; Matyjasik, Michal M; Lockhart, Roxanne M; Lubin, Farah D

    2015-01-01

    Objective Temporal lobe epilepsy (TLE) patients exhibit signs of memory impairments even when seizures are pharmacologically controlled. Surprisingly, the underlying molecular mechanisms involved in TLE-associated memory impairments remain elusive. Memory consolidation requires epigenetic transcriptional regulation of genes in the hippocampus; therefore, we aimed to determine how epigenetic DNA methylation mechanisms affect learning-induced transcription of memory-permissive genes in the epileptic hippocampus. Methods Using the kainate rodent model of TLE and focusing on the brain-derived neurotrophic factor (Bdnf) gene as a candidate of DNA methylation-mediated transcription, we analyzed DNA methylation levels in epileptic rats following learning. After detection of aberrant DNA methylation at the Bdnf gene, we investigated functional effects of altered DNA methylation on hippocampus-dependent memory formation in our TLE rodent model. Results We found that behaviorally driven BdnfDNA methylation was associated with hippocampus-dependent memory deficits. Bisulfite sequencing revealed that decreased BdnfDNA methylation levels strongly correlated with abnormally high levels of BdnfmRNA in the epileptic hippocampus during memory consolidation. Methyl supplementation via methionine (Met) increased BdnfDNA methylation and reduced BdnfmRNA levels in the epileptic hippocampus during memory consolidation. Met administration reduced interictal spike activity, increased theta rhythm power, and reversed memory deficits in epileptic animals. The rescue effect of Met treatment on learning-induced BdnfDNA methylation, Bdnf gene expression, and hippocampus-dependent memory, were attenuated by DNA methyltransferase blockade. Interpretation Our findings suggest that manipulation of DNA methylation in the epileptic hippocampus should be considered as a viable treatment option to ameliorate memory impairments associated with TLE. PMID:25909085

  8. BDNF Val66Met is associated with introversion and interacts with 5-HTTLPR to influence neuroticism.

    PubMed

    Terracciano, Antonio; Tanaka, Toshiko; Sutin, Angelina R; Deiana, Barbara; Balaci, Lenuta; Sanna, Serena; Olla, Nazario; Maschio, Andrea; Uda, Manuela; Ferrucci, Luigi; Schlessinger, David; Costa, Paul T

    2010-04-01

    Brain-derived neurotrophic factor (BDNF) regulates synaptic plasticity and neurotransmission, and has been linked to neuroticism, a major risk factor for psychiatric disorders. A recent genome-wide association (GWA) scan, however, found the BDNF Val66Met polymorphism (rs6265) associated with extraversion but not with neuroticism. In this study, we examine the links between BDNF and personality traits, assessed using the Revised NEO Personality Inventory (NEO-PI-R), in a sample from SardiNIA (n=1560) and the Baltimore Longitudinal Study of Aging (BLSA; n=1131). Consistent with GWA results, we found that BDNF Met carriers were more introverted. By contrast, in both samples and in a meta-analysis inclusive of published data (n=15251), we found no evidence for a main effect of BDNF Val66Met on neuroticism. Finally, on the basis of recent reports of an epistatic effect between BDNF and the serotonin transporter, we explored a Val66Met x 5-HTTLPR interaction in a larger SardiNIA sample (n=2333). We found that 5-HTTLPR LL carriers scored lower on neuroticism in the presence of the BDNF Val variant, but scored higher on neuroticism in the presence of the BDNF Met variant. Our findings support the association between the BDNF Met variant and introversion and suggest that BDNF interacts with the serotonin transporter gene to influence neuroticism.

  9. BDNF Val66Met Polymorphism Influences Age Differences in Microstructure of the Corpus Callosum

    PubMed Central

    Kennedy, Kristen M.; Rodrigue, Karen M.; Land, Susan J.; Raz, Naftali

    2009-01-01

    Brain-derived neurotrophic factor (BDNF) plays an important role in neuroplasticity and promotes axonal growth, but its secretion, regulated by a BDNF gene, declines with age. The low-activity (met) allele of common polymorphism BDNF val66met is associated with reduced production of BDNF. We examined whether age-related reduction in the integrity of cerebral white matter (WM) depends on the BDNF val66met genotype. Forty-one middle-aged and older adults participated in the study. Regional WM integrity was assessed by fractional anisotropy (FA) computed from manually drawn regions of interest in the genu and splenium of the corpus callosum on diffusion tensor imaging scans. After controlling for effects of sex and hypertension, we found that only the BDNF 66met carriers displayed age-related declines in the splenium FA, whereas no age-related declines were shown by BDNF val homozygotes. No genotype-related differences were observed in the genu of the corpus callosum. This finding is consistent with a view that genetic risk for reduced BDNF affects posterior regions that otherwise are considered relatively insensitive to normal aging. Those individuals with a genetic predisposition for decreased BDNF expression may not be able to fully benefit from BDNF-based plasticity and repair mechanisms. PMID:19738930

  10. An adaptive role for BDNF Val66Met polymorphism in motor recovery in chronic stroke.

    PubMed

    Qin, Luye; Jing, Deqiang; Parauda, Sarah; Carmel, Jason; Ratan, Rajiv R; Lee, Francis S; Cho, Sunghee

    2014-02-12

    Little is known about the influence of genetic diversity on stroke recovery. One exception is the polymorphism in brain derived neurotrophic factor (BDNF), a critical neurotrophin for brain repair and plasticity. Humans have a high-frequency single nucleotide polymorphism (SNP) in the prodomain of the BDNF gene. Previous studies show that the BDNF Val66Met variant negatively affects motor learning and severity of acute stroke. To investigate the impact of this common BDNF SNP on stroke recovery, we used a mouse model that contains the human BDNF Val66Met variant in both alleles (BDNF(M/M)). Male BDNF(+/+) and BDNF(M/M) littermates received sham or transient middle cerebral artery occlusion. We assessed motor function regularly for 6 months after stroke and then performed anatomical analyses. Despite reported negative association of the SNP with motor learning and acute deficits, we unexpectedly found that BDNF(M/M) mice displayed significantly enhanced motor/kinematic performance in the chronic phase of motor recovery, especially in ipsilesional hindlimb. The enhanced recovery was associated with significant increases in striatum volume, dendritic arbor, and elevated excitatory synaptic markers in the contralesional striatum. Transient inactivation of the contralateral striatum during recovery transiently abolished the enhanced function. This study showed an unexpected benefit of the BDNFVal66Met carriers for functional recovery, involving structural and molecular plasticity in the nonstroked hemisphere. Clinically, this study suggests a role for BDNF genotype in predicting stroke recovery and identifies a novel systems-level mechanism for enhanced motor recovery.

  11. BDNF Val66Met is Associated with Introversion and Interacts with 5-HTTLPR to Influence Neuroticism

    PubMed Central

    Terracciano, Antonio; Tanaka, Toshiko; Sutin, Angelina R; Deiana, Barbara; Balaci, Lenuta; Sanna, Serena; Olla, Nazario; Maschio, Andrea; Uda, Manuela; Ferrucci, Luigi; Schlessinger, David; Costa, Paul T

    2010-01-01

    Brain-derived neurotrophic factor (BDNF) regulates synaptic plasticity and neurotransmission, and has been linked to neuroticism, a major risk factor for psychiatric disorders. A recent genome-wide association (GWA) scan, however, found the BDNF Val66Met polymorphism (rs6265) associated with extraversion but not with neuroticism. In this study, we examine the links between BDNF and personality traits, assessed using the Revised NEO Personality Inventory (NEO-PI-R), in a sample from SardiNIA (n=1560) and the Baltimore Longitudinal Study of Aging (BLSA; n=1131). Consistent with GWA results, we found that BDNF Met carriers were more introverted. By contrast, in both samples and in a meta-analysis inclusive of published data (n=15251), we found no evidence for a main effect of BDNF Val66Met on neuroticism. Finally, on the basis of recent reports of an epistatic effect between BDNF and the serotonin transporter, we explored a Val66Met × 5-HTTLPR interaction in a larger SardiNIA sample (n=2333). We found that 5-HTTLPR LL carriers scored lower on neuroticism in the presence of the BDNF Val variant, but scored higher on neuroticism in the presence of the BDNF Met variant. Our findings support the association between the BDNF Met variant and introversion and suggest that BDNF interacts with the serotonin transporter gene to influence neuroticism. PMID:20042999

  12. Antidepressant-Like Effects of Central BDNF Administration in Mice of Antidepressant Sensitive Catalepsy (ASC) Strain.

    PubMed

    Tikhonova, Maria; Kulikov, Alexander V

    2012-08-31

    Although numerous data evidence the implication of brain-derived neurotrophic factor (BDNF) in the pathophysiology of depression, the potential for BDNF to correct genetically defined depressive-like states is poorly studied. This study was aimed to reveal antidepressant-like effects of BDNF (300 ng, 2×, i.c.v.) on behavior and mRNA expression of genes associated with depression-like state in the brain in mice of antidepressant sensitive catalepsy (ASC) strain characterized by high hereditary predisposition to catalepsy and depressive-like features. Behavioral tests were held on the 7th-16th days after the first (4th-13th after the second) BDNF injection. Results showed that BDNF normalized impaired sexual motivation in the ASC males, and this BDNF effect differed, with advantageous effects, from that of widely used antidepressants. The anticataleptic effect of two BDNF injections was enhanced compared with a single administration. A tendency to decrease the immobility duration in tail-suspension test was observed in BDNF-treated ASC mice. The effects on catalepsy and sexual motivation were specific since BDNF did not alter locomotor and exploratory activity or social interest in the ASC mice. Along with behavioral antidepressant-like effects on the ASC mice, BDNF increased hippocampal mRNA levels of Bdnf and Creb1 (cAMP response element-binding protein gene). BDNF also augmented mRNA levels of Arc gene encoding Arc (Activity-regulated cytoskeleton-associated) protein involved in BDNF-induced processes of neuronal and synaptic plasticity in hippocampus and prefrontal cortex. The data suggest that: [1] BDNF is effective in the treatment of some genetically defined behavioral disturbances; [2] BDNF influences sexually-motivated behavior; [3] Arc mRNA levels may serve as a molecular marker of BDNF physiological activity associated with its long-lasting behavioral effects; [4] ASC mouse strain can be used as a suitable model to study mechanisms of BDNF effects on

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

    PubMed

    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.

  14. Physical exercise improves peripheral BDNF levels and cognitive functions in mild cognitive impairment elderly with different bdnf Val66Met genotypes.

    PubMed

    Nascimento, Carla Manuela Crispim; Pereira, Jessica Rodrigues; Pires de Andrade, Larissa; Garuffi, Marcelo; Ayan, Carlos; Kerr, Daniel Shikanai; Talib, Leda Leme; Cominetti, Márcia Regina; Stella, Florindo

    2015-01-01

    The benefits of physical exercise on improvements in brain-derived neurotrophic factor (BDNF) levels and cognitive functioning have been reported in the literature. However, the variability of individual responses may be linked to genetic differences. BDNF is considered one of the most plausible factors involved in the cognitive benefits associated with physical activity practice. A single nucleotide polymorphism localized in the gene that codes BDNF results in a missense mutation that promotes an amino acid substitution (Val66Met) in the protein. This process has been associated with decreased levels of BDNF secretion, with corresponding impairments in specific cognitive functions. Therefore, the objective of this study was to analyze the effects of a multimodal physical exercise program on peripheral BDNF levels and cognitive functions in elderly individuals with mild cognitive impairment (MCI). The participants were genotyped for the BDNF Val66Met polymorphism. Cognitive functions were assessed by the Montreal Cognitive Assessment (MoCA) prior to and after the intervention. Forty-five participants were assigned to the control and trained groups. The trained group participated in a multimodal physical training for a 16-week period. The results showed a significant between-subjects interaction (p < 0.05), which indicates the beneficial contribution of training on cognitive functions independent of the BDNF genotype. However, only participants with BDNF-Met genotypes exhibited significant improvements in peripheral BDNF levels. The BDNF genotype appears to modulate the effects of physical exercise on BDNF secretion, but it does not influence cognition. This is the first study that evaluated the influence of a BDNF polymorphism on physical activity and cognition performance in elderly MCI individuals.

  15. Autocrine action of BDNF on dendrite development of adult-born hippocampal neurons.

    PubMed

    Wang, Liang; Chang, Xingya; She, Liang; Xu, Duo; Huang, Wei; Poo, Mu-ming

    2015-06-03

    Dendrite development of newborn granule cells (GCs) in the dentate gyrus of adult hippocampus is critical for their incorporation into existing hippocampal circuits, but the cellular mechanisms regulating their dendrite development remains largely unclear. In this study, we examined the function of brain-derived neurotrophic factor (BDNF), which is expressed in adult-born GCs, in regulating their dendrite morphogenesis. Using retrovirus-mediated gene transfection, we found that deletion and overexpression of BDNF in adult-born GCs resulted in the reduction and elevation of dendrite growth, respectively. This effect was mainly due to the autocrine rather than paracrine action of BDNF, because deletion of BDNF only in the newborn GCs resulted in dendrite abnormality of these neurons to a similar extent as that observed in conditional knockout (cKO) mice with BDNF deleted in the entire forebrain. Furthermore, selective expression of BDNF in adult-born GCs in BDNF cKO mice fully restored normal dendrite development. The BDNF autocrine action was also required for the development of normal density of spines and normal percentage of spines containing the postsynaptic marker PSD-95, suggesting autocrine BDNF regulation of synaptogenesis. Furthermore, increased dendrite growth of adult-born GCs caused by voluntary exercise was abolished by BDNF deletion specifically in these neurons and elevated dendrite growth due to BDNF overexpression in these neurons was prevented by reducing neuronal activity with coexpression of inward rectifier potassium channels, consistent with activity-dependent autocrine BDNF secretion. Therefore, BDNF expressed in adult-born GCs plays a critical role in dendrite development by acting as an autocrine factor.

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

    PubMed

    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.

  17. Requirement for BDNF in the reconsolidation of fear extinction.

    PubMed

    Radiske, Andressa; Rossato, Janine I; Köhler, Cristiano A; Gonzalez, Maria Carolina; Medina, Jorge H; Cammarota, Martín

    2015-04-22

    Therapies based on the impairment of reconsolidation or the enhancement of extinction offer the possibility of decreasing the persistent recollection of distressing memories. However, the direct interplay between reconsolidation and extinction has rarely been considered. Previously, we reported that reactivation induces reconsolidation of fear extinction memory. Here, using a step-down inhibitory avoidance learning paradigm in rats, we show that intrahippocampus infusion of function-blocking anti-BDNF antibody immediately or 6 h after extinction memory reactivation impairs the reconsolidation of extinction. Extinction memory reactivation increases proBDNF, BDNF, and tropomyosin receptor kinase B (TrkB) phosphorylation levels in dorsal CA1, while blocking BDNF maturation in the hippocampus with plasminogen activator inhibitor 1 hinders the persistence of extinction and induces the recurrence of fear. Moreover, coinfusion of recombinant BDNF (0.25 μg/side) after extinction memory reactivation impedes the recovery of the avoidance response induced by inhibiting gene expression and protein synthesis in the dorsal hippocampus. Our findings unravel a new role for BDNF, suggesting that this neurotrophin is necessary and sufficient to maintain the reactivated fear extinction engram.

  18. Association between BDNF-rs6265 and obesity in the Boston Puerto Rican Health Study

    USDA-ARS?s Scientific Manuscript database

    The objective of this study is to examine a functional variant (rs6265) in the BDNF gene interacting with dietary intake modulate obesity traits in the Boston Puerto Rican Health Study population. BDNF rs6265 was genotyped in 1147 Puerto Ricans (aged 45-75 years), and examined for association with o...

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

    PubMed

    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 < 0.0001), but the distribution of the SNP was not significantly different. Nor were plasma 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 (<5 years) users. We conclude that plasma BDNF concentration in habitual heroin users are not affected by BDNF Val66Met gene variants, but by the length of the heroin dependency.

  20. Early exposure to caffeine affects gene expression of adenosine receptors, DARPP-32 and BDNF without affecting sensibility and morphology of developing zebrafish (Danio rerio).

    PubMed

    Capiotti, Katiucia Marques; Menezes, Fabiano Peres; Nazario, Luiza Reali; Pohlmann, Julhana Bianchini; de Oliveira, Giovanna M T; Fazenda, Lidiane; Bogo, Maurício Reis; Bonan, Carla Denise; Da Silva, Rosane Souza

    2011-01-01

    Adenosine receptors are the most important biochemical targets of caffeine, a common trimethylxanthine found in food and beverages. Adenosine plays modulatory action during the development through adenosine receptors and their intracellular pathways activation. In this study, we aimed to evaluate if caffeine gave to zebrafish in the very first steps of development is able to affect its direct targets, through the adenosine receptors mRNA expression evaluation, and latter indirect targets, through evaluation of the pattern of dopamine and cAMP-regulated phosphoprotein and brain-derived neurotrophic factor (BDNF) mRNA expression. Here, we demonstrate that zebrafish express adenosine receptor subtypes (A1, A2A1, A2A2 and A2B) since 24h post-fertilization (hpf) and that caffeine exposure is able to affect the expression of these receptors. Caffeine exposure from 1 hpf is able to increase A1 expression at 72-96 hpf and A2A1 expression at 72 hpf. No alterations occurred in A2A2 and A2B expression after caffeine treatment. DARPP-32, a phosphoprotein involved in adenosine intracellular pathway is also expressed since 24 hpf and early exposure to caffeine increased DARPP-32 expression at 168 hpf. We also evaluate the expression of BDNF as one of the targets of adenosine intracellular pathway activation. BDNF was also expressed since 24 hpf and caffeine treatment increased its expression at 48 and 72 hpf. No morphological alterations induced by caffeine treatment were registered by the check of general body features and total body length. Assessment of tactile sensibility also demonstrated no alterations by caffeine treatment. Altogether, these results suggest that caffeine is able to affect expression of its cellular targets since early phases of development in zebrafish without affect visible features. The up-regulation of direct and indirect targets of caffeine presents as a compensatory mechanism of maintenance of adenosinergic modulation during the developmental phase

  1. Taste bud-derived BDNF maintains innervation of a subset of TrkB-expressing gustatory nerve fibers.

    PubMed

    Tang, Tao; Rios-Pilier, Jennifer; Krimm, Robin

    2017-07-01

    Taste receptor cells transduce different types of taste stimuli and transmit this information to gustatory neurons that carry it to the brain. Taste receptor cells turn over continuously in adulthood, requiring constant new innervation from nerve fibers. Therefore, the maintenance of innervation to taste buds is an active process mediated by many factors, including brain-derived neurotrophic factor (BDNF). Specifically, 40% of taste bud innervation is lost when Bdnf is removed during adulthood. Here we speculated that not all gustatory nerve fibers express the BDNF receptor, TrkB, resulting in subsets of neurons that vary in their response to BDNF. However, it is also possible that the partial loss of innervation occurred because the Bdnf gene was not effectively removed. To test these possibilities, we first determined that not all gustatory nerve fibers express the TrkB receptor in adult mice. We then verified the efficiency of Bdnf removal specifically in taste buds of K14-CreER:Bdnf mice and found that Bdnf expression was reduced to 1%, indicating efficient Bdnf gene recombination. BDNF removal resulted in a 55% loss of TrkB-expressing nerve fibers, which was greater than the loss of P2X3-positive fibers (39%), likely because taste buds were innervated by P2X3+/TrkB- fibers that were unaffected by BDNF removal. We conclude that gustatory innervation consists of both TrkB-positive and TrkB-negative taste fibers and that BDNF is specifically important for maintaining TrkB-positive innervation to taste buds. In addition, although taste bud size was not affected by inducible Bdnf removal, the expression of the γ subunit of the ENaC channel was reduced. So, BDNF may regulate expression of some molecular components of taste transduction pathways. Copyright © 2017. Published by Elsevier Inc.

  2. BDNF: no gain without pain?

    PubMed

    Smith, Peter A

    2014-12-26

    Injury to the adult nervous system promotes the expression and secretion of brain-derived neurotrophic factor (BDNF). Because it promotes neuronal growth, survival and neurogenesis, BDNF may initiate compensatory processes that mitigate the deleterious effects of injury, disease or stress. Despite this, BDNF has been implicated in several injury-induced maladaptive processes including pain, spasticity and convulsive activity. This review will concentrate on the predominant role of BDNF in the initiation and maintenance of chronic and/or neuropathic pain at the spinal, peripheral and central levels. Within the spinal dorsal horn, the pattern of BDNF-induced changes in synaptic transmission across five different, identified neuronal phenotypes bears a striking resemblance to that produced by chronic constriction injury (CCI) of peripheral nerves. The appearance of this "pain footprint" thus reflects multiple sensitizing actions of microglial-derived BDNF. These include changes in the chloride equilibrium potential, decreased excitatory synaptic drive to inhibitory neurons, complex changes in inhibitory (GABA/glycinergic) synaptic transmission, increases in excitatory synaptic drive to excitatory neurons and the appearance of oscillatory activity. BDNF effects are confined to changes in synaptic transmission as there is little change in the passive or active properties of neurons in the superficial dorsal horn. Actions of BDNF in the brain stem and periphery also contribute to the onset and persistence of chronic pain. In spite of its role in compensatory processes that facilitate the recovery of the nervous system from injury, the widespread maladaptive actions of BDNF mean that there is literally "no gain without pain".

  3. BDNF Variants May Modulate Long-Term Visual Memory Performance in a Healthy Cohort.

    PubMed

    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.

  4. BDNF Variants May Modulate Long-Term Visual Memory Performance in a Healthy Cohort

    PubMed Central

    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

  5. Gain of BDNF Function in Engrafted Neural Stem Cells Promotes the Therapeutic Potential for Alzheimer's Disease.

    PubMed

    Wu, Cheng-Chun; Lien, Cheng-Chang; Hou, Wen-Hsien; Chiang, Po-Min; Tsai, Kuen-Jer

    2016-06-06

    Stem cell-based therapy is a potential treatment for neurodegenerative diseases, but its application to Alzheimer's disease (AD) remains limited. Brain-derived neurotrophic factor (BDNF) is critical in the pathogenesis and treatment of AD. Here, we present a novel therapeutic approach for AD treatment using BDNF-overexpressing neural stem cells (BDNF-NSCs). In vitro, BDNF overexpression was neuroprotective to beta-amyloid-treated NSCs. In vivo, engrafted BDNF-NSCs-derived neurons not only displayed the Ca(2+)-response fluctuations, exhibited electrophysiological properties of mature neurons and integrated into local brain circuits, but recovered the cognitive deficits. Furthermore, BDNF overexpression improved the engrafted cells' viability, neuronal fate, neurite complexity, maturation of electrical property and the synaptic density. In contrast, knockdown of the BDNF in BDNF-NSCs diminished stem cell-based therapeutic efficacy. Together, our findings indicate BDNF overexpression improves the therapeutic potential of engrafted NSCs for AD via neurogenic effects and neuronal replacement, and further support the feasibility of NSC-based ex vivo gene therapy for AD.

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

    PubMed Central

    Falcicchia, Chiara; Trempat, Pascal; Binaschi, Anna; Perrier-Biollay, Coline; Roncon, Paolo; Soukupova, Marie; Berthommé, Hervé; Simonato, Michele

    2016-01-01

    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. PMID:26954758

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

    PubMed

    Falcicchia, Chiara; Trempat, Pascal; Binaschi, Anna; Perrier-Biollay, Coline; Roncon, Paolo; Soukupova, Marie; Berthommé, Hervé; Simonato, Michele

    2016-01-01

    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.

  8. BDNF as a pain modulator.

    PubMed

    Merighi, Adalberto; Salio, Chiara; Ghirri, Alessia; Lossi, Laura; Ferrini, Francesco; Betelli, Chiara; Bardoni, Rita

    2008-07-01

    At least some neurotrophins may be powerful modulators of synapses, thereby influencing short- and long-term synaptic efficiency. BDNF acts at central synapses in pain pathways both at spinal and supraspinal levels. Neuronal synthesis, subcellular storage/co-storage and release of BDNF at these synapses have been characterized on anatomical and physiological grounds, in parallel with trkB (the high affinity BDNF receptor) distribution. Histological and functional evidence has been provided, mainly from studies on acute slices and intact animals, that BDNF modulates fast excitatory (glutamatergic) and inhibitory (GABAergic/glycinergic) signals, as well as slow peptidergic neurotrasmission in spinal cord. Recent studies have unraveled some of the neuronal circuitries and mechanisms involved, highlighting the key role of synaptic glomeruli in lamina II as the main sites for such a modulation.

  9. Efficient use of a translation start codon in BDNF exon I.

    PubMed

    Koppel, Indrek; Tuvikene, Jürgen; Lekk, Ingrid; Timmusk, Tõnis

    2015-09-01

    The brain-derived neurotrophic factor (BDNF) gene contains a number of 5' exons alternatively spliced with a common 3' exon. BDNF protein is synthesized from alternative transcripts as a prepro-precursor encoded by the common 3' exon IX, which has a translation start site 21 bp downstream of the splicing site. BDNF mRNAs containing exon I are an exception to this arrangement as the last three nucleotides of this exon constitute an in-frame AUG. Here, we show that this AUG is efficiently used for translation initiation in PC12 cells and cultured cortical neurons. Use of exon I-specific AUG produces higher levels of BDNF protein than use of the common translation start site, resulting from a higher translation rate. No differences in protein degradation, constitutive or regulated secretion were detected between BDNF isoforms with alternative 5' termini. As the BDNF promoter preceding exon I is known to be highly regulated by neuronal activity, our results suggest that the function of this translation start site may be efficient stimulus-dependent synthesis of BDNF protein. The brain-derived neurotrophic factor (BDNF) gene contains multiple untranslated 5' exons alternatively spliced to one common protein-coding 3' exon. However, exon I contains an in-frame ATG in a favorable translation context. Here, we show that use of this ATG is associated with more efficient protein synthesis than the commonly used ATG in exon IX. © 2015 International Society for Neurochemistry.

  10. Val66Met polymorphism association with serum BDNF and inflammatory biomarkers in major depression.

    PubMed

    Caldieraro, Marco Antonio; McKee, Madison; Leistner-Segal, Sandra; Vares, Edgar Arrua; Kubaski, Francyne; Spanemberg, Lucas; Brusius-Facchin, Ana Carolina; Fleck, Marcelo P; Mischoulon, David

    2017-07-12

    Current evidence supports participation of neurotrophic and inflammatory factors in the pathogenesis of major depressive disorder (MDD). Some studies reported an association between the Val66Met polymorphism (rs6265) of brain-derived neurotrophic factor (BDNF) gene with MDD and peripheral BDNF levels. However, no previous studies have examined the association of this polymorphism with inflammation. The present study assessed the association of the Val66Met polymorphism with serum levels of BDNF and inflammatory markers among depressed outpatients. All participants (n = 73) met DSM-IV criteria for a unipolar depressive episode. The serum levels of BDNF and inflammatory biomarkers (IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ) were compared between individuals presenting with at least one Met allele (Met-carriers) and those homozygous for the Val allele. In our sample (84.9% female, mean age 52.4 ± 10.3 years), 24.7% (n = 18) were Met-carriers. After Bonferroni correction, the Met allele was significantly associated with higher BDNF and lower TNF-α. These associations persisted after adjusting for potential confounders. The pattern of low BDNF and high inflammation in MDD may be influenced by the Val66Met polymorphism. The association of a polymorphism in the BDNF gene with inflammatory markers in addition to BDNF levels suggests an interaction between these systems.

  11. Long Non-coding RNA in Neurons: New Players in Early Response to BDNF Stimulation.

    PubMed

    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.

  12. 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.

    PubMed

    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.

  13. BDNF function as a potential mediator of bipolar disorder and post-traumatic stress disorder comorbidity

    PubMed Central

    Rakofsky, JJ; Ressler, KJ; Dunlop, BW

    2013-01-01

    Bipolar disorder (BD) and post-traumatic stress disorder (PTSD) frequently co-occur among psychiatric patients, leading to increased morbidity and mortality. Brain-derived neurotrophic factor (BDNF) function is associated with core characteristics of both BD and PTSD. We propose a neurobiological model that underscores the role of reduced BDNF function resulting from several contributing sources, including the met variant of the BDNF val66met (rs6265) single-nucleotide polymorphism, trauma-induced epigenetic regulation and current stress, as a contributor to the onset of both illnesses within the same person. Further studies are needed to evaluate the genetic association between the val66met allele and the BD-PTSD population, along with central/peripheral BDNF levels and epigenetic patterns of BDNF gene regulation within these patients. PMID:21931317

  14. Molecular and neural bases underlying roles of BDNF in the control of body weight

    PubMed Central

    Vanevski, Filip; Xu, Baoji

    2013-01-01

    Brain-derived neurotrophic factor (BDNF) is a potent regulator of neuronal development and synaptic plasticity that is fundamental to neural circuit formation and cognition. It is also involved in the control of appetite and body weight, with mutations in the genes for BDNF and its receptor, TrkB, resulting in remarkable hyperphagia and severe obesity in humans and mice. Recent studies have made significant progress in elucidating the source, action sites, and regulatory pathways of BDNF with regard to its role in the control of energy homeostasis, and have shed light on the relationships between BDNF and other molecules involved in the control of body weight. Here we provide a comprehensive review of evidence from pharmacological, genetic, and mechanistic studies, linking BDNF to the control of body weight. This review also aims to organize the main findings on this subject into a more refined framework and to discuss the future research directions necessary to advance the field. PMID:23519010

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

    PubMed

    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.

  16. Plasma BDNF Concentration, Val66Met Genetic Variant, and Depression-Related Personality Traits

    PubMed Central

    Terracciano, Antonio; Martin, Bronwen; Ansari, David; Tanaka, Toshiko; Ferrucci, Luigi; Maudsley, Stuart; Mattson, Mark P.; Costa, Paul T.

    2010-01-01

    Brain derived neurotrophic factor (BDNF) regulates synaptic plasticity and neurogenesis, and BDNF plasma and serum levels have been associated with depression, Alzheimer's disease, and other psychiatric and neurodegenerative disorders. In a relatively large community sample, drawn from the Baltimore Longitudinal Study of Aging (BLSA), we examine whether BDNF plasma concentration is associated with the Val66Met functional polymorphism of the BDNF gene (n = 335) and with depression-related personality traits assessed with the NEO-PI-R (n = 391). Plasma concentration of BDNF was not associated with the Val66Met variant in either men or women. However, in men, but not in women, BDNF plasma level was associated with personality traits linked to depression. Contrary to the notion that low BDNF is associated with negative outcomes, we found lower plasma levels in men who score lower on depression and vulnerability to stress (two facets of Neuroticism) and higher on Conscientiousness and Extraversion. These findings challenge the prevailing hypothesis that lower peripheral levels of BDNF are a marker of depression. PMID:20345896

  17. Chronic Mild Stress Modulates Activity-Dependent Transcription of BDNF in Rat Hippocampal Slices.

    PubMed

    Molteni, Raffaella; Rossetti, Andrea C; Savino, Elisa; Racagni, Giorgio; Calabrese, Francesca

    2016-01-01

    Although activity-dependent transcription represents a crucial mechanism for long-lasting experience-dependent changes in the hippocampus, limited data exist on its contribution to pathological conditions. We aim to investigate the influence of chronic stress on the activity-dependent transcription of brain-derived neurotrophic factor (BDNF). The ex vivo methodology of acute stimulation of hippocampal slices obtained from rats exposed to chronic mild stress (CMS) was used to evaluate whether the adverse experience may alter activity-dependent BDNF gene expression. CMS reduces BDNF expression and that acute depolarization significantly upregulates total BDNF mRNA levels only in control animals, showing that CMS exposure may alter BDNF transcription under basal conditions and during neuronal activation. Moreover, while the basal effect of CMS on total BDNF reflects parallel modulations of all the transcripts examined, isoform-specific changes were found after depolarization. This different effect was also observed in the activation of intracellular signaling pathways related to the neurotrophin. In conclusion, our study discloses a functional alteration of BDNF transcription as a consequence of stress. Being the activity-regulated transcription a critical process in synaptic and neuronal plasticity, the different regulation of individual BDNF promoters may contribute to long-lasting changes, which are fundamental for the vulnerability of the hippocampus to stress-related diseases.

  18. The BDNF Val66Met polymorphism impairs NMDA receptor-dependent synaptic plasticity in the hippocampus.

    PubMed

    Ninan, Ipe; Bath, Kevin G; Dagar, Karishma; Perez-Castro, Rosalia; Plummer, Mark R; Lee, Francis S; Chao, Moses V

    2010-06-30

    The Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene results in a defect in regulated release of BDNF and affects episodic memory and affective behaviors. However, the precise role of the BDNF Val66Met polymorphism in hippocampal synaptic transmission and plasticity has not yet been studied. Therefore, we examined synaptic properties in the hippocampal CA3-CA1 synapses of BDNF(Met/Met) mice and matched wild-type mice. Although basal glutamatergic neurotransmission was normal, both young and adult mice showed a significant reduction in NMDA receptor-dependent long-term potentiation. We also found that NMDA receptor-dependent long-term depression was decreased in BDNF(Met/Met) mice. However, mGluR-dependent long-term depression was not affected by the BDNF Val66Met polymorphism. Consistent with the NMDA receptor-dependent synaptic plasticity impairment, we observed a significant decrease in NMDA receptor neurotransmission in the CA1 pyramidal neurons of BDNF(Met/Met) mice. Thus, these results show that the BDNF Val66Met polymorphism has a direct effect on NMDA receptor transmission, which may account for changes in synaptic plasticity in the hippocampus.

  19. Plasma BDNF concentration, Val66Met genetic variant and depression-related personality traits.

    PubMed

    Terracciano, A; Martin, B; Ansari, D; Tanaka, T; Ferrucci, L; Maudsley, S; Mattson, M P; Costa, P T

    2010-07-01

    Brain-derived neurotrophic factor (BDNF) regulates synaptic plasticity and neurogenesis, and BDNF plasma and serum levels have been associated with depression, Alzheimer's disease, and other psychiatric and neurodegenerative disorders. In a relatively large community sample, drawn from the Baltimore Longitudinal Study of Aging (BLSA), we examine whether BDNF plasma concentration is associated with the Val66Met functional polymorphism of the BDNF gene (n = 335) and with depression-related personality traits assessed with the NEO-PI-R (n = 391). Plasma concentration of BDNF was not associated with the Val66Met variant in either men or women. However, in men, but not in women, BDNF plasma level was associated with personality traits linked to depression. Contrary to the notion that low BDNF is associated with negative outcomes, we found lower plasma levels in men who score lower on depression and vulnerability to stress (two facets of Neuroticism) and higher on Conscientiousness and Extraversion. These findings challenge the prevailing hypothesis that lower peripheral levels of BDNF are a marker of depression.

  20. Dendritically targeted Bdnf mRNA is essential for energy balance and response to leptin.

    PubMed

    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.

  1. Bdnf overexpression in hippocampal neurons prevents dendritic atrophy caused by Rett-associated MECP2 mutations.

    PubMed

    Larimore, Jennifer L; Chapleau, Christopher A; Kudo, Shinichi; Theibert, Anne; Percy, Alan K; Pozzo-Miller, Lucas

    2009-05-01

    The expression of the methylated DNA-binding protein MeCP2 increases during neuronal development, which suggests that this epigenetic factor is crucial for neuronal terminal differentiation. We evaluated dendritic and axonal development in embryonic day-18 hippocampal neurons in culture by measuring total length and counting branch point numbers at 4 days in vitro, well before synapse formation. Pyramidal neurons transfected with a plasmid encoding a small hairpin RNA (shRNA) to knockdown endogenous Mecp2 had shorter dendrites than control untransfected neurons, without detectable changes in axonal morphology. On the other hand, overexpression of wildtype (wt) human MECP2 increased dendritic branching, in addition to axonal branching and length. Consistent with reduced neuronal growth and complexity in Rett syndrome (RTT) brains, overexpression of human MECP2 carrying missense mutations common in RTT individuals (R106W or T158M) reduced dendritic and axonal length. One of the targets of MeCP2 transcriptional control is the Bdnf gene. Indeed, endogenous Mecp2 knockdown increased the intracellular levels of BDNF protein compared to untransfected neurons, suggesting that MeCP2 represses Bdnf transcription. Surprisingly, overexpression of wt MECP2 also increased BDNF levels, while overexpression of RTT-associated MECP2 mutants failed to affect BDNF levels. The extracellular BDNF scavenger TrkB-Fc prevented dendritic overgrowth in wt MECP2-overexpressing neurons, while overexpression of the Bdnf gene reverted the dendritic atrophy caused by Mecp2-knockdown. However, this effect was only partial, since Bdnf increased dendritic length only to control levels in mutant MECP2-overexpressing neurons, but not as much as in Bdnf-transfected cells. Our results demonstrate that MeCP2 plays varied roles in dendritic and axonal development during neuronal terminal differentiation, and that some of these effects are mediated by autocrine actions of BDNF.

  2. BDNF in fragile X syndrome.

    PubMed

    Castrén, Maija L; Castrén, Eero

    2014-01-01

    Fragile X syndrome (FXS) is a monogenic disorder that is caused by the absence of FMR1 protein (FMRP). FXS serves as an excellent model disorder for studies investigating disturbed molecular mechanisms and synapse function underlying cognitive impairment, autism, and behavioral disturbance. Abnormalities in dendritic spines and synaptic transmission in the brain of FXS individuals and mouse models for FXS indicate perturbations in the development, maintenance, and plasticity of neuronal network connectivity. However, numerous alterations are found during the early development in FXS, including abnormal differentiation of neural progenitors and impaired migration of newly born neurons. Several aspects of FMRP function are modulated by brain-derived neurotrophic factor (BDNF) signaling. Here, we review the evidence of the role for BDNF in the developing and adult FXS brain. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'.

  3. BDNF Methylation and Maternal Brain Activity in a Violence-Related Sample

    PubMed Central

    Moser, Dominik A.; Paoloni-Giacobino, Ariane; Stenz, Ludwig; Adouan, Wafae; Manini, Aurélia; Suardi, Francesca; Cordero, Maria I.; Vital, Marylene; Sancho Rossignol, Ana; Rusconi-Serpa, Sandra; Ansermet, François; Dayer, Alexandre G.; Schechter, Daniel S.

    2015-01-01

    It is known that increased circulating glucocorticoids in the wake of excessive, chronic, repetitive stress increases anxiety and impairs Brain-Derived Neurotrophic Factor (BDNF) signaling. Recent studies of BDNF gene methylation in relation to maternal care have linked high BDNF methylation levels in the blood of adults to lower quality of received maternal care measured via self-report. Yet the specific mechanisms by which these phenomena occur remain to be established. The present study examines the link between methylation of the BDNF gene promoter region and patterns of neural activity that are associated with maternal response to stressful versus non-stressful child stimuli within a sample that includes mothers with interpersonal violence-related PTSD (IPV-PTSD). 46 mothers underwent fMRI. The contrast of neural activity when watching children—including their own—was then correlated to BDNF methylation. Consistent with the existing literature, the present study found that maternal BDNF methylation was associated with higher levels of maternal anxiety and greater childhood exposure to domestic violence. fMRI results showed a positive correlation of BDNF methylation with maternal brain activity in the anterior cingulate (ACC), and ventromedial prefrontal cortex (vmPFC), regions generally credited with a regulatory function toward brain areas that are generating emotions. Furthermore we found a negative correlation of BDNF methylation with the activity of the right hippocampus. Since our stimuli focus on stressful parenting conditions, these data suggest that the correlation between vmPFC/ACC activity and BDNF methylation may be linked to mothers who are at a disadvantage with respect to emotion regulation when facing stressful parenting situations. Overall, this study provides evidence that epigenetic signatures of stress-related genes can be linked to functional brain regions regulating parenting stress, thus advancing our understanding of mothers at risk

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

    PubMed

    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.

  5. Epigenetic modification of hippocampal Bdnf DNA in adult rats in an animal model of post-traumatic stress disorder.

    PubMed

    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.

  6. The Met allele of BDNF Val66Met polymorphism is associated with increased BDNF levels in generalized anxiety disorder.

    PubMed

    Moreira, Fernanda P; Fabião, Júlia D; Bittencourt, Guilherme; Wiener, Carolina D; Jansen, Karen; Oses, Jean P; Quevedo, Luciana de Ávila; Souza, Luciano D M; Crispim, Daisy; Portela, Luiz V; Pinheiro, Ricardo T; Lara, Diogo R; Kaster, Manuella P; da Silva, Ricardo A; Ghisleni, Gabriele

    2015-10-01

    Generalized anxiety disorder (GAD) is a common psychiatric disorder characterized by long-term worry, tension, nervousness, fidgeting, and symptoms of autonomic system hyperactivity. The neurobiology of this disorder is still unclear, although it has been shown consistently that the environment and the genetic profile could increase its risk. We examined whether a polymorphism in the brain-derived neurotrophic factor (BDNF) gene, which plays a role in neuroplasticity and memory, could increase the vulnerability to this disorder. In our study, 816 participants from a population-based study were genotyped by qPCR for the BDNF functional variant rs6265 (Val66Met) and the BDNF serum levels were measured by ELISA. Our results showed a significant association between the Met allele and risk for GAD (P=0.014), but no differences were observed in the serum levels of BDNF according to diagnosis (P=0.531) or genotype distribution (P=0.197). However, after stratification according to the GAD diagnosis, the Met allele was associated significantly with an increase in serum BDNF levels compared with the Val/Val genotype in GAD participants (F=3.93; P=0.048). The logistic regression analysis confirmed the independent association of Met allele as a risk factor for development of GAD after adjusting for confounder variables (β=0.528; 95% confidence interval: 0.320-0.871; P=0.012). These results suggest that BDNF could be involved in the neurobiology of GAD and might represent a useful marker associated with the disease.

  7. AP-1 Transcription Factors Mediate BDNF-Positive Feedback Loop in Cortical Neurons.

    PubMed

    Tuvikene, Jürgen; Pruunsild, Priit; Orav, Ester; Esvald, Eli-Eelika; Timmusk, Tõnis

    2016-01-27

    Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, regulates both survival and differentiation of several neuronal populations in the nervous system during development, as well as synaptic plasticity in the adult brain. BDNF exerts its biological functions through its receptor TrkB. Although the regulation of BDNF transcription by neuronal activity has been widely studied, little is known about TrkB signaling-dependent expression of BDNF. Using rat primary cortical neuron cultures, we show that the BDNF gene is a subject to an extensive autoregulatory loop, where TrkB signaling upregulates the expression of all major BDNF transcripts, mainly through activating MAPK pathways. Investigating the mechanisms behind this autoregulation, we found that AP-1 transcription factors, comprising Jun and Fos family members, participate in the induction of BDNF exon I, III, and VI transcripts. AP-1 transcription factors directly upregulate the expression of exon I transcripts by binding two novel AP-1 cis-elements in promoter I. Moreover, our results show that the effect of AP-1 proteins on the activity of rat BDNF promoters III and VI is indirect, because AP-1 proteins were not detected to bind the respective promoter regions by chromatin immunoprecipitation (ChIP). Collectively, we describe an extensive positive feedback system in BDNF regulation, adding a new layer to the elaborate control of BDNF gene expression. Here, we show for the first time that in rat primary cortical neurons the expression of all major BDNF transcripts (exon I, II, III, IV, VI, and IXa transcripts) is upregulated in response to TrkB signaling, and that AP-1 transcription factors participate in the induction of exon I, III, and VI transcripts. Moreover, we have described two novel functional AP-1 cis-elements in BDNF promoter I, responsible for the activation of the promoter in response to TrkB signaling. Our results indicate the existence of a positive feedback loop for

  8. Brain-Derived Neurotrophic Factor (BDNF) and Traumatic Brain Injury (Head and Spinal)

    DTIC Science & Technology

    2000-01-01

    of BDNF and its receptor, trkB in response to injury. This study demonstrated that regions of the brain that are resistant to cell damage have...increased gene expression for BDNF and its high affinity receptor, tyrosine kinase B ( trkB ) during the acute periods after injury. Study 2 examined whether...the alterations in mRNA levels following FP injury resulted in subsequent alterations in protein levels of BDNF and trkB and activation of the ERK/MAP

  9. MicroRNA function and neurotrophin BDNF.

    PubMed

    Numakawa, Tadahiro; Richards, Misty; Adachi, Naoki; Kishi, Soichiro; Kunugi, Hiroshi; Hashido, Kazuo

    2011-10-01

    MicroRNAs (miRs), endogenous small RNAs, regulate gene expression through repression of translational activity after binding to target mRNAs. miRs are involved in various cellular processes including differentiation, metabolism, and apoptosis. Furthermore, possible involvement of miRs in neuronal function have been proposed. For example, miR-132 is closely related to neuronal outgrowth while miR-134 plays a role in postsynaptic regulation, suggesting that brain-specific miRs are critical for synaptic plasticity. On the other hand, numerous studies indicate that BDNF (brain-derived neurotrophic factor), one of the neurotrophins, is essential for a variety of neuronal aspects such as cell differentiation, survival, and synaptic plasticity in the central nervous system (CNS). Interestingly, recent studies, including ours, suggest that BDNF exerts its beneficial effects on CNS neurons via up-regulation of miR-132. Here, we present a broad overview of the current knowledge concerning the association between neurotrophins and various miRs.

  10. BDNF - a key transducer of antidepressant effects.

    PubMed

    Björkholm, Carl; Monteggia, Lisa M

    2016-03-01

    How do antidepressants elicit an antidepressant response? Here, we review accumulating evidence that the neurotrophin brain-derived neurotrophic factor (BDNF) serves as a transducer, acting as the link between the antidepressant drug and the neuroplastic changes that result in the improvement of the depressive symptoms. Over the last decade several studies have consistently highlighted BDNF as a key player in antidepressant action. An increase in hippocampal and cortical expression of BDNF mRNA parallels the antidepressant-like response of conventional antidepressants such as SSRIs. Subsequent studies showed that a single bilateral infusion of BDNF into the ventricles or directly into the hippocampus is sufficient to induce a relatively rapid and sustained antidepressant-like effect. Importantly, the antidepressant-like response to conventional antidepressants is attenuated in mice where the BDNF signaling has been disrupted by genetic manipulations. Low dose ketamine, which has been found to induce a rapid antidepressant effect in patients with treatment-resistant depression, is also dependent on increased BDNF signaling. Ketamine transiently increases BDNF translation in hippocampus, leading to enhanced synaptic plasticity and synaptic strength. Ketamine has been shown to increase BDNF translation by blocking NMDA receptor activity at rest, thereby inhibiting calcium influx and subsequently halting eukaryotic elongation factor 2 (eEF2) kinase leading to a desuppression of protein translation, including BDNF translation. The antidepressant-like response of ketamine is abolished in BDNF and TrkB conditional knockout mice, eEF2 kinase knockout mice, in mice carrying the BDNF met/met allele, and by intra-cortical infusions of BDNF-neutralizing antibodies. In summary, current data suggests that conventional antidepressants and ketamine mediate their antidepressant-like effects by increasing BDNF in forebrain regions, in particular the hippocampus, making BDNF an

  11. Gain of BDNF Function in Engrafted Neural Stem Cells Promotes the Therapeutic Potential for Alzheimer’s Disease

    PubMed Central

    Wu, Cheng-Chun; Lien, Cheng-Chang; Hou, Wen-Hsien; Chiang, Po-Min; Tsai, Kuen-Jer

    2016-01-01

    Stem cell-based therapy is a potential treatment for neurodegenerative diseases, but its application to Alzheimer’s disease (AD) remains limited. Brain-derived neurotrophic factor (BDNF) is critical in the pathogenesis and treatment of AD. Here, we present a novel therapeutic approach for AD treatment using BDNF-overexpressing neural stem cells (BDNF-NSCs). In vitro, BDNF overexpression was neuroprotective to beta-amyloid-treated NSCs. In vivo, engrafted BDNF-NSCs-derived neurons not only displayed the Ca2+-response fluctuations, exhibited electrophysiological properties of mature neurons and integrated into local brain circuits, but recovered the cognitive deficits. Furthermore, BDNF overexpression improved the engrafted cells’ viability, neuronal fate, neurite complexity, maturation of electrical property and the synaptic density. In contrast, knockdown of the BDNF in BDNF-NSCs diminished stem cell-based therapeutic efficacy. Together, our findings indicate BDNF overexpression improves the therapeutic potential of engrafted NSCs for AD via neurogenic effects and neuronal replacement, and further support the feasibility of NSC-based ex vivo gene therapy for AD. PMID:27264956

  12. Neurochemical properties of BDNF-containing neurons projecting to rostral ventromedial medulla in the ventrolateral periaqueductal gray

    PubMed Central

    Yin, Jun-Bin; Wu, Huang-Hui; Dong, Yu-Lin; Zhang, Ting; Wang, Jian; Zhang, Yong; Wei, Yan-Yan; Lu, Ya-Cheng; Wu, Sheng-Xi; Wang, Wen; Li, Yun-Qing

    2014-01-01

    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, detailed information is still lacking 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 microglia. By combining retrograde tracing methods and formalin pain model, there were more BDNF-containing neurons projecting to RVM being activated in the ventrolateral subregion of 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 the autoreceptor 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. PMID:25477786

  13. Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate

    PubMed Central

    Sleiman, Sama F; Henry, Jeffrey; Al-Haddad, Rami; El Hayek, Lauretta; Abou Haidar, Edwina; Stringer, Thomas; Ulja, Devyani; Karuppagounder, Saravanan S; Holson, Edward B; Ratan, Rajiv R; Ninan, Ipe; Chao, Moses V

    2016-01-01

    Exercise induces beneficial responses in the brain, which is accompanied by an increase in BDNF, a trophic factor associated with cognitive improvement and the alleviation of depression and anxiety. However, the exact mechanisms whereby physical exercise produces an induction in brain Bdnf gene expression are not well understood. While pharmacological doses of HDAC inhibitors exert positive effects on Bdnf gene transcription, the inhibitors represent small molecules that do not occur in vivo. Here, we report that an endogenous molecule released after exercise is capable of inducing key promoters of the Mus musculus Bdnf gene. The metabolite β-hydroxybutyrate, which increases after prolonged exercise, induces the activities of Bdnf promoters, particularly promoter I, which is activity-dependent. We have discovered that the action of β-hydroxybutyrate is specifically upon HDAC2 and HDAC3, which act upon selective Bdnf promoters. Moreover, the effects upon hippocampal Bdnf expression were observed after direct ventricular application of β-hydroxybutyrate. Electrophysiological measurements indicate that β-hydroxybutyrate causes an increase in neurotransmitter release, which is dependent upon the TrkB receptor. These results reveal an endogenous mechanism to explain how physical exercise leads to the induction of BDNF. DOI: http://dx.doi.org/10.7554/eLife.15092.001 PMID:27253067

  14. Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate.

    PubMed

    Sleiman, Sama F; Henry, Jeffrey; Al-Haddad, Rami; El Hayek, Lauretta; Abou Haidar, Edwina; Stringer, Thomas; Ulja, Devyani; Karuppagounder, Saravanan S; Holson, Edward B; Ratan, Rajiv R; Ninan, Ipe; Chao, Moses V

    2016-06-02

    Exercise induces beneficial responses in the brain, which is accompanied by an increase in BDNF, a trophic factor associated with cognitive improvement and the alleviation of depression and anxiety. However, the exact mechanisms whereby physical exercise produces an induction in brain Bdnf gene expression are not well understood. While pharmacological doses of HDAC inhibitors exert positive effects on Bdnf gene transcription, the inhibitors represent small molecules that do not occur in vivo. Here, we report that an endogenous molecule released after exercise is capable of inducing key promoters of the Mus musculus Bdnf gene. The metabolite β-hydroxybutyrate, which increases after prolonged exercise, induces the activities of Bdnf promoters, particularly promoter I, which is activity-dependent. We have discovered that the action of β-hydroxybutyrate is specifically upon HDAC2 and HDAC3, which act upon selective Bdnf promoters. Moreover, the effects upon hippocampal Bdnf expression were observed after direct ventricular application of β-hydroxybutyrate. Electrophysiological measurements indicate that β-hydroxybutyrate causes an increase in neurotransmitter release, which is dependent upon the TrkB receptor. These results reveal an endogenous mechanism to explain how physical exercise leads to the induction of BDNF.

  15. Stress and trauma: BDNF control of dendritic-spine formation and regression.

    PubMed

    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

  16. Mineralocorticoid receptor genotype moderates the association between physical neglect and serum BDNF.

    PubMed

    Bortoluzzi, Andressa; Salum, Giovanni Abrahão; Blaya, Carolina; Silveira, Patrícia Pelufo; Grassi-Oliveira, Rodrigo; da Rosa, Eduarda Dias; de Aguiar, Bianca Wollenhaupt; Stertz, Laura; Bosa, Vera Lúcia; Schuch, Ilaine; Goldani, Marcelo; Kapczinski, Flavio; Leistner-Segal, Sandra; Manfro, Gisele Gus

    2014-12-01

    The objective of this study is to investigate if a polymorphism in the NR3C2 gene moderates the association between childhood trauma on serum levels of brain derived neurothrophic factor (sBDNF). sBDNF was used here as a general marker of alteration in brain function. This is a community cross sectional study comprising 90 adolescents (54 with anxiety disorders). DNA was extracted from saliva in order to genotype the MR-2G/C (rs2070951) polymorphism using real time PCR. Blood was collected for sBDNF Elisa immunoassay. The Childhood Trauma Questionnaire (CTQ) was used to evaluate childhood abuse and neglect. Main effects and gene environment interactions were tested using linear regression models. Anxiety disorders were not associated with the MR-2G/C polymorphism or with sBDNF levels, but the number of C alleles of the MR-2G/C polymorphism was significantly associated with higher sBDNF levels (b = 8.008; p-value = 0.001). Subjects with intermediate and high exposure to physical neglect showed higher sBDNF levels if compared to subjects non-exposed (b = 11.955; p = 0.004 and b = 16.186; p = 0.009, respectively). In addition, we detected a significant physical neglect by MR-2G/C C allele interaction on sBDNF levels (p = 0.005), meaning that intermediate and high exposure to childhood neglect were only associated with increased sBDNF levels in subjects with the CC genotype, but not in subjects with other genotypes. Our findings suggest that genetic variants in NR3C2 gene may partially explain plastic brain vulnerability to traumatic events. Further studies are needed to investigate the moderating effects of NR3C2 gene in more specific markers of alteration in brain function.

  17. Exercise Does Not Protect against MPTP-Induced Neurotoxicity in BDNF Happloinsufficent Mice

    PubMed Central

    Gerecke, Kim M.; Jiao, Yun; Pagala, Viswajeeth; Smeyne, Richard J.

    2012-01-01

    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. PMID:22912838

  18. Chronic antidepressant administration alleviates frontal and hippocampal BDNF deficits in CUMS rat.

    PubMed

    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.

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

    PubMed

    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 < 0.05) elevated in multiple brain regions, including the dentate gyrus, CA3, and CA1 regions of the hippocampal formation, as well as the piriform cortex, hypothalamus, amygdala, and thalamus, 72 h after the last 0.4 LD(50) 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.

  20. Altered White Matter Architecture in BDNF Met Carriers

    PubMed Central

    Ziegler, Erik; Foret, Ariane; Mascetti, Laura; Muto, Vincenzo; Le Bourdiec-Shaffii, Anahita; Stender, Johan; Balteau, Evelyne; Dideberg, Vinciane; Bours, Vincent; Maquet, Pierre; Phillips, Christophe

    2013-01-01

    Brain-derived neurotrophic factor (BDNF) modulates the pruning of synaptically silent axonal arbors. The Met allele of the BDNF gene is associated with a reduction in the neurotrophin's activity-dependent release. We used diffusion-weighted imaging to construct structural brain networks for 36 healthy subjects with known BDNF genotypes. Through permutation testing we discovered clear differences in connection strength between subjects carrying the Met allele and those homozygotic for the Val allele. We trained a Gaussian process classifier capable of identifying the subjects' allelic group with 86% accuracy and high predictive value. In Met carriers structural connectivity was greatly increased throughout the forebrain, particularly in connections corresponding to the anterior and superior corona radiata as well as corticothalamic and corticospinal projections from the sensorimotor, premotor, and prefrontal portions of the internal capsule. Interhemispheric connectivity was also increased via the corpus callosum and anterior commissure, and extremely high connectivity values were found between inferior medial frontal polar regions via the anterior forceps. We propose that the decreased availability of BDNF leads to deficits in axonal maintenance in carriers of the Met allele, and that this produces mesoscale changes in white matter architecture. PMID:23935975

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

    PubMed

    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.

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

    PubMed

    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.

  3. Fear extinction and BDNF: translating animal models of PTSD to the clinic.

    PubMed

    Andero, R; Ressler, K J

    2012-07-01

    Brain-derived neurotrophic factor (BDNF) is the most studied neurotrophin involved in synaptic plasticity processes that are required for long-term learning and memory. Specifically, BDNF gene expression and activation of its high-affinity tropomyosin-related kinase B (TrkB) receptor are necessary in the amygdala, hippocampus and prefrontal cortex for the formation of emotional memories, including fear memories. Among the psychiatric disorders with altered fear processing, there is post-traumatic stress disorder (PTSD) which is characterized by an inability to extinguish fear memories. Since BDNF appears to enhance extinction of fear, targeting impaired extinction in anxiety disorders such as PTSD via BDNF signalling may be an important and novel way to enhance treatment efficacy. The aim of this review is to provide a translational point of view that stems from findings in the BDNF regulation of synaptic plasticity and fear extinction. In addition, there are different systems that seem to alter fear extinction through BDNF modulation like the endocannabinoid system and the hypothalamic-pituitary adrenal axis. Recent work also finds that the pituitary adenylate cyclase-activating polypeptide and PAC1 receptor, which are upstream of BDNF activation, may be implicated in PTSD. Especially interesting are data that exogenous fear extinction enhancers such as antidepressants, histone deacetylases inhibitors and D-cycloserine, a partial N-methyl d-aspartate agonist, may act through or in concert with the BDNF-TrkB system. Finally, we review studies where recombinant BDNF and a putative TrkB agonist, 7,8-dihydroxyflavone, may enhance extinction of fear. These approaches may lead to novel agents that improve extinction in animal models and eventually humans.

  4. TOOTH PULP INFLAMMATION INCREASES BDNF EXPRESSION IN RODENT TRIGEMINAL GANGLION NEURONS

    PubMed Central

    Tarsa, Leila; Bałkowiec-Iskra, Ewa; Kratochvil, F. James; Jenkins, Victoria K.; McLean, Anne; Brown, Alexandra; Smith, Julie Ann; Baumgartner, J. Craig; Balkowiec, Agnieszka

    2010-01-01

    Nociceptive pathways with first-order neurons located in the trigeminal ganglion (TG) provide sensory innervation to the head, and are responsible for a number of common chronic pain conditions, including migraines, temporomandibular disorders and trigeminal neuralgias. Many of those conditions are associated with inflammation. Yet, the mechanisms of chronic inflammatory pain remain poorly understood. Our previous studies show that the neurotrophin brain-derived neurotrophic factor (BDNF) is expressed by adult rat TG neurons, and released from cultured newborn rat TG neurons by electrical stimulation and calcitonin gene-related peptide (CGRP), a well-established mediator of trigeminal inflammatory pain. These data suggest that BDNF plays a role in activity-dependent plasticity at first-order trigeminal synapses, including functional changes that take place in trigeminal nociceptive pathways during chronic inflammation. The present study was designed to determine the effects of peripheral inflammation, using tooth pulp inflammation as a model, on regulation of BDNF expression in TG neurons of juvenile rats and mice. Cavities were prepared in right-side maxillary first and second molars of 4-week-old animals, and left open to oral microflora. BDNF expression in right TG was compared with contralateral TG of the same animal, and with right TG of sham-operated controls, 7 and 28 days after cavity preparation. Our ELISA data indicate that exposing the tooth pulp for 28 days, with confirmed inflammation, leads to a significant upregulation of BDNF in the TG ipsilateral to the affected teeth. Double-immunohistochemistry with antibodies against BDNF combined with one of nociceptor markers, CGRP or TRPV1, revealed that BDNF is significantly upregulated in TRPV1-immunoreactive (IR) neurons in both rats and mice, and CGRP-IR neurons in mice, but not rats. Overall, the inflammation-induced upregulation of BDNF is stronger in mice compared to rats. Thus, mouse TG provides a

  5. Fear extinction and BDNF: Translating animal models of PTSD to the clinic

    PubMed Central

    Andero, Raül; Ressler, Kerry J

    2012-01-01

    Brain-derived neurotrophic factor (BDNF) is the most studied neurotrophin involved in synaptic plasticity processes that are required for long-term learning and memory. Specifically, BDNF gene expression and activation of its high-affinity TrkB receptor are necessary in the amygdala, hippocampus and prefrontal cortex for the formation of emotional memories, including fear memories. Among the psychiatric disorders with altered fear processing there is Post-traumatic Stress Disorder (PTSD) which is characterized by an inability to extinguish fear memories. Since BDNF appears to enhance extinction of fear, targeting impaired extinction in anxiety disorders such as PTSD via BDNF signalling may be an important and novel way to enhance treatment efficacy. The aim of this review is to provide a translational point of view that stems from findings in the BDNF regulation of synaptic plasticity and fear extinction. In addition, there are different systems that seem to alter fear extinction through BDNF modulation like the endocannabionoid system and the hypothalamic-pituitary adrenal axis (HPA). Recent work also finds that the pituitary adenylate cyclase-activating polypeptide (PACAP) and PAC1 receptor, which are upstream of BDNF activation, may be implicated in PTSD. Especially interesting are data that exogenous fear extinction enhancers such as antidepressants, histone deacetylases inhibitors (HDACi) and D-cycloserine, a partial NMDA agonist, may act through or in concert with the BDNF-TrkB system. Finally, we review studies where recombinant BDNF and a putative TrkB agonist, 7,8-DHF, may enhance extinction of fear. These approaches may lead to novel agents that improve extinction in animal models and eventually humans. PMID:22530815

  6. Prelimbic cortical BDNF is required for memory of learned fear but not extinction or innate fear

    PubMed Central

    Choi, Dennis C.; Maguschak, Kimberly A.; Ye, Keqiang; Jang, Sung-Wuk; Myers, Karyn M.; Ressler, Kerry J.

    2010-01-01

    In the medial prefrontal cortex, the prelimbic area is emerging as a major modulator of fear behavior, but the mechanisms remain unclear. Using a selective neocortical knockout mouse, virally mediated prelimbic cortical-specific gene deletion, and pharmacological rescue with a TrkB agonist, we examined the role of a primary candidate mechanism, BDNF, in conditioned fear. We found consistently robust deficits in consolidation of cued fear but no effects on acquisition, expression of unlearned fear, sensorimotor function, and spatial learning. This deficit in learned fear in the BDNF knockout mice was rescued with systemic administration of a TrkB receptor agonist, 7,8-dihydroxyflavone. These data indicate that prelimbic BDNF is critical for consolidation of learned fear memories, but it is not required for innate fear or extinction of fear. Moreover, use of site-specific, inducible BDNF deletions shows a powerful mechanism that may further our understanding of the pathophysiology of fear-related disorders. PMID:20133801

  7. Multiple faces of BDNF in cocaine addiction.

    PubMed

    Li, Xuan; Wolf, Marina E

    2015-02-15

    Brain-derived neurotrophic factor (BDNF) has been found to play roles in many types of plasticity including drug addiction. Here, we focus on rodent studies over the past two decades that have demonstrated diverse roles of BDNF in models of cocaine addiction. First, we will provide an overview of studies showing that cocaine exposure alters (and generally increases) BDNF levels in reward-related regions including the ventral tegmental area, nucleus accumbens, prefrontal cortex, and amygdala. Then we will review evidence that BDNF contributes to behavioral changes in animal models of cocaine addiction, focusing on conditioned place preference, behavioral sensitization, maintenance and reinstatement of self-administration, and incubation of cocaine craving. Last, we will review the role of BDNF in synaptic plasticity, particularly as it relates to plasticity of AMPA receptor transmission after cocaine exposure. We conclude that BDNF regulates cocaine-induced behaviors in a highly complex manner that varies depending on the brain region (and even among different cell types within the same brain region), the nature of cocaine exposure, and the "addiction phase" examined (e.g., acquisition vs maintenance; early vs late withdrawal). These complexities make BDNF a daunting therapeutic target for treating cocaine addiction. However, recent clinical evidence suggests that the serum BDNF level may serve as a biomarker in cocaine addicts to predict future relapse, providing an alternative direction for exploring BDNF's potential relevance to treating cocaine addiction. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. Effect of Val66Met polymorphism in BDNF on attentional bias in an extroverted Chinese Han population.

    PubMed

    Gong, Pingyuan; Xi, Shoumin; Li, She; Cao, Guochang; Zhang, Peizhe; Shen, Guomin; Zhang, Fuchang; Shen, Yan; Ma, Hua

    2013-01-01

    Studies have indicated that a functional polymorphism (Val66Met) in a brain-derived neurotrophic factor (BDNF) gene can influences human cognitive functions and mood disorders. In this study, we examined associations of BDNF Val66Met with attentional bias and personality in an unaffected population. The results showed that BDNF Val66Met was significantly associated with attentional disengagement for positive cueing words in extraverts. Moreover, there was a positive correlation between the dosages of Met allele and attentional disengagement, however, we did not observe any significant influences of BDNF Val66Met on personality traits. These preliminary results indicate that the individual differences in attentional bias for positive words are partially underpinned by BDNF.

  9. Neurotrophic Factors (BDNF and GDNF) and the Serotonergic System of the Brain.

    PubMed

    Popova, N K; Ilchibaeva, T V; Naumenko, V S

    2017-03-01

    Neurotrophic factors play a key role in development, differentiation, synaptogenesis, and survival of neurons in the brain as well as in the process of their adaptation to external influences. The serotonergic (5-HT) system is another major factor in the development and neuroplasticity of the brain. In the present review, the results of our own research as well as data provided in the corresponding literature on the interaction of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) with the 5-HT-system of the brain are considered. Attention is given to comparison of BDNF and GDNF, the latter belonging to a different family of neurotrophic factors and being mainly considered as a dopaminergic system controller. Data cited in this review show that: (i) BDNF and GDNF interact with the 5-HT-system of the brain through feedback mechanisms engaged in autoregulation of the complex involving 5-HT-system and neurotrophic factors; (ii) GDNF, as well as BDNF, stimulates the growth of 5-HT neurons and affects the expression of key genes of the brain 5-HT-system - those coding tryptophan hydroxylase-2 and 5-HT1A and 5-HT2A receptors. In turn, 5-HT affects the expression of genes that control BDNF and GDNF in brain structures; (iii) the difference between BDNF and GDNF is manifested in different levels and relative distribution of expression of these factors in brain structures (BDNF expression is highest in hippocampus and cortex, GDNF expression in the striatum), in varying reaction of 5-HT2A receptors on BDNF and GDNF administration, and in different effects on certain types of behavior.

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

    PubMed Central

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

    2016-01-01

    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. PMID:27640722

  11. The Bdnf Val68 to Met Polymorphism Increases Compulsive Alcohol Drinking In Mice Which Is Reversed By TrkB Activation

    PubMed Central

    Warnault, Vincent; Darcq, Emmanuel; Morisot, Nadege; Phamluong, Khanhky; Wilbrecht, Linda; Massa, Stephen M.; Longo, Frank M.; Ron, Dorit

    2015-01-01

    Background The Val66 to Met polymorphism within the brain-derived neurotrophic factor (BDNF) sequence reduces activity-dependent BDNF release, and is associated with psychiatric disorders in humans. Alcoholism is one of the most prevalent psychiatric diseases. Here, we tested the hypothesis that this polymorphism increases the severity of alcohol abuse disorders. Methods We generated transgenic mice carrying the mouse homolog of the human Met66BDNF allele (Met68BDNF), and used alcohol-drinking paradigms in combination with viral-mediated gene delivery and pharmacology. Results We found that Met68BDNF mice consumed excessive amounts of alcohol and continued to drink despite negative consequences, a hallmark of addiction. Importantly, compulsive alcohol intake was reversed by overexpression of the wild-type Val68BDNF allele in the ventromedial prefrontal cortex of the Met68BDNF mice, or by systemic administration of the TrkB agonist, LM22A-4. Conclusions Our findings suggest that carrying the Met66BDNF allele increases the risk of developing uncontrolled and excessive alcohol drinking that can be reversed by directly activating the BDNF receptor, TrkB. Importantly, this work identifies a potential therapeutic strategy for the treatment of compulsive alcohol drinking in humans carrying the Met66BDNF allele. PMID:26204799

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

    PubMed

    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.

  13. BDNF and NT-3 expression by using glucocorticoid-induced bicistronic expression vector pGC-BDNF-IRES-NT3 protects apoptotic cells in a cellular injury model.

    PubMed

    Wang, Yongxiang; Gu, Jiaxiang; Wang, Jingcheng; Feng, Xingmin; Tao, Yuping; Jiang, Baichuan; He, Jinshan; Wang, Qiang; Yang, Jiandong; Zhang, Shenfei; Cai, Jun; Sun, Yu

    2012-04-11

    Spinal cord injury (SCI) is a severe traumatic disease in the central nervous system with high incidence and high morbidity. Recent study demonstrated that cell transplantation therapy may improve local microenvironment of the injury site and promote nerve regeneration to restore spinal cord functions. In this study, we constructed a glucocorticoid-induced bicistronic eukaryotic expression vector pGC-BDNF-IRES-NT3 by using molecular cloning techniques and examined the protective effect of neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF) expressed by this vector in a rat spinal cord injury (SCI) model. We first connected glucocorticoid response element (GRE) to cytomegalovirus (CMV) promoter and then the GRE-CMV gene was inserted into pEGFP-1 vector to construct the eukaryotic expression vector pGC-EGFP. Western blot analysis was used to confirm the expression of EGFP by transfecting this vector in RN-DSC cells. The IRES was used to connect BDNF gene and NT-3 gene and replaced the EGFP gene in pGC-EGFP plasmid to form the bicistronic expression vector-pGC-BDNF-IRES-NT3. After RN-DSC cells were transfected with the plasmid and treated with glucocorticoid, BDNF and NT-3 expression in the culture medium were measured by ELISA method. Finally, we found that combination therapy with the transfection of this vector and glucocorticoid had an anti-apoptotic effect in a cellular SCI model of RN-DSC cells. Therefore, the co-expression of BDNF and NT-3 by using this vector rescued the injured cells. This provided useful information for the gene-modification cell transplantation combined with glucocorticoid for the treatment of SCI.

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

    PubMed

    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.

  15. Long noncoding RNA BDNF-AS regulates ketamine-induced neurotoxicity in neural stem cell derived neurons.

    PubMed

    Zheng, Xiaozhu; Lin, Chunshui; Li, Yuhong; Ye, Jing; Zhou, Jiali; Guo, Peipei

    2016-08-01

    Ketamine is an anesthetic commonly used in both humans and animals. Emerging evidence has demonstrated that ketamine may induce neurotoxicity in neural stem cell-derived neurons. In this work, we investigated whether long noncoding RNA (lncRNA) Brain derived neurotrophic factor antisense (BDNF-AS) was involved in ketamine-induced neurotoxicity in differentiation of mouse embryonic neural stem cells. Mouse embryonic neural stem cells were differentiated in vitro, and treated with ketamine. The corresponding change in gene expression levels of BDNF and BDNF-AS were assessed by qRT-PCR. BDNF-AS was subsequently downregulated by siRNA. And its effect on protecting neuronal apoptosis, promoting neurite regrowth, and activating TrkB signaling pathways were assessed by TUNEL assay, neurite outgrowth assay, and western blot assay, respectively. In ketamine-injured mouse embryonic neural stem cell-derived neurons, BDNF was downregulated, whereas BDNF-AS was upregulated in dose-dependent manner. SiRNA-mediated BDNF-AS downregulation ameliorated neuronal apoptosis, induced neurite outgrowth, and phosphorylated TrkB signaling pathway after ketamine-induce neurotoxicity in mouse embryonic neural stem cell-derived neurons. Inhibition of BDNF-AS is a novel method to protect ketamine-induced neurotoxicity in mouse embryonic neural stem cell-derived neurons, very likely through the activation of TrkB signaling pathway. Copyright © 2016. Published by Elsevier Masson SAS.

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

    PubMed

    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.

  17. Disruption of a novel regulatory locus results in decreased Bdnf expression, obesity, and type 2 diabetes in mice.

    PubMed

    Sha, Haibo; Xu, Jingyue; Tang, Jing; Ding, Jun; Gong, Jianfeng; Ge, Xiaomei; Kong, Dong; Gao, Xiang

    2007-10-22

    Mutants of brain-derived neurotrophic factor (BDNF) are associated with obesity. However, the regulatory mechanism of BDNF expression is still unclear. We developed a novel mutant mouse line, transgenic insertional mutants with obesity, named Timo, in which a potential regulatory locus of Bdnf was disrupted by transgene insertion. The insertion site was identified and lies 857 kb upstream of the Bdnf gene. The disrupted genomic locus is conserved across the mouse, rat, dog, and human genome and contains several highly conserved elements that are able to upregulate reporter gene expression in vitro. Along with downregulation of BDNF to approximately 30% of wild-type animals, Timo/Timo mice exhibited increased body weight and fat content with hepatic steatosis and elevated serum levels of leptin, cholesterol, and LDL cholesterol. These mutant mice also showed obesity-independent insulin resistance, hyperinsulinemia, impaired glucose tolerance, age-dependent hyperglycemia, and shortened life span. Molecular and phenotype analysis of Timo/Timo mice indicated the existence of a genome locus, lying 857 kb upstream of the Bdnf gene, that regulates BDNF expression, body weight, and glucose homeostasis.

  18. Boswellia serrata gum resin aqueous extract upregulatesBDNF but not CREB expression in adult male rat hippocampus.

    PubMed

    Khalaj-Kondori, Mohammad; Sadeghi, Farzaneh; Hosseinpourfeizi, Mohammad Ali; Shaikhzadeh-Hesari, Farzam; Nakhlband, Aylar; Rahmati-Yamchi, Mohammad

    2016-11-17

    Boswellia from the family Burseraceae has been proposed for prevention of amnesia; however, the molecular mechanism by which it affects memory is not clear. To reveal the potential molecular mechanism, the effects of boswellia on the expression of two memory related genes, CREB and BDNF, were investigated. Twenty-one male rats were randomly divided into 3 groups (n = 7): the control group received distilled water and the treatment groups received two doses of aqueous extract of Boswellia serrata gum resin (boswellia) (50 and 100 mg/kg) every day for 4 weeks. The animals were tested by the Morris water maze (MWM) and their hippocampus was isolated. Expression of CREB and BDNF genes was analyzed by Q-RT-PCR. The MWM test showed improvement in spatial learning and memory in both treatment groups. Gene expression analysis revealed a significant increase in BDNF but not CREB expression in rats treated with both 50 and 100 mg/kg doses in comparison with the control group. Although boswellia exerts its effects on memory formation at least partly by affecting the expression of BDNF, the results imply that boswellia probably affects memory via another BDNF-related pathway than the BDNF-CREB-BDNF cycle.

  19. Multiple faces of BDNF in cocaine addiction

    PubMed Central

    Li, Xuan; Wolf, Marina E.

    2014-01-01

    Brain-derived neurotrophic factor (BDNF) has been found to play roles in many types of plasticity including drug addiction. Here we focus on rodent studies over the past two decades that have demonstrated diverse roles of BDNF in models of cocaine addiction. First, we will provide an overview of studies showing that cocaine exposure alters (and generally increases) BDNF levels in reward-related regions including the ventral tegmental area, nucleus accumbens, prefrontal cortex, and amygdala. Then we will review evidence that BDNF contributes to behavioral changes in animal models of cocaine addiction, focusing on conditioned place preference, behavioral sensitization, maintenance and reinstatement of self-administration, and incubation of cocaine craving. Last, we will review the role of BDNF in synaptic plasticity, particularly as it relates to plasticity of AMPA receptor transmission after cocaine exposure. We conclude that BDNF regulates cocaine-induced behaviors in a highly complex manner that varies depending on the brain region (and even among different cell types within the same brain region), the nature of cocaine exposure, and the “addiction phase” examined (e.g., acquisition vs maintenance; early vs late withdrawal). These complexities make BDNF a daunting therapeutic target for treating cocaine addiction. However, recent clinical evidence suggests that the serum BDNF level may serve as a biomarker in cocaine addicts to predict future relapse, providing an alternative direction for exploring BDNF’s potential relevance to treating cocaine addiction. PMID:25449839

  20. BDNF controls object recognition memory reconsolidation.

    PubMed

    Radiske, Andressa; Rossato, Janine I; Gonzalez, Maria Carolina; Köhler, Cristiano A; Bevilaqua, Lia R; Cammarota, Martín

    2017-03-06

    Reconsolidation restabilizes memory after reactivation. Previously, we reported that the hippocampus is engaged in object recognition memory reconsolidation to allow incorporation of new information into the original engram. Here we show that BDNF is sufficient for this process, and that blockade of BDNF function in dorsal CA1 impairs updating of the reactivated recognition memory trace.

  1. Suicide Attempt, Clinical Correlates, and BDNF Val66Met Polymorphism in Chronic Patients With Schizophrenia.

    PubMed

    Xia, Haisen; Zhang, Guangya; Du, Xiangdong; Zhang, Yingyang; Yin, Guangzhong; Dai, Jing; He, Man-Xi; Soares, Jair C; Li, Xiaosi; Zhang, Xiang Yang

    2017-08-31

    Recent evidence suggests the role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of suicidal behavior. Because schizophrenia patients usually have high suicide rates and numerous studies have suggested that BDNF may contribute to the psychopathology of schizophrenia, we hypothesized that the functional polymorphism of BDNF (Val66Met) was associated with suicide attempts in patients with schizophrenia in a Chinese Han population. This polymorphism was genotyped in 825 chronic schizophrenia patients with (n = 123) and without (n = 702) suicide attempts and 445 healthy controls without a history of suicide attempts using a case-control design. The schizophrenia symptoms were assessed by the Positive and Negative Syndrome Scale. There were no significant differences in BDNF Val66Met genotype and allele distributions between the patients and healthy controls. However, we found the Val allele (p = .023) and the Val/Val genotypes (p = .058) to be associated with a history of suicide attempts. Moreover, some clinical characteristics, including age and cigarettes smoked each day, interacted with the BDNF gene variant and appeared to play an important role in suicide attempts among schizophrenia patients. The BDNF Val66Met polymorphism itself and its interaction with some clinical variables may influence suicide attempts among schizophrenia patients. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  2. A significant association between BDNF promoter methylation and the risk of drug addiction.

    PubMed

    Xu, Xuting; Ji, Huihui; Liu, Guili; Wang, Qinwen; Liu, Huifen; Shen, Wenwen; Li, Longhui; Xie, Xiaohu; Zhou, Wenhua; Duan, Shiwei

    2016-06-10

    As a member of the neurotrophic factor family, brain derived neurotrophic factor (BDNF) plays an important role in the survival and differentiation of neurons. The aim of our work was to evaluate the role of BDNF promoter methylation in drug addiction. A total of 60 drug abusers (30 heroin and 30 methylamphetamine addicts) and 52 healthy age- and gender-matched controls were recruited for the current case control study. Bisulfite pyrosequencing technology was used to determine the methylation levels of five CpGs (CpG1-5) on the BDNF promoter. Among the five CpGs, CpG5 methylation was significantly lower in drug abusers than controls. Moreover, significant associations were found between CpG5 methylation and addictive phenotypes including tension-anxiety, anger-hostility, fatigue-inertia, and depression-dejection. In addition, luciferase assay showed that the DNA fragment of BDNF promoter played a key role in the regulation of gene expression. Our results suggest that BDNF promoter methylation is associated with drug addiction, although further studies are needed to understand the mechanisms by which BDNF promoter methylation contributes to the pathophysiology of drug addiction.

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

    PubMed

    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.

  4. Regulation of BDNF chromatin status and promoter accessibility in a neural correlate of associative learning

    PubMed Central

    Ambigapathy, Ganesh; Zheng, Zhaoqing; Keifer, Joyce

    2015-01-01

    Brain-derived neurotrophic factor (BDNF) gene expression critically controls learning and its aberrant regulation is implicated in Alzheimer's disease and a host of neurodevelopmental disorders. The BDNF gene is target of known DNA regulatory mechanisms but details of its activity-dependent regulation are not fully characterized. We performed a comprehensive analysis of the epigenetic regulation of the turtle BDNF gene (tBDNF) during a neural correlate of associative learning using an in vitro model of eye blink classical conditioning. Shortly after conditioning onset, the results from ChIP-qPCR show conditioning-dependent increases in methyl-CpG-binding protein 2 (MeCP2) and repressor basic helix-loop-helix binding protein 2 (BHLHB2) binding to tBDNF promoter II that corresponds with transcriptional repression. In contrast, enhanced binding of ten-eleven translocation protein 1 (Tet1), extracellular signal-regulated kinase 1/2 (ERK1/2), and cAMP response element-binding protein (CREB) to promoter III corresponds with transcriptional activation. These actions are accompanied by rapid modifications in histone methylation and phosphorylation status of RNA polymerase II (RNAP II). Significantly, these remarkably coordinated changes in epigenetic factors for two alternatively regulated tBDNF promoters during conditioning are controlled by Tet1 and ERK1/2. Our findings indicate that Tet1 and ERK1/2 are critical partners that, through complementary functions, control learning-dependent tBDNF promoter accessibility required for rapid transcription and acquisition of classical conditioning. PMID:26336984

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

    PubMed

    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'.

  6. BDNF Val66Met Polymorphism Is Associated with Self-Reported Empathy.

    PubMed

    Taschereau-Dumouchel, Vincent; Hétu, Sébastien; Bagramian, Anaït; Labrecque, Alexandre; Racine, Marion; Chagnon, Yvon C; Jackson, Philip L

    2016-01-01

    Empathy is an important driver of human social behaviors and presents genetic roots that have been studied in neuroimaging using the intermediate phenotype approach. Notably, the Val66Met polymorphism of the Brain-derived neurotrophic factor (BDNF) gene has been identified as a potential target in neuroimaging studies based on its influence on emotion perception and social cognition, but its impact on self-reported empathy has never been documented. Using a neurogenetic approach, we investigated the association between the BDNF Val66Met polymorphism and self-reported empathy (Davis' Interpersonal Reactivity Index; IRI) in a sample of 110 young adults. Our results indicate that the BDNF genotype is significantly associated with the linear combination of the four facets of the IRI, one of the most widely used self-reported empathy questionnaire. Crucially, the effect of BDNF Val66Met goes beyond the variance explained by two polymorphisms of the oxytocin transporter gene previously associated with empathy and its neural underpinnings (OXTR rs53576 and rs2254298). These results represent the first evidence suggesting a link between the BDNF gene and self-reported empathy and warrant further studies of this polymorphism due to its potential clinical significance.

  7. BDNF Val66Met Polymorphism Is Associated with Self-Reported Empathy

    PubMed Central

    Taschereau-Dumouchel, Vincent; Hétu, Sébastien; Bagramian, Anaït; Labrecque, Alexandre; Racine, Marion; Chagnon, Yvon C.; Jackson, Philip L.

    2016-01-01

    Empathy is an important driver of human social behaviors and presents genetic roots that have been studied in neuroimaging using the intermediate phenotype approach. Notably, the Val66Met polymorphism of the Brain-derived neurotrophic factor (BDNF) gene has been identified as a potential target in neuroimaging studies based on its influence on emotion perception and social cognition, but its impact on self-reported empathy has never been documented. Using a neurogenetic approach, we investigated the association between the BDNF Val66Met polymorphism and self-reported empathy (Davis’ Interpersonal Reactivity Index; IRI) in a sample of 110 young adults. Our results indicate that the BDNF genotype is significantly associated with the linear combination of the four facets of the IRI, one of the most widely used self-reported empathy questionnaire. Crucially, the effect of BDNF Val66Met goes beyond the variance explained by two polymorphisms of the oxytocin transporter gene previously associated with empathy and its neural underpinnings (OXTR rs53576 and rs2254298). These results represent the first evidence suggesting a link between the BDNF gene and self-reported empathy and warrant further studies of this polymorphism due to its potential clinical significance. PMID:26901829

  8. Microglia promote learning-dependent synapse formation through BDNF

    PubMed Central

    Parkhurst, Christopher N.; Yang, Guang; Ninan, Ipe; Savas, Jeffrey N.; Yates, John R.; Lafaille, Juan J.; Hempstead, Barbara L.; Littman, Dan R.; Gan, Wen-Biao

    2014-01-01

    SUMMARY Microglia are the resident macrophages of the central nervous system and their functions have been extensively studied in various brain pathologies. The physiological roles of microglia in brain plasticity and function, however, remain unclear. To address this question, we generated CX3CR1CreER mice expressing tamoxifen-inducible Cre recombinase that allow for specific manipulation of gene function in microglia. Using CX3CR1CreER to drive diphtheria toxin receptor expression in microglia, we found that microglia could be specifically depleted from the brain upon diphtheria toxin administration. Mice depleted of microglia show deficits in multiple learning tasks and a significant reduction in motor learning-dependent synapse formation. Furthermore, Cre-dependent removal of brain-derived neurotrophic factor (BDNF) from microglia largely recapitulated the effects of microglia depletion. Microglial BDNF increases neuronal TrkB phosphorylation, a key mediator of synaptic plasticity. Together, our findings reveal important physiological functions of microglia in learning and memory by promoting learning-related synapse formation through BDNF signaling. PMID:24360280

  9. BDNF Val66Met polymorphism and plasma levels in Chinese Han population with obsessive-compulsive disorder and generalized anxiety disorder.

    PubMed

    Wang, Yuan; Zhang, Haiyin; Li, Ying; Wang, Zhen; Fan, Qing; Yu, Shunying; Lin, Zhiguang; Xiao, Zeping

    2015-11-01

    Anxiety disorders are a category of mental disorders characterized by feelings of anxiety and fear, which include generalized anxiety disorder (GAD). Obsessive-Compulsive Disorder (OCD) used to be categorized as anxiety disorder in DSM-IV. However OCD was no longer included in anxiety disorders and came into its own category titled as Obsessive-Compulsive and Related Disorders (OCRD) in DSM-5. It will be interesting to explore is there any different biological characteristics between OCD and anxiety disorders. Brain-derived neurotrophic factor (BDNF) was a potential candidate gene in both OCD and GAD. The results of genetic association studies between BDNF and OCD have been inconsistent. BDNF plasma/serum levels in OCD have been found lower than those in healthy controls. However the heritable reason of the lowered BDNF levels was not well elucidated. The amount of studies about BDNF and GAD were relatively small. The aims of this study were to determine whether single nucleotide polymorphism Val66Met of BDNF was associated with OCD and GAD, to examine BDNF plasma levels in OCD and GAD, and to explore whether Val66Met variation influences BDNF plasma levels. We genotyped Val66Met variation in 148 OCD patients, 108 GAD patients and 99 healthy controls. Within the same sample, BDNF plasma levels were determined in 113 OCD patients, 102 GAD patients and 63 healthy controls. Val66Met variation was not associated with OCD or GAD. BDNF plasma levels in OCD and GAD patients were significant lower than those in healthy controls. Val66Met variation had no influence on BDNF plasma levels. No difference was found between OCD and GAD. Results do not change no matter taking OCD and GAD as one group or separated two. First, the sample size for genotyping was relatively small, which leaded to a low statistical power of the genetic part in this study. Second, we genotyped just one SNP in BDNF gene. Third, parts of the participants did not be assayed for BDNF plasma levels. Our

  10. Are BDNF and glucocorticoid activities calibrated?

    PubMed Central

    Jeanneteau, Freddy; Chao, Moses V.

    2012-01-01

    One hypothesis to account for the onset and severity of neurological disorders is the loss of trophic support. Indeed, changes in the levels and activities of brain-derived neurotrophic factor (BDNF) occur in numerous neurodegenerative and neuropsychiatric diseases. A deficit promotes vulnerability whereas a gain of function facilitates recovery by enhancing survival, synapse formation and synaptic plasticity. Implementation of ‘BDNF therapies’, however, faces numerous methodological and pharmacokinetic issues. Identifying BDNF mimetics that activate the BDNF receptor or downstream targets of BDNF signaling represent an alternative approach. One mechanism that shows great promise is to study the interplay of BDNF and glucocorticoid hormones, a major class of natural steroid secreted during stress reactions and in synchrony with circadian rhythms. While small amounts of glucocorticoids support normal brain function, excess stimulation by these steroid hormones precipitate stress-related affective disorders. To date, however, because of the paucity of knowledge of underlying cellular mechanisms, deleterious effects of glucocorticoids are not prevented following extreme stress. In the present review, we will discuss the complementary roles share by BDNF and glucocorticoids in synaptic plasticity, and delineate possible signaling mechanisms mediating these effects. PMID:23022538

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

    ERIC Educational Resources Information Center

    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…

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

    ERIC Educational Resources Information Center

    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…

  13. Effect of food deprivation or short-term Western diet feeding on BDNF protein expression in the hypothalamic arcuate, paraventricular, and ventromedial nuclei.

    PubMed

    Gilland, Kaitlyn E; Fox, Edward A

    2017-04-01

    Mutations in the brain-derived neurotrophic factor (BDNF) gene are associated with human obesity, and BDNF has potent inhibitory effects on eating and body weight. Little is known about the effects of energy balance manipulations on BDNF protein in the hypothalamus, though this brain region is critical for regulation of feeding and body weight and has high levels of BDNF. Here we investigated the effects of negative and positive energy status on BDNF protein levels in the arcuate (ARC), paraventricular, and ventromedial (VMH) hypothalamic nuclei and the ectorhinal cortex. To achieve this, mice were food deprived for 48 h or fed a Western diet (WD), a restricted amount of WD, or chow for 6 h, 48 h, 1 wk, or 3 wk. BDNF protein levels were estimated as the number of neurons in each brain region that exhibited BDNF-like immunoreactivity. Food deprivation decreased BDNF protein (and mRNA) expression in the ARC compared with fed mice (32%). In contrast, 1 wk of WD consumption increased BDNF protein expression in the VMH compared with chow or restricted WD feeding (40%) and, unexpectedly, increased BDNF protein in the ectorhinal cortex (20%). Furthermore, of the diet conditions and durations tested, only 1 wk of WD consumption was associated with both hyperphagia and excess weight, suggesting that effects of one or both contributed to the changes in BDNF levels. The decrease in ARC BDNF may support increased feeding in food-deprived mice, whereas the increase in the VMH may moderate overeating in WD-fed mice.

  14. A selective histone deacetylase-6 inhibitor improves BDNF trafficking in hippocampal neurons from Mecp2 knockout mice: implications for Rett syndrome

    PubMed Central

    Xu, Xin; Kozikowski, Alan P.; Pozzo-Miller, Lucas

    2014-01-01

    Rett syndrome (RTT) is a neurodevelopmental disorder caused by loss-of-function mutations in the transcriptional modulator methyl-CpG-binding protein 2 (MECP2). One of the most prominent gene targets of MeCP2 is brain-derived neurotrophic factor (Bdnf), a potent modulator of activity-dependent synaptic development, function and plasticity. Dysfunctional BDNF signaling has been demonstrated in several pathophysiological mechanisms of RTT disease progression. To evaluate whether the dynamics of BDNF trafficking is affected by Mecp2 deletion, we analyzed movements of BDNF tagged with yellow fluorescent protein (YFP) in cultured hippocampal neurons by time-lapse fluorescence imaging. We found that both anterograde and retrograde vesicular trafficking of BDNF-YFP are significantly impaired in Mecp2 knockout hippocampal neurons. Selective inhibitors of histone deacetylase 6 (HDAC6) show neuroprotective effects in neurodegenerative diseases and stimulate microtubule-dependent vesicular trafficking of BDNF-containing dense core vesicles. Here, we show that the selective HDAC6 inhibitor Tubastatin-A increased the velocity of BDNF-YFP vesicles in Mecp2 knockout neurons in both directions by increasing α–tubulin acetylation. Tubastatin-A also restored activity-dependent BDNF release from Mecp2 knockout neurons to levels comparable to those shown by wildtype neurons. These findings demonstrate that a selective HDAC6 inhibitor is a potential pharmacological strategy to reverse cellular and synaptic impairments in RTT resulting from impaired BDNF signaling. PMID:24639629

  15. Genetics of bipolar disorder: focus on BDNF Val66Met polymorphism.

    PubMed

    Fan, Jinbo; Sklar, Pamela

    2008-01-01

    Bipolar disorder is a chronic severe mood disorder that has been consistently demonstrated to have a strong inherited component. Traditional approaches to gene discovery have produced conflicting results regarding the association between genes and bipolar disorder. Numerous genes have been proposed as associated with bipolar disorder. This paper will focus on one of these, brain-derived neurotrophic factor (BDNF). BDNF is an interesting candidate gene for bipolar disorder because of its important role in the neurodevelopment of the CNS. Previous genetic work has identified a potential association between a Val66Met polymorphism in the BDNF gene and bipolar disorder. Meta-analysis based on all original published association studies between the Val66Met polymorphism and bipolar disorder up to May 2007 shows modest but statistically significant evidence for the association between the Val66Met polymorphism and bipolar disorder (random-effects pooled odds ratio [OR] = 1.13, 95% Confidence Interval [CI] = 1.04-1.23, Z = 2.85, P = 0.004) from 14 studies consisting of 4248 cases, 7080 control subjects and 858 nuclear families. Further large-scale studies are warranted to elucidate the relevant BDNF gene variation(s) that act as risk factors for bipolar disorder susceptibility.

  16. Association between the BDNF Val66Met Polymorphism and Chronicity of Depression

    PubMed Central

    Lee, Yujin; Lim, Shinn Won; Kim, Soo Yeon; Chung, Jae Won; Kim, Jinwoo; Myung, Woojae; Song, Jihae; Kim, Seonwoo; Carroll, Bernard J

    2013-01-01

    Objective Both clinical and biological factors influence the course of depressive disorders. This study tested for associations between the brain-derived neurotrophic factor (BDNF) gene at the Val66Met locus and the course of major depressive disorder (MDD). Methods Three hundred ten Korean subjects (209 patients, 101 controls) were genotyped for rs6265 at nucleotide 196 (G/A), which produces an amino acid substitution at codon 66 (Val66Met) of the gene for BDNF. Course of illness was evaluated both by chronicity of current episode (episode duration >24 months) and by the lifetime history of recurrences. Results Patients with the Met/Met BDNF genotype had a significantly higher rate of chronic depression than all others. There was a significant dose effect of the Met allele on chronicity. Compared with the Val/Val genotype, the relative risk of chronicity was 1.67 for the Val/Met genotype, and 2.58 for the Met/Met genotype. Lifetime history of recurrent episodes was not related to BDNF genotypes but was significantly associated with younger age of onset and with a history of depression in first degree relatives. Conclusion BDNF genotyping may be informative for anticipating chronicity in major depression. PMID:23482723

  17. Genetic moderation of child maltreatment effects on depression and internalizing symptoms by serotonin transporter linked polymorphic region (5-HTTLPR), brain-derived neurotrophic factor (BDNF), norepinephrine transporter (NET), and corticotropin releasing hormone receptor 1 (CRHR1) genes in African American children.

    PubMed

    Cicchetti, Dante; Rogosch, Fred A

    2014-11-01

    Genetic moderation of the effects of child maltreatment on depression and internalizing symptoms was investigated in a sample of low-income maltreated and nonmaltreated African American children (N = 1,096). Lifetime child maltreatment experiences were independently coded from Child Protective Services records and maternal report. Child depression and internalizing problems were assessed in the context of a summer research camp by self-report on the Children's Depression Inventory and adult counselor report on the Teacher Report Form. DNA was obtained from buccal cell or saliva samples and genotyped for polymorphisms of the following genes: serotonin transporter linked polymorphic region (5-HTTLPR), brain-derived neurotrophic factor (BDNF), norepinephrine transporter, and corticotropin releasing hormone receptor 1. Analyses of covariance with age and gender as covariates were conducted, with maltreatment status and respective polymorphism as main effects and their Gene × Environment (G × E) interactions. Maltreatment consistently was associated with higher Children's Depression Inventory and Teacher Report Form symptoms. The results for child self-report symptoms indicated a G × E interaction for BDNF and maltreatment. In addition, BDNF and triallelic 5-HTTLPR interacted with child maltreatment in a G × G × E interaction. Analyses for counselor report of child anxiety/depression symptoms on the Teacher Report Form indicated moderation of child maltreatment effects by triallelic 5-HTTLPR. These effects were elaborated based on variation in developmental timing of maltreatment experiences. Norepinephrine transporter was found to further moderate the G × E interaction of 5-HTTLPR and maltreatment status, revealing a G × G × E interaction. This G × G × E was extended by consideration of variation in maltreatment subtype experiences. Finally, G × G × E effects were observed for the co-action of BDNF and the corticotropin releasing hormone receptor 1

  18. BDNF and Huntingtin protein modifications by manganese: implications for striatal medium spiny neuron pathology in manganese neurotoxicity.

    PubMed

    Stansfield, Kirstie H; Bichell, Terry Jo; Bowman, Aaron B; Guilarte, Tomás R

    2014-12-01

    High levels of manganese (Mn) exposure decrease striatal medium spiny neuron (MSN) dendritic length and spine density, but the mechanism(s) are not known. The Huntingtin (HTT) gene has been functionally linked to cortical brain-derived neurotrophic factor (BDNF) support of striatal MSNs via phosphorylation at serine 421. In Huntington's disease, pathogenic CAG repeat expansions of HTT decrease synthesis and disrupt transport of cortical-striatal BDNF, which may contribute to disease, and Mn is a putative environmental modifier of Huntington's disease pathology. Thus, we tested the hypothesis that changes in MSN dendritic morphology Mn due to exposure are associated with decreased BDNF levels and alterations in Htt protein. We report that BDNF levels are decreased in the striatum of Mn-exposed non-human primates and in the cerebral cortex and striatum of mice exposed to Mn. Furthermore, proBDNF and mature BDNF concentrations in primary cortical and hippocampal neuron cultures were decreased by exposure to Mn confirming the in vivo findings. Mn exposure decreased serine 421 phosphorylation of Htt in cortical and hippocampal neurons and increased total Htt levels. These data strongly support the hypothesis that Mn-exposure-related MSN pathology is associated with decreased BDNF trophic support via alterations in Htt.

  19. Ipsilateral versus contralateral spontaneous post-stroke neuroplastic changes: involvement of BDNF?

    PubMed

    Madinier, A; Bertrand, N; Rodier, M; Quirié, A; Mossiat, C; Prigent-Tessier, A; Marie, C; Garnier, P

    2013-02-12

    Stroke is a leading cause of death and disability in industrialized countries. Although surviving patients exhibit a certain degree of restoration of function attributable to brain plasticity, the majority of stroke survivors has to struggle with persisting deficits. In order to potentiate post-stroke recovery, several rehabilitation therapies have been undertaken and many experimental studies have reported that brain-derived neurotrophic factor (BDNF) is central to many facets of neuroplastic processes. However, although BDNF role in brain plasticity is well characterized through strategies that manipulate its content, the involvement of this neurotrophin in spontaneous post-stroke recovery remains to be clarified. Besides, while the neuroplastic role of BDNF is restricted to its mature form, most studies investigating the proper effect of ischemia on post-stroke BDNF metabolism focused on mRNA or total protein expressions. In addition, these studies are mainly performed in brain regions collected either at or around the lesion site. Therefore, the objective of the present study was to investigate in both hemispheres, the long-term expression (up to one month) of both pro- and mature BDNF forms in rats subjected to photothrombotic ischemia. These assessments were performed in the cortex and in the hippocampus, two regions known to subserve functional recovery after stroke and were coupled to the study of synaptophysin expression, a marker of synaptogenesis. Our study reports that stroke induces an early and transient increase (4h) in mature BDNF expression in the cortex of both hemispheres that was associated with a delayed rise (30d) in synaptophysin levels ipsilateraly. In both hippocampal territories, the pattern of mature BDNF expression shows a more delayed increase (from 8 to 30d), which coincides with the evolution of synaptophysin expression. Interestingly, in these hippocampal territories, pro-BDNF levels evolve differently suggesting a differential gene

  20. BDNF production by olfactory ensheathing cells contributes to axonal regeneration of cultured adult CNS neurons.

    PubMed

    Pastrana, Erika; Moreno-Flores, Maria Teresa; Avila, Jesus; Wandosell, Francisco; Minichiello, Liliana; Diaz-Nido, Javier

    2007-02-01

    Olfactory ensheathing cells (OECs) are the main glial cell type that populates mammalian olfactory nerves. These cells have a great capacity to promote the regeneration of axons when transplanted into the injured adult mammalian CNS. However, little is still known about the molecular mechanisms they employ in mediating such a task. Brain-derived neurotrophic factor (BDNF) was identified as a candidate molecule in a genomic study that compared three functionally different OEC populations: Early passage OECs (OEC Ep), Late passage OECs (OEC Lp) and the OEC cell line TEG3 [Pastrana, E., Moreno-Flores, M.T., Gurzov, E.N., Avila, J., Wandosell, F., Diaz-Nido, J., 2006. Genes associated with adult axon regeneration promoted by olfactory ensheathing cells: a new role for matrix metalloproteinase 2. J. Neurosci. 26, 5347-5359]. We have here set out to determine the role played by BDNF in the stimulation of axon outgrowth by OECs. We compared the extracellular BDNF levels in the three OEC populations and show that it is produced in significant amounts by the OECs that can stimulate axon regeneration in adult retinal neurons (OEC Ep and TEG3) but it is absent from the extracellular medium of OEC Lp cells which lack this capacity. Blocking BDNF signalling impaired axonal regeneration of adult retinal neurons co-cultured with TEG3 cells and adding BDNF increased the proportion of adult neurons that regenerate their axons on OEC Lp monolayers. Combining BDNF with other extracellular proteins such as Matrix Metalloproteinase 2 (MMP2) further augmented this effect. This study shows that BDNF production by OECs plays a direct role in the promotion of axon regeneration of adult CNS neurons.

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

    PubMed Central

    Guo, J; Ji, Y; Ding, Y; Jiang, W; Sun, Y; Lu, B; 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, 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. PMID:27310873

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

    PubMed

    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.

  3. Associations between parenting behavior and anxiety in a rodent model and a clinical sample: relationship to peripheral BDNF levels

    PubMed Central

    Dalle Molle, R; Portella, A K; Goldani, M Z; Kapczinski, F P; Leistner-Segala, S; Salum, G A; Manfro, G G; Silveira, P P

    2012-01-01

    Adverse early-life environment is associated with anxiety-like behaviors and disorders. Brain-derived neurotrophic factor (BDNF) is sensitive to this environment and could be a marker of underlying brain changes. We aimed at evaluating the development of anxiety-like behaviors in a rat model of early adversity, as well as the possible association with BDNF levels. Similar associations were investigated in a sample of adolescent humans. For the rat study, Wistar rat litters were divided into: early-life stress (ELS, limited access to nesting material) and control groups. Maternal behavior was observed from days 1 to 9 of life and, as adults, rats were subjected to behavioral testing and BDNF measurements in plasma, hippocampus, amygdala and periaqueductal gray. For the human study, 129 adolescents were evaluated for anxiety symptoms and perceived parental care. Serum BDNF levels and the Val66Met polymorphism of the BDNF gene were investigated. We found that ELS dams showed more pure contact, that is, contact with low care and high control, toward pups, and their adult offspring demonstrated higher anxiety-like behaviors and plasma BDNF. Also the pure contact correlated positively with adult peripheral BDNF. Similarly in humans, there was a positive correlation between maternal overprotection and serum BDNF only in Met carriers. We also found negative correlations between maternal warmth and separation anxiety, social phobia and school phobia. Finally, our translational approach revealed that ELS, mediated through variations in maternal care, is associated with anxiety in both rats and humans and increased peripheral BDNF may be marking these phenomena. PMID:23168995

  4. Prolonged maternal separation attenuates BDNF-ERK signaling correlated with spine formation in the hippocampus during early brain development.

    PubMed

    Ohta, Ken-Ichi; Suzuki, Shingo; Warita, Katsuhiko; Kaji, Tomohiro; Kusaka, Takashi; Miki, Takanori

    2017-04-01

    Maternal separation (MS) is known to affect hippocampal function such as learning and memory, yet the molecular mechanism remains unknown. We hypothesized that these impairments are attributed to abnormities of neural circuit formation by MS, and focused on brain-derived neurotrophic factor (BDNF) as key factor because BDNF signaling has an essential role in synapse formation during early brain development. Using rat offspring exposed to MS for 6 h/day during postnatal days (PD) 2-20, we estimated BDNF signaling in the hippocampus during brain development. Our results show that MS attenuated BDNF expression and activation of extracellular signal-regulated kinase (ERK) around PD 7. Moreover, plasticity-related immediate early genes, which are transcriptionally regulated by BDNF-ERK signaling, were also reduced by MS around PD 7. Interestingly, detailed analysis revealed that MS particularly reduced expression of BDNF gene and immediate early genes in the cornu ammonis 1 (CA1) of hippocampus at PD 7. Considering that BDNF-ERK signaling is involved in spine formation, we next evaluated spine formation in the hippocampus during the weaning period. Our results show that MS particularly reduced mature spine density in proximal apical dendrites of CA1 pyramidal neurons at PD 21. These results suggest that MS could attenuate BDNF-ERK signaling during primary synaptogenesis with a region-specific manner, which is likely to lead to decreased spine formation and maturation observed in the hippocampal CA1 region. It is speculated that this incomplete spine formation during early brain development has an influence on learning capabilities throughout adulthood.

  5. Impact of BDNF -196 G>A and BDNF -270 C>T polymorphisms on stroke rehabilitation outcome: sex and age differences.

    PubMed

    Mirowska-Guzel, Dagmara; Gromadzka, Grazyna; Mendel, Tadeusz; Janus-Laszuk, Barbara; Dzierka, Justyna; Sarzynska-Dlugosz, Iwona; Czlonkowski, Andrzej; Czlonkowska, Anna

    2014-01-01

    Genetic factors, including gene polymorphisms, are promising in determining stroke rehabilitation outcome. Brain-derived neurotrophic factor (BDNF) is one of the most attractive because of its role in neuroplasticity and brain repair. The aim of present study was to assess the role of BDNF -196 G≯A (val66met) and -270 C≯T on clinical parameters and functional outcome in patients with ischemic and hemorrhagic stroke. Additional analyses according to sex and age (≤55 and ≯55 years) were performed. Three hundred thirty-eight patients (287 with ischemic and 51 with hemorrhagic stroke) were evaluated in terms of neurological deficit (National Institute of Heath Stroke Scale [NIHSS]), activities of daily living (Barthel Index [BI]), and everyday functionality (Rankin score [RS]) before and after rehabilitation. BDNF polymorphism genotyping was performed by polymerase chain reaction restriction fragment length polymorphism analysis. In multivariative analysis, unfavorable outcome of stroke rehabilitation (RS ≥2) was associated with independent factors: ischemic stroke (odds ratio [OR], 2.59; 95% CI, 1.03-6.47), female gender (OR, 2.80; 95% CI, 1.39-5.64), depression (OR, 4.24; 95% CI, 1.45-12.35), falls (OR, 2.61; 95% CI, 1.16-5.87), and BDNF -196 GG polymorphism (OR, 2.18; 95% CI, 1.09-4.35). The differences of functional parameters measured with BI and RS on admission and at discharge are apparent only for comparisons between patients ≤55 and ≯55 years old carrying BDNF -196 GA+AA genotypes but not in those carrying -196 GG genotype; the differences were evident in women but not in men. BDNF -196 G≯A polymorphism might affect functional outcome of stroke rehabilitation, but this hypothesis needs further verification.

  6. DNA methylation of BDNF as a biomarker of early-life adversity

    PubMed Central

    Kundakovic, Marija; Gudsnuk, Kathryn; Herbstman, Julie B.; Tang, Deliang; Perera, Frederica P.; Champagne, Frances A.

    2015-01-01

    Early-life adversity increases the risk for psychopathology in later life. The underlying mechanism(s) is unknown, but epigenetic variation represents a plausible candidate. Early-life exposures can disrupt epigenetic programming in the brain, with lasting consequences for gene expression and behavior. This evidence is primarily derived from animal studies, with limited study in humans due to inaccessibility of the target brain tissue. In humans, although there is evidence for DNA methylation changes in the peripheral blood of psychiatric patients, a fundamental question remains as to whether epigenetic markers in the blood can predict epigenetic changes occurring in the brain. We used in utero bisphenol A (BPA) exposure as a model environmental exposure shown to disrupt neurodevelopment and exert long-term effects on behavior in animals and humans. We show that prenatal BPA induces lasting DNA methylation changes in the transcriptionally relevant region of the Bdnf gene in the hippocampus and blood of BALB/c mice and that these changes are consistent with BDNF changes in the cord blood of humans exposed to high maternal BPA levels in utero. Our data suggest that BDNF DNA methylation in the blood may be used as a predictor of brain BDNF DNA methylation and gene expression as well as behavioral vulnerability induced by early-life environmental exposure. Because BDNF expression and DNA methylation are altered in several psychiatric disorders that are associated with early-life adversity, including depression, schizophrenia, bipolar disorder, and autism, BDNF DNA methylation in the blood may represent a novel biomarker for the early detection of psychopathology. PMID:25385582

  7. BDNF epigenetic modifications associated with schizophrenia-like phenotype induced by prenatal stress in mice

    PubMed Central

    Dong, Erbo; Dzitoyeva, Svetlana G.; Matrisciano, Francesco; Tueting, Patricia; Grayson, Dennis R.; Guidotti, Alessandro

    2014-01-01

    Background Prenatal stress is considered a risk factor for several neurodevelopmental disorders including schizophrenia (SZ). An animal model involving restraint stress of pregnant mice suggests that prenatal stress (PRS) induces epigenetic changes in specific GABAergic and glutamatergic genes likely to be implicated in SZ including the gene for brain derived neurotrophic factor (BDNF). Methods Studying adult offspring of pregnant mice subjected to PRS, we explored the long-term effect of PRS on behavior and on the expression of key chromatin remodeling factors including DNA methyltransferase 1 (DNMT1), ten-eleven translocation hydroxylases (TETs), methyl CpG binding protein 2 (MeCP2), histone deacetylases (HDACs), histone methyltransferases (MLL1, SETD1, G9A and EZH1) and demethylase (LSD1) in the frontal cortex (FC) and hippocampus (HP). We also measured the expression of BDNF. Results Adult PRS offspring demonstrate behavioral abnormalities suggestive of SZ and molecular changes similar to SZ postmortem brain: a significant increase in DNMT1 and TET1 in the FC and HP but not in cerebellum, no changes in HDACs, histone methytransferases/demethylases or MeCP2, and a significant decrease in BDNF variants measured in the FC and HP. The decrease of the corresponding BDNF transcript level was paralleled by an enrichment of 5-methylcytosine and 5-hydroxylmethylcytosine levels at Bdnf gene regulatory regions. In addition, the expression of BDNF transcripts (IV and IX) was positively correlated with social approach in both PRS and non-stressed mice. Conclusions Since patients with psychosis and PRS mice show similar epigenetic signature, PRS offspring may be a suitable model for understanding the behavioral and molecular epigenetic changes observed in SZ patients. PMID:25444166

  8. Multigenerational effects of fetal-neonatal iron deficiency on hippocampal BDNF signaling

    PubMed Central

    Blegen, Mariah B; Kennedy, Bruce C; Thibert, Katie A; Gewirtz, Jonathan C; Tran, Phu V; Georgieff, Michael K

    2013-01-01

    Fetal-neonatal iron deficiency induces adult learning impairments concomitant with changes in expression of key genes underlying hippocampal learning and memory in spite of neonatal iron replenishment. Notably, expression of brain-derived neurotrophic factor (BDNF), a gene critical for neuronal maturation and synaptic plasticity, is lowered both acutely and in adulthood following early-life iron deficiency. Although the mechanism behind its long-term downregulation remains unclear, epigenetic modification in BDNF, as seen in other models of early-life adversity, may play a role. Given that early iron deficiency occurs during critical periods in both hippocampal and gonadal development, we hypothesized that the iron-sufficient offspring (F2 IS) of formerly iron-deficient (F1 FID) rats would show a similar suppression of the BDNF gene as their parents. We compared hippocampal mRNA levels of BDNF and functionally related genes among F1 IS, F1 ID, and F2 IS male rats at postnatal day (P) 15 and P65 using RT-qPCR. As expected, the F1 ID group showed a downregulation of BDNF and associated genes acutely at P15 and chronically at P65. However, the F2 IS group showed an upregulation of these genes at P15, returning to control levels at P65. These results demonstrate that adverse effects of early iron deficiency on hippocampal gene expression observed in the F1 are not present in the F2 generation, suggesting differential effects of nutritionally induced epigenetic programing during the critical periods of hippocampal and gonadal development. PMID:24303168

  9. Multigenerational effects of fetal-neonatal iron deficiency on hippocampal BDNF signaling.

    PubMed

    Blegen, Mariah B; Kennedy, Bruce C; Thibert, Katie A; Gewirtz, Jonathan C; Tran, Phu V; Georgieff, Michael K

    2013-10-01

    Fetal-neonatal iron deficiency induces adult learning impairments concomitant with changes in expression of key genes underlying hippocampal learning and memory in spite of neonatal iron replenishment. Notably, expression of brain-derived neurotrophic factor (BDNF), a gene critical for neuronal maturation and synaptic plasticity, is lowered both acutely and in adulthood following early-life iron deficiency. Although the mechanism behind its long-term downregulation remains unclear, epigenetic modification in BDNF, as seen in other models of early-life adversity, may play a role. Given that early iron deficiency occurs during critical periods in both hippocampal and gonadal development, we hypothesized that the iron-sufficient offspring (F2 IS) of formerly iron-deficient (F1 FID) rats would show a similar suppression of the BDNF gene as their parents. We compared hippocampal mRNA levels of BDNF and functionally related genes among F1 IS, F1 ID, and F2 IS male rats at postnatal day (P) 15 and P65 using RT-qPCR. As expected, the F1 ID group showed a downregulation of BDNF and associated genes acutely at P15 and chronically at P65. However, the F2 IS group showed an upregulation of these genes at P15, returning to control levels at P65. These results demonstrate that adverse effects of early iron deficiency on hippocampal gene expression observed in the F1 are not present in the F2 generation, suggesting differential effects of nutritionally induced epigenetic programing during the critical periods of hippocampal and gonadal development.

  10. Cranial irradiation regulates CREB-BDNF signaling and variant BDNF transcript levels in the mouse hippocampus.

    PubMed

    Son, Yeonghoon; Yang, Miyoung; Kang, Sohi; Lee, Sueun; Kim, Jinwook; Kim, Juhwan; Park, Seri; Kim, Joong-Sun; Jo, Sung-Kee; Jung, Uhee; Shin, Taekyun; Kim, Sung-Ho; Wang, Hongbing; Moon, Changjong

    2015-05-01

    The brain can be exposed to ionizing radiation in various ways, and such irradiation can trigger adverse effects, particularly on learning and memory. However, the precise mechanisms of cognitive impairments induced by cranial irradiation remain unknown. In the hippocampus, brain-derived neurotrophic factor (BDNF) plays roles in neurogenesis, neuronal survival, neuronal differentiation, and synaptic plasticity. The significance of BDNF transcript variants in these contexts is becoming clearer. In the present study, both object recognition memory and contextual fear conditioning task performance in adult C57BL/6 mice were assessed 1 month after a single exposure to cranial irradiation (10 Gy) to evaluate hippocampus-related behavioral dysfunction following such irradiation. Furthermore, changes in the levels of BDNF, the cAMP-response element binding protein (CREB) phosphorylation, and BDNF transcript variants were measured in the hippocampus 1 month after cranial irradiation. On object recognition memory and contextual fear conditioning tasks, mice evaluated 1 month after irradiation exhibited significant memory deficits compared to sham-irradiated controls, but no apparent change was evident in locomotor activity. Both phosphorylated CREB and BDNF protein levels were significantly downregulated after irradiation of the hippocampus. Moreover, the levels of mRNAs encoding common BDNF transcripts, and exons IIC, III, IV, VII, VIII, and IXA, were significantly downregulated after irradiation. The reductions in CREB phosphorylation and BDNF expression induced by differential regulation of BDNF hippocampal exon transcripts may be associated with the memory deficits evident in mice after cranial irradiation.

  11. Increased BDNF expression in fetal brain in the valproic acid model of autism.

    PubMed

    Almeida, Luis E F; Roby, Clinton D; Krueger, Bruce K

    2014-03-01

    Human fetal exposure to valproic acid (VPA), a widely-used anti-epileptic and mood-stabilizing drug, leads to an increased incidence of behavioral and intellectual impairments including autism; VPA administration to pregnant rats and mice at gestational days 12.5 (E12.5) or E13.5 leads to autistic-like symptoms in the offspring and is widely used as an animal model for autism. We report here that this VPA administration protocol transiently increased both BDNF mRNA and BDNF protein levels 5-6-fold in the fetal mouse brain. VPA exposure in utero induced smaller increases in the expression of mRNA encoding the other neurotrophins, NT3 (2.5-fold) and NT4 (2-fold). Expression of the neurotrophin receptors, trkA, trkB and trkC were minimally affected, while levels of the low-affinity neurotrophin receptor, p75(NTR), doubled. Of the nine 5'-untranslated exons of the mouse BDNF gene, only expression of exons I, IV and VI was stimulated by VPA in utero. In light of the well-established role of BDNF in regulating neurogenesis and the laminar fate of postmitotic neurons in the developing cortex, an aberrant increase in BDNF expression in the fetal brain may contribute to VPA-induced cognitive disorders by altering brain development. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. BDNF Signaling in the VTA Links the Drug-Dependent State to Drug Withdrawal Aversions

    PubMed Central

    Bahi, Amine; Bufalino, Mary Rose; Ting-A-Kee, Ryan; Maal-Bared, Geith; Lam, Jenny; Fahmy, Ahmed; Clarke, Laura; Blanchard, Jennifer K.; Larsen, Brett R.; Steffensen, Scott; Dreyer, Jean-Luc; van der Kooy, Derek

    2014-01-01

    Drug administration to avoid unpleasant drug withdrawal symptoms has been hypothesized to be a crucial factor that leads to compulsive drug-taking behavior. However, the neural relationship between the aversive motivational state produced by drug withdrawal and the development of the drug-dependent state still remains elusive. It has been observed that chronic exposure to drugs of abuse increases brain-derived neurotrophic factor (BDNF) levels in ventral tegmental area (VTA) neurons. In particular, BDNF expression is dramatically increased during drug withdrawal, which would suggest a direct connection between the aversive state of withdrawal and BDNF-induced neuronal plasticity. Using lentivirus-mediated gene transfer to locally knock down the expression of the BDNF receptor tropomyosin-receptor-kinase type B in rats and mice, we observed that chronic opiate administration activates BDNF-related neuronal plasticity in the VTA that is necessary for both the establishment of an opiate-dependent state and aversive withdrawal motivation. Our findings highlight the importance of a bivalent, plastic mechanism that drives the negative reinforcement underlying addiction. PMID:24899712

  13. Different serum BDNF levels in depression: results from BDNF studies in FYR Macedonia and Bulgaria.

    PubMed

    Ristevska-Dimitrovska, Gordana; Shishkov, Rinaldo; Gerazova, Vesna Pejoska; Vujovik, Viktorija; Stefanovski, Branislav; Novotni, Antoni; Marinov, Petar; Filov, Izabela

    2013-06-01

    A growing body of evidence shows that brain-derived neurotrophic factor (BDNF) plays a role in depressive disorder. Serum BDNF levels are lower in depressed patients and they increase after a long course of antidepressant treatment. Our study aims to test the effect of antidepressant treatment on serum BDNF levels in patients with a depressive episode, after they have achieved remission in two studies in Macedonia and Bulgaria. In the Macedonian study 23 patients were included (11 female, 12 male) diagnosed with a first depressive episode according to ICD-10, as well as 23 control subjects age- and sex-matched without a history of psychiatric disorder. In the Bulgarian study 10 female patients with depression and 10 control subjects were included. We have applied the Hamilton Depression Rating Scale (HDRS) to assess depression severity. Blood samples were collected before antidepressive treatment and after remission was achieved (decrease to 7 points or less on HDRS). In the Macedonian study, mean serum BDNF level at baseline was 13.15±6.75 ng/ml and the mean HDRS score was 28.52±4.02. Untreated depressed patients showed significantly lower serum BDNF levels compared to the control group (25.95±9.17 ng/ml). After remission was achieved, the mean serum BDNF level was 24.73±11.80 ng/ml whereas the mean HDRS score was 7.04±3.15. After 8 weeks of treatment there was no statistically significant difference in the serum BDNF levels between the two groups. In the Bulgarian study, baseline mean serum BDNF levels were 26.84±8.66 ng/ml, after 3 weeks treatment and remission was achieved mean serum BDNF levels were 30.33±9.25 ng/ml and in the control group mean serum BDNF levels were 25.04±2.88 ng/ml. Integrated results showed baseline mean serum BDNF levels of 17.30±9.66 ng/ml, after achieved remission 26.43±11.25 ng/ml and in the control group mean serum BDNF levels of 25.68±7.76 ng/ml. The Bulgarian results showed no statistical difference between the depressed

  14. An association between BDNF Val66Met polymorphism and impulsivity in methamphetamine abusers.

    PubMed

    Su, Hang; Tao, Jingyan; Zhang, Jie; Xie, Ying; Sun, Yeming; Li, Liren; Xu, Ke; Han, Bin; Lu, Yuling; Sun, Haiwei; Wei, Youdan; Wang, Yue; Zhang, Yu; Zou, Shengzhen; Wu, Wenxiu; Zhang, Jiajia; Zhang, Xiangyang; He, Jincai

    2014-10-17

    Recent studies showed an association between a functional polymorphism of BDNF gene (Val66Met) and the susceptibility to methamphetamine addiction. We hypothesized that this polymorphism was associated with methamphetamine abuse and impulsivity in methamphetamine-abuse patients. The polymorphism was genotyped in 200 methamphetamine-abuse patients and 219 healthy controls. The association of the Val66Met polymorphism of the BDNF gene and impulsivity in 138 methamphetamine abusers were assessed using Barratt Impulsivity Scale-11(BIS-11) Chinese version. The relationship between the polymorphism and age of onset of methamphetamine abuse was also examined. Our results showed no significant differences in genotype and allele distributions between the methamphetamine abusers and controls. Within the methamphetamine-abuse group, subjects carried the Met allele had significantly higher attentional impulsivity scores of BIS compared to those with the Val/Val genotype. The Met allele was also associated with earlier age onset of methamphetamine use. Our findings suggest that the BDNF Val66Met gene polymorphism may influence attentional impulsivity in methamphetamine abusers. Moreover, the BDNF Val66Met gene polymorphism may contribute to onset age of methamphetamine use. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  15. Altering BDNF expression by genetics and/or environment: impact for emotional and depression-like behaviour in laboratory mice.

    PubMed

    Chourbaji, Sabine; Brandwein, Christiane; Gass, Peter

    2011-01-01

    According to the "neurotrophin hypothesis", brain-derived neurotrophic factor (BDNF) is an important candidate gene in depression. Moreover, environmental stress is known to represent a risk factor in the pathophysiology and treatment of this disease. To elucidate, whether changes of BDNF availability signify cause or consequence of depressive-like alterations, it is essential to look for endophenotypes under distinct genetic conditions (e.g. altered BDNF expression). Furthermore it is crucial to examine environment-driven BDNF regulation and its effect on depressive-linked features. Consequently, gene × environment studies investigating prospective genetic mouse models of depression in different environmental contexts become increasingly important. The present review summarizes recent findings in BDNF-mutant mice, which have been controversially discussed as models of depression and anxiety. It furthermore illustrates the potential of environment to serve as naturalistic stressor with the potential to modulate the phenotype in wildtype and mutant mice. Moreover, environment may exert protective effects by regulating BDNF levels as attributed to "environmental enrichment". The effect of this beneficial condition will also be discussed with regard to probable "curative/therapeutic" approaches. Copyright © 2010 Elsevier Ltd. All rights reserved.

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

    PubMed

    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.

  17. NRSF and BDNF polymorphisms as biomarkers of cognitive dysfunction in adults with newly diagnosed epilepsy

    PubMed Central

    Warburton, Alix; Miyajima, Fabio; Shazadi, Kanvel; Crossley, Joanne; Johnson, Michael R.; Marson, Anthony G.; Baker, Gus A.; Quinn, John P.; Sills, Graeme J.

    2016-01-01

    Cognitive dysfunction is a common comorbidity in people with epilepsy, but its causes remain unclear. It may be related to the etiology of the disorder, the consequences of seizures, or the effects of antiepileptic drug treatment. Genetics may also play a contributory role. We investigated the influence of variants in the genes encoding neuron-restrictive silencer factor (NRSF) and brain-derived neurotrophic factor (BDNF), proteins previously associated with cognition and epilepsy, on cognitive function in people with newly diagnosed epilepsy. A total of 82 patients who had previously undergone detailed neuropsychological assessment were genotyped for single nucleotide polymorphisms (SNPs) across the NRSF and BDNF genes. Putatively functional SNPs were included in a genetic association analysis with specific cognitive domains, including memory, psychomotor speed, and information processing. Cross-sectional and longitudinal designs were used to explore genetic influences on baseline cognition at diagnosis and change from baseline over the first year since diagnosis, respectively. We found a statistically significant association between genotypic variation and memory function at both baseline (NRSF: rs1105434, rs2227902 and BDNF: rs1491850, rs2030324, rs11030094) and in our longitudinal analysis (NRSF: rs2227902 and BDNF: rs12273363). Psychomotor speed was also associated with genotype (NRSF rs3796529) in the longitudinal assessment. In line with our previous work on general cognitive function in the healthy aging population, we observed an additive interaction between risk alleles for the NRSF rs2227902 (G) and BDNF rs6265 (A) polymorphisms which was again consistent with a significantly greater decline in delayed recall over the first year since diagnosis. These findings support a role for the NRSF–BDNF pathway in the modulation of cognitive function in patients with newly diagnosed epilepsy. PMID:26708060

  18. NRSF and BDNF polymorphisms as biomarkers of cognitive dysfunction in adults with newly diagnosed epilepsy.

    PubMed

    Warburton, Alix; Miyajima, Fabio; Shazadi, Kanvel; Crossley, Joanne; Johnson, Michael R; Marson, Anthony G; Baker, Gus A; Quinn, John P; Sills, Graeme J

    2016-01-01

    Cognitive dysfunction is a common comorbidity in people with epilepsy, but its causes remain unclear. It may be related to the etiology of the disorder, the consequences of seizures, or the effects of antiepileptic drug treatment. Genetics may also play a contributory role. We investigated the influence of variants in the genes encoding neuron-restrictive silencer factor (NRSF) and brain-derived neurotrophic factor (BDNF), proteins previously associated with cognition and epilepsy, on cognitive function in people with newly diagnosed epilepsy. A total of 82 patients who had previously undergone detailed neuropsychological assessment were genotyped for single nucleotide polymorphisms (SNPs) across the NRSF and BDNF genes. Putatively functional SNPs were included in a genetic association analysis with specific cognitive domains, including memory, psychomotor speed, and information processing. Cross-sectional and longitudinal designs were used to explore genetic influences on baseline cognition at diagnosis and change from baseline over the first year since diagnosis, respectively. We found a statistically significant association between genotypic variation and memory function at both baseline (NRSF: rs1105434, rs2227902 and BDNF: rs1491850, rs2030324, rs11030094) and in our longitudinal analysis (NRSF: rs2227902 and BDNF: rs12273363). Psychomotor speed was also associated with genotype (NRSF rs3796529) in the longitudinal assessment. In line with our previous work on general cognitive function in the healthy aging population, we observed an additive interaction between risk alleles for the NRSF rs2227902 (G) and BDNF rs6265 (A) polymorphisms which was again consistent with a significantly greater decline in delayed recall over the first year since diagnosis. These findings support a role for the NRSF-BDNF pathway in the modulation of cognitive function in patients with newly diagnosed epilepsy.

  19. Increased Olfactory Bulb BDNF Expression Does Not Rescue Deficits in Olfactory Neurogenesis in the Huntington's Disease R6/2 Mouse.

    PubMed

    Smail, Shamayra; Bahga, Dalbir; McDole, Brittnee; Guthrie, Kathleen

    2016-03-01

    Huntington's disease (HD) is an inherited neurodegenerative disorder caused by expansion of CAG trinucleotide repeats in the huntingtin gene. Mutant huntingtin protein (mhtt) interferes with the actions of brain-derived neurotrophic factor (BDNF), and BDNF signaling is reduced in the diseased striatum. Loss of this trophic support is thought to contribute to loss of striatal medium spiny neurons in HD. Increasing BDNF in the adult striatum or ventricular ependyma slows disease progression in HD mouse models, and diverts subventricular zone (SVZ)-derived neuroblasts from their normal destination, the olfactory bulb, to the striatum, where some survive and develop features of mature neurons. Most neuroblasts that migrate to the olfactory bulb differentiate as granule cells, with approximately half surviving whereas others undergo apoptosis. In the R6/2 HD mouse model, survival of adult-born granule cells is reduced. Newly maturing cells express the BDNF receptor TrkB, suggesting that mhtt may interfere with normal BDNF trophic activity, increasing their loss. To determine if augmenting BDNF counteracts this, we examined granule cell survival in R6/2 mice that overexpress BDNF in olfactory bulb. Although we detected a decline in apoptosis, increased BDNF was not sufficient to normalize granule cell survival within their normal target in R6/2 mice. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  20. Mature BDNF, but not proBDNF, reduces excitability of fast-spiking interneurons in mouse dentate gyrus.

    PubMed

    Holm, Mai Marie; Nieto-Gonzalez, Jose Luis; Vardya, Irina; Vaegter, Christian Bjerggaard; Nykjaer, Anders; Jensen, Kimmo

    2009-10-07

    Mature BDNF and its precursor proBDNF may both be secreted to exert opposite effects on synaptic plasticity in the hippocampus. However, it is unknown how proBDNF and mature BDNF affect the excitability of GABAergic interneurons and thereby regulate GABAergic inhibition. We made recordings of GABAergic spontaneous IPSCs (sIPSCs) in mouse dentate gyrus granule cells and found that chronic or acute BDNF reductions led to large increases in the sIPSC frequencies, which were TTX (tetrodotoxin) sensitive and therefore action-potential driven. Conversely, addition of mature BDNF, but not proBDNF, within minutes led to a decrease in the sIPSC frequency to 44%. Direct recordings from fast-spiking GABAergic interneurons revealed that mature BDNF reduced their excitability and depressed their action potential firing, whereas proBDNF had no effect. Using the TrkB inhibitor K-252a, or mice deficient for the common neurotrophin receptor p75(NTR), the regulation of GABAergic activity was shown specifically to be mediated by BDNF binding to the neurotrophin receptor TrkB. In agreement, immunohistochemistry demonstrated that TrkB, but not p75(NTR), was expressed in parvalbumin-positive interneurons. Our results suggest that mature BDNF decreases the excitability of GABAergic interneurons via activation of TrkB, while proBDNF does not impact on GABAergic activity. Thus, by affecting the firing of GABAergic interneurons, mature BDNF may play an important role in regulating network oscillations in the hippocampus.

  1. Molecular evidence for BDNF- and GABA-related dysfunctions in the amygdala of female subjects with major depression.

    PubMed

    Guilloux, J-P; Douillard-Guilloux, G; Kota, R; Wang, X; Gardier, A M; Martinowich, K; Tseng, G C; Lewis, D A; Sibille, E

    2012-11-01

    Women are twice as likely as men to develop major depressive disorder (MDD) and are more prone to recurring episodes. Hence, we tested the hypothesis that the illness may associate with robust molecular changes in female subjects, and investigated large-scale gene expression in the post-mortem brain of MDD subjects paired with matched controls (n=21 pairs). We focused on the lateral/basolateral/basomedian complex of the amygdala as a neural hub of mood regulation affected in MDD. Among the most robust findings were downregulated transcripts for genes coding for γ-aminobutyric acid (GABA) interneuron-related peptides, including somatostatin (SST), tachykinin, neuropeptide Y (NPY) and cortistatin, in a pattern reminiscent to that previously reported in mice with low brain-derived neurotrophic factor (BDNF). Changes were confirmed by quantitative PCR and not explained by demographic, technical or known clinical parameters. BDNF itself was significantly downregulated at the RNA and protein levels in MDD subjects. Investigating putative mechanisms, we show that this core MDD-related gene profile (including SST, NPY, TAC1, RGS4 and CORT) is recapitulated by complementary patterns in mice with constitutive (BDNF-heterozygous) or activity-dependent (exon IV knockout) decreases in BDNF function, with a common effect on SST and NPY. Together, these results provide both direct (low RNA/protein) and indirect (low BDNF-dependent gene pattern) evidence for reduced BDNF function in the amygdala of female subjects with MDD. Supporting studies in mutant mice models suggest a complex mechanism of low constitutive and activity-dependent BDNF function in MDD, particularly affecting SST/NPY-related GABA neurons, thus linking the neurotrophic and GABA hypotheses of depression.

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

    PubMed

    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.

  3. Prenatal Cocaine Exposure Upregulates BDNF-TrkB Signaling

    PubMed Central

    Stucky, Andres; Bakshi, Kalindi P.; Friedman, Eitan; Wang, Hoau-Yan

    2016-01-01

    Prenatal cocaine exposure causes profound changes in neurobehavior as well as synaptic function and structure with compromised glutamatergic transmission. Since synaptic health and glutamatergic activity are tightly regulated by brain-derived neurotrophic factor (BDNF) signaling through its cognate tyrosine receptor kinase B (TrkB), we hypothesized that prenatal cocaine exposure alters BDNF-TrkB signaling during brain development. Here we show prenatal cocaine exposure enhances BDNF-TrkB signaling in hippocampus and prefrontal cortex (PFCX) of 21-day-old rats without affecting the expression levels of TrkB, P75NTR, signaling molecules, NMDA receptor—NR1 subunit as well as proBDNF and BDNF. Prenatal cocaine exposure reduces activity-dependent proBDNF and BDNF release and elevates BDNF affinity for TrkB leading to increased tyrosine-phosphorylated TrkB, heightened Phospholipase C-γ1 and N-Shc/Shc recruitment and higher downstream PI3K and ERK activation in response to ex vivo BDNF. The augmented BDNF-TrkB signaling is accompanied by increases in association between activated TrkB and NMDARs. These data suggest that cocaine exposure during gestation upregulates BDNF-TrkB signaling and its interaction with NMDARs by increasing BDNF affinity, perhaps in an attempt to restore the diminished excitatory neurotransmission. PMID:27494324

  4. BDNF control of adult SVZ neurogenesis.

    PubMed

    Bath, Kevin G; Akins, Michael R; Lee, Francis S

    2012-09-01

    The sensory processing of odorants is a dynamic process that requires plasticity at multiple levels. In the olfactory bulb (OB), inhibitory interneurons undergo lifelong replacement through a process known as adult neurogenesis. These newly born cells are incorporated in a learning-dependent fashion, a process which has led some to suggest this as a primary mechanism through which the OB retains a high degree of plasticity throughout life. A continued focus of researchers in this field has been to understand the molecular mechanisms controlling adult subventricular zone (SVZ) neurogenesis and the innate functional role of these cells. Brain-derived neurotrophic factor (BDNF) has been identified as a strong candidate molecule regulating adult OB neurogenesis. We review what is known regarding the functional role of newly born cells, highlight the role of BDNF in this process, and describe preliminary findings from our lab implicating BDNF in the process of selecting of newly born cells for survival.

  5. Impact of Repetitive Transcranial Magnetic Stimulation on Post-Stroke Dysmnesia and the Role of BDNF Val66Met SNP

    PubMed Central

    Lu, Haitao; Zhang, Tong; Wen, Mei; Sun, Li

    2015-01-01

    Background Little is known about the effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) on dysmnesia and the impact of brain nucleotide neurotrophic factor (BDNF) Val66Met single-nucleotide polymorphism (SNP). This study investigated the impact of low-frequency rTMS on post-stroke dysmnesia and the impact of BDNF Val66Met SNP. Material/Methods Forty patients with post-stroke dysmnesia were prospectively randomized into the rTMS and sham groups. BDNF Val66Met SNP was determined using restriction fragment length polymorphism. Montreal Cognitive Assessment (MoCA), Loewenstein Occupational Therapy of Cognitive Assessment (LOTCA), and Rivermead Behavior Memory Test (RBMT) scores, as well as plasma BDNF concentrations, were measured at baseline and at 3 days and 2 months post-treatment. Results MoCA, LOTCA, and RBMT scores were higher after rTMS. Three days after treatment, BDNF decreased in the rTMS group but it increased in the sham group (P<0.05). Two months after treatment, RMBT scores in the rTMS group were higher than in the sham group, but not MoCA and LOTCA scores. Conclusions Low-frequency rTMS may improve after-stoke memory through various pathways, which may involve polymorphisms and several neural genes, but not through an increase in BDNF levels. PMID:25770310

  6. The role of the BDNF Val66Met polymorphism for the synchronization of error-specific neural networks.

    PubMed

    Beste, Christian; Kolev, Vasil; Yordanova, Juliana; Domschke, Katharina; Falkenstein, Michael; Baune, Bernhard T; Konrad, Carsten

    2010-08-11

    Behavioral adaptation depends on the recognition of response errors and processing of this error-information. Error processing is a specific cognitive function crucial for behavioral adaptation. Neurophysiologically, these processes are reflected by an event-related potential (ERP), the error negativity (Ne/ERN). Even though synchronization processes are important in information processing, its role and neurobiological foundation in behavioral adaptation are not understood. The brain-derived neurotrophic factor (BDNF) strongly modulates the establishment of neural connectivity that determines neural network dynamics and synchronization properties. Therefore altered synchronization processes may constitute a mechanism via which BDNF affects processes of error-induced behavioral adaptation. We investigate how variants of the BDNF gene regulate EEG-synchronization processes underlying error processing. Subjects (n=65) were genotyped for the functional BDNF Val66Met polymorphism (rs6265). We show that Val/Val genotype is associated with stronger error-specific phase-locking, compared with Met allele carriers. Posterror behavioral adaptation seems to be strongly dependent on these phase-locking processes and efficacy of EEG-phase-locking-behavioral coupling was genotype dependent. After correct responses, neurophysiological processes were not modulated by the polymorphism, underlining that BDNF becomes especially necessary in situations requiring behavioral adaptation. The results suggest that alterations in neural synchronization processes modulated by the genetic variants of BDNF Val66Met may be the mechanism by which cognitive functions are affected.

  7. Genetic Contributions to Age-Related Decline in Executive Function: A 10-Year Longitudinal Study of COMT and BDNF Polymorphisms

    PubMed Central

    Erickson, Kirk I.; Kim, Jennifer S.; Suever, Barbara L.; Voss, Michelle W.; Francis, B. Magnus; Kramer, Arthur F.

    2008-01-01

    Genetic variability in the dopaminergic and neurotrophic systems could contribute to age-related impairments in executive control and memory function. In this study we examined whether genetic polymorphisms for catechol-O-methyltransferase (COMT) and brain-derived neurotrophic factor (BDNF) were related to the trajectory of cognitive decline occurring over a 10-year period in older adults. A single nucleotide polymorphism in the COMT (Val158/108Met) gene affects the concentration of dopamine in the prefrontal cortex. In addition, a Val/Met substitution in the pro-domain for BDNF (Val66Met) affects the regulated secretion and trafficking of BDNF with Met carriers showing reduced secretion and poorer cognitive function. We found that impairments over the 10-year span on a task-switching paradigm did not vary as a function of the COMT polymorphism. However, for the BDNF polymorphism the Met carriers performed worse than Val homozygotes at the first testing session but only the Val homozygotes demonstrated a significant reduction in performance over the 10-year span. Our results argue that the COMT polymorphism does not affect the trajectory of age-related executive control decline, whereas the Val/Val polymorphism for BDNF may promote faster rates of cognitive decay in old age. These results are discussed in relation to the role of BDNF in senescence and the transforming impact of the Met allele on cognitive function in old age. PMID:18958211

  8. Impact of repetitive transcranial magnetic stimulation on post-stroke dysmnesia and the role of BDNF Val66Met SNP.

    PubMed

    Lu, Haitao; Zhang, Tong; Wen, Mei; Sun, Li

    2015-03-14

    Little is known about the effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) on dysmnesia and the impact of brain nucleotide neurotrophic factor (BDNF) Val66Met single-nucleotide polymorphism (SNP). This study investigated the impact of low-frequency rTMS on post-stroke dysmnesia and the impact of BDNF Val66Met SNP. Forty patients with post-stroke dysmnesia were prospectively randomized into the rTMS and sham groups. BDNF Val66Met SNP was determined using restriction fragment length polymorphism. Montreal Cognitive Assessment (MoCA), Loewenstein Occupational Therapy of Cognitive Assessment (LOTCA), and Rivermead Behavior Memory Test (RBMT) scores, as well as plasma BDNF concentrations, were measured at baseline and at 3 days and 2 months post-treatment. MoCA, LOTCA, and RBMT scores were higher after rTMS. Three days after treatment, BDNF decreased in the rTMS group but it increased in the sham group (P<0.05). Two months after treatment, RMBT scores in the rTMS group were higher than in the sham group, but not MoCA and LOTCA scores. Low-frequency rTMS may improve after-stoke memory through various pathways, which may involve polymorphisms and several neural genes, but not through an increase in BDNF levels.

  9. Paradoxical visuomotor adaptation to reversed visual input is predicted by BDNF Val66Met polymorphism

    PubMed Central

    Barton, Brian; Treister, Andrew; Humphrey, Melanie; Abedi, Garen; Cramer, Steven C.; Brewer, Alyssa A.

    2014-01-01

    Brain-derived neurotrophic factor (BDNF) is the most abundant neurotrophin in the brain, influencing neural development, plasticity, and repair (Chen et al., 2004; Thoenen, 1995). The BDNF gene contains a single-nucleotide polymorphism (SNP) called Val66Met. The Met allele interferes with intracellular BDNF-trafficking, decreases activity-dependent BDNF secretion, and consequently is often associated with a shift from plasticity to stability in neural circuits (Egan et al., 2003). We investigated the behavioral consequences of the presence of the Met allele by comparing how 40 heterozygous subjects with the Val/Met genotype and 35 homozygous subjects with the Val/Val genotype performed on visuomotor tasks (reaching and navigation) under two conditions: normal vision and completely left-right reversed vision. As expected, subjects did not differ in their short-term ability to learn the tasks with normal vision (p = 0.58). Intuitively, it would be expected that homozygous Val/Val subjects with a propensity for greater BDNF-induced activity-dependent plasticity would learn new tasks more quickly than heterozygous Val/Met subjects with decreased BDNF secretion (Gilbert, Li, & Piech, 2009). However, we found the opposite here. When short-term mechanisms of visuomotor adaptation were engaged to compensate for the misalignment of visual and somatomotor information created by the left-right reversal of vision, heterozygous Val/Met subjects learned significantly more quickly than their homozygous Val/Val counterparts (p = 0.027). Our results demonstrate the paradoxical finding that the presence of the Met allele, which is thought to promote cortical stability, here improves immediate visuomotor adaptation to left–right-reversed visual input. PMID:25104829

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

    PubMed

    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.

  11. Quantitative Analysis of BDNF/TrkB Protein and mRNA in Cortical and Striatal Neurons Using α-Tubulin as a Normalization Factor

    PubMed Central

    Ma, Bin; Savas, Jeffrey N.; Chao, Moses V.; Tanese, Naoko

    2013-01-01

    The neurotrophin brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase TrkB serve important regulatory roles for multiple aspects of the biology of neurons including cell death, survival, growth, differentiation, and plasticity. Regulation of the local availability of BDNF/TrkB at distinct subcellular domains such as soma, dendrites, axons, growth cones, nerve terminals, and spines appears to contribute to their specific functions. In view of the variance in size and shape of neurons and their compartments, previous quantitative studies of the BDNF/TrkB protein and mRNA lacked a robust normalization procedure. To overcome this problem, we have established methods that use immunofluorescence detection of α-tubulin as a normalization factor for the quantitative analysis of protein and mRNA in primary rat cortical and striatal neurons in culture. The efficacy of this approach is demonstrated by studying the dynamic distribution of proteins and mRNA at different growth stages or conditions. Treatment of cultured neurons with KCl resulted in increased levels of TrkB protein, reduced levels of BDNF mRNA (composite of multiple transcripts) and a slight reduction in BDNF protein levels in the dendrites from the cortex. The KCl treatment also lowered the percentage of BDNF and TrkB proteins in the soma indicative of protein transport. Finally, analysis of the rat cortical and striatal neurons demonstrated comparable or even higher levels of BDNF/TrkB protein and BDNF mRNA in the neurons from the striatum. Thus, in contrast to previous observations made in vivo, striatal neurons are capable of synthesizing BDNF mRNA when cultured in growth media in vitro. The analytical approach presented here provides a detailed understanding of BDNF/TrkB levels in response to a variety of neuronal activities. Our methods could be used broadly, including applications in cell and tissue cytometry, to yield accurate quantitative data of gene expression in cellular and

  12. Brain Derived Neurotrophic Factor (BDNF) Expression Is Regulated by MicroRNAs miR-26a and miR-26b Allele-Specific Binding

    PubMed Central

    Caputo, Viviana; Parisi, Chiara; Catalanotto, Caterina; Pasini, Augusto; Cogoni, Carlo; Pizzuti, Antonio

    2011-01-01

    Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays an essential role in neuronal development and plasticity. MicroRNA (miRNAs) are small non-coding RNAs of about 22-nucleotides in length regulating gene expression at post-transcriptional level. In this study we explore the role of miRNAs as post-transcriptional inhibitors of BDNF and the effect of 3′UTR sequence variations on miRNAs binding capacity. Using an in silico approach we identified a group of miRNAs putatively regulating BDNF expression and binding to BDNF 3′UTR polymorphic sequences. Luciferase assays demonstrated that these miRNAs (miR-26a1/2 and miR-26b) downregulates BDNF expression and that the presence of the variant alleles of two single nucleotide polymorphisms (rs11030100 and rs11030099) mapping in BDNF 3′UTR specifically abrogates miRNAs targeting. Furthermore we found a high linkage disequilibrium rate between rs11030100, rs11030099 and the non-synonymous coding variant rs6265 (Val66Met), which modulates BDNF mRNA localization and protein intracellular trafficking. Such observation led to hypothesize that miR-26s mediated regulation could extend to rs6265 leading to an allelic imbalance with potentially functional effects, such as peptide's localization and activity-dependent secretion. Since rs6265 has been previously implicated in various neuropsychiatric disorders, we evaluated the distribution of rs11030100, rs11030099 and rs6265 both in a control and schizophrenic group, but no significant difference in allele frequencies emerged. In conclusion, in the present study we identified two novel miRNAs regulating BDNF expression and the first BDNF 3′UTR functional variants altering miRNAs-BDNF binding. PMID:22194877

  13. Interactive effects of BDNF Val66Met genotype and trauma on limbic brain anatomy in childhood

    PubMed Central

    Marusak, Hilary A.; Kuruvadi, Nisha; Vila, Angela M.; Shattuck, David W.; Joshi, Shantanu H.; Joshi, Anand A.; Jella, Pavan K.; Thomason, Moriah E.

    2015-01-01

    Childhood trauma is a major precipitating factor in psychiatric disease. Emerging data suggest that stress susceptibility is genetically determined, and that risk is mediated by changes in limbic brain circuitry. There is a need to identify markers of disease vulnerability, and it is critical that these markers be investigated in childhood and adolescence, a time when neural networks are particularly malleable and when psychiatric disorders frequently emerge. In this preliminary study, we evaluated whether a common variant in the brain-derived neurotrophic factor (BDNF) gene (Val66Met; rs6265) interacts with childhood trauma to predict limbic gray matter volume in a sample of 55 youth high in sociodemographic risk. We found trauma-by-BDNF interactions in the right subcallosal area and right hippocampus, wherein BDNF-related gray matter changes were evident in youth without histories of trauma. In youth without trauma exposure, lower hippocampal volume was related to higher symptoms of anxiety. These data provide preliminary evidence for a contribution of a common BDNF gene variant to the neural correlates of childhood trauma among high-risk urban youth. Altered limbic structure in early life may lay the foundation for longer-term patterns of neural dysfunction, and hold implications for understanding the psychiatric and psychobiological consequences of traumatic stress on the developing brain. PMID:26286685

  14. CREB-Dependent Regulation of GAD65 Transcription by BDNF/TrkB in Cortical Interneurons.

    PubMed

    Sánchez-Huertas, Carlos; Rico, Beatriz

    2011-04-01

    In the cerebral cortex, the functional output of projection neurons is fine-tuned by inhibitory neurons present in the network, which use γ-aminobutyric acid (GABA) as their main neurotransmitter. Previous studies have suggested that the expression levels of the rate-limiting GABA synthetic enzyme, GAD65, depend on brain derived neurotrophic factor (BDNF)/TrkB activation. However, the molecular mechanisms by which this neurotrophic factor and its receptor controls GABA synthesis are still unknown. Here, we show a direct regulation of the GAD65 gene by BDNF-TrkB signaling via CREB in cortical interneurons. Conditional ablation of TrkB in cortical interneurons causes a cell-autonomous decrease in the synaptically enriched GAD65 protein and its transcripts levels, suggesting that transcriptional regulation of the GAD65 gene is altered. Dissection of the intracellular pathway that underlies this process revealed that BDNF/TrkB signaling controls the transcription of GAD65 in a Ras-ERK-CREB-dependent manner. Our study reveals a novel molecular mechanism through which BDNF/TrkB signaling may modulate the maturation and function of cortical inhibitory circuits.

  15. Interactive effects of BDNF Val66Met genotype and trauma on limbic brain anatomy in childhood.

    PubMed

    Marusak, Hilary A; Kuruvadi, Nisha; Vila, Angela M; Shattuck, David W; Joshi, Shantanu H; Joshi, Anand A; Jella, Pavan K; Thomason, Moriah E

    2016-05-01

    Childhood trauma is a major precipitating factor in psychiatric disease. Emerging data suggest that stress susceptibility is genetically determined, and that risk is mediated by changes in limbic brain circuitry. There is a need to identify markers of disease vulnerability, and it is critical that these markers be investigated in childhood and adolescence, a time when neural networks are particularly malleable and when psychiatric disorders frequently emerge. In this preliminary study, we evaluated whether a common variant in the brain-derived neurotrophic factor (BDNF) gene (Val66Met; rs6265) interacts with childhood trauma to predict limbic gray matter volume in a sample of 55 youth high in sociodemographic risk. We found trauma-by-BDNF interactions in the right subcallosal area and right hippocampus, wherein BDNF-related gray matter changes were evident in youth without histories of trauma. In youth without trauma exposure, lower hippocampal volume was related to higher symptoms of anxiety. These data provide preliminary evidence for a contribution of a common BDNF gene variant to the neural correlates of childhood trauma among high-risk urban youth. Altered limbic structure in early life may lay the foundation for longer term patterns of neural dysfunction, and hold implications for understanding the psychiatric and psychobiological consequences of traumatic stress on the developing brain.

  16. HDAC1 negatively regulates Bdnf and Pvalb required for parvalbumin interneuron maturation in an experience-dependent manner.

    PubMed

    Koh, Dawn X P; Sng, Judy C G

    2016-11-01

    During early postnatal development, neuronal circuits are sculpted by sensory experience provided by the external environment. This experience-dependent regulation of circuitry development consolidates the balance of excitatory-inhibitory (E/I) neurons in the brain. The cortical barrel-column that innervates a single principal whisker is used to provide a clear reference frame for studying the consolidation of E/I circuitry. Sensory deprivation of S1 at birth disrupts the consolidation of excitatory-inhibitory balance by decreasing inhibitory transmission of parvalbumin interneurons. The molecular mechanisms underlying this decrease in inhibition are not completely understood. Our findings show that epigenetic mechanisms, in particular histone deacetylation by histone deacetylases, negatively regulate the expression of brain-derived neurotrophic factor (Bdnf) and parvalbumin (Pvalb) genes during development, which are required for the maturation of parvalbumin interneurons. After whisker deprivation, increased histone deacetylase 1 expression and activity led to increased histone deacetylase 1 binding and decreased histone acetylation at Bdnf promoters I-IV and Pvalb promoter, resulting in the repression of Bdnf and Pvalb gene transcription. The decrease in Bdnf expression further affected parvalbumin interneuron maturation at layer II/III in S1, demonstrated by decreased parvalbumin expression, a marker for parvalbumin interneuron maturation. Knockdown of HDAC1 recovered Bdnf and Pvalb gene transcription and also prevented the decrease of inhibitory synapses accompanying whisker deprivation.

  17. BDNF parabrachio-amygdaloid pathway in morphine-induced analgesia.

    PubMed

    Sarhan, Maysa; Pawlowski, Sophie Anne; Barthas, Florent; Yalcin, Ipek; Kaufling, Jennifer; Dardente, Hugues; Zachariou, Venetia; Dileone, Ralph Joseph; Barrot, Michel; Veinante, Pierre

    2013-08-01

    In addition to its neurotrophic role, brain-derived neurotrophic factor (BDNF) is involved in a wide array of functions, including anxiety and pain. The central amygdaloid nucleus (CeA) contains a high concentration of BDNF in terminals, originating from the pontine parabrachial nucleus. Since the spino-parabrachio-amygdaloid neural pathway is known to convey nociceptive information, we hypothesized a possible involvement of BDNF in supraspinal pain-related processes. To test this hypothesis, we generated localized deletion of BDNF in the parabrachial nucleus using local bilateral injections of adeno-associated viruses in adult floxed-BDNF mice. Basal thresholds of thermal and mechanical nociceptive responses were not altered by BDNF loss and no behavioural deficit was noticed in anxiety and motor tests. However, BDNF-deleted animals displayed a major decrease in the analgesic effect of morphine. In addition, intra-CeA injections of the BDNF scavenger TrkB-Fc in control mice also decreased morphine-induced analgesia. Finally, the number of c-Fos immunoreactive nuclei after acute morphine injection was decreased by 45% in the extended amygdala of BDNF-deleted animals. The absence of BDNF in the parabrachial nucleus thus altered the parabrachio-amygdaloid pathway. Overall, our study provides evidence that BDNF produced in the parabrachial nucleus modulates the functions of the parabrachio-amygdaloid pathway in opiate analgesia.

  18. Blood BDNF Level Is Gender Specific in Severe Depression

    PubMed Central

    Kreinin, Anatoly; Lisson, Serah; Nesher, Elimelech; Schneider, Jenny; Bergman, Josef; Farhat, Kamal; Farah, Joseph; Lejbkowicz, Flavio; Yadid, Gal; Raskin, Leon; Koman, Igor; Pinhasov, Albert

    2015-01-01

    Though the role of brain derived neurotrophic factor (BDNF) as a marker for major depressive disorder (MDD) and antidepressant efficacy has been widely studied, the role of BDNF in distinct groups of patients remains unclear. We evaluated the diagnostic value of BDNF as a marker of disease severity measured by HAM-D scores and antidepressants efficacy among MDD patients. Fifty-one patients who met DSM-IV criteria for MDD and were prescribed antidepressants and 38 controls participated in this study. BDNF in serum was measured at baseline, 1st, 2nd and 8th treatment weeks. Depression severity was evaluated using the Hamilton Rating Scale for Depression (HAM-D). BDNF polymorphism rs6265 (val66met) was genotyped. We found a positive correlation between blood BDNF levels and severity of depression only among untreated women with severe MDD (HAM-D>24). Serum BDNF levels were lower in untreated MDD patients compared to control group. Antidepressants increased serum BDNF levels and reduced between-group differences after two weeks of treatment. No correlations were observed between BDNF polymorphism, depression severity, duration of illness, age and BDNF serum levels. Further supporting the role of BDNF in the pathology and treatment of MDD, we suggest that it should not be used as a universal biomarker for diagnosis of MDD in the general population. However, it has diagnostic value for the assessment of disease progression and treatment efficacy in individual patients. PMID:26010085

  19. Induction of fear extinction with hippocampal-infralimbic BDNF.

    PubMed

    Peters, Jamie; Dieppa-Perea, Laura M; Melendez, Loyda M; Quirk, Gregory J

    2010-06-04

    The extinction of conditioned fear memories requires plasticity in the infralimbic medial prefrontal cortex (IL mPFC), but little is known about the molecular mechanisms involved. Brain-derived neurotrophic factor (BDNF) is a key mediator of synaptic plasticity in multiple brain areas. In rats subjected to auditory fear conditioning, BDNF infused into the IL mPFC reduced conditioned fear for up to 48 hours, even in the absence of extinction training, which suggests that BDNF substituted for extinction. Similar to extinction, BDNF-induced reduction in fear required N-methyl-D-aspartate receptors and did not erase the original fear memory. Rats failing to learn extinction showed reduced BDNF in hippocampal inputs to the IL mPFC, and augmenting BDNF in this pathway prevented extinction failure. Hence, boosting BDNF activity in hippocampal-infralimbic circuits may ameliorate disorders of learned fear.

  20. Pharmacological characterization of BDNF promoters I, II and IV reveals that serotonin and norepinephrine input is sufficient for transcription activation.

    PubMed

    Musazzi, L; Rimland, J M; Ieraci, A; Racagni, G; Domenici, E; Popoli, M

    2014-05-01

    Compelling evidence has shown that the effects of antidepressants, increasing extracellular serotonin and noradrenaline as a primary mechanism of action, involve neuroplastic and neurotrophic mechanisms. Brain-derived neurotrophic factor (BDNF) has been shown to play a key role in neuroplasticity and synaptic function, as well as in the pathophysiology of neuropsychiatric disorders and the mechanism of action of antidepressants. The expression of BDNF is mediated by the transcription of different mRNAs derived by the splicing of one of the eight 5' non-coding exons with the 3' coding exon (in rats). The transcription of each non-coding exon is driven by unique and different promoters. We generated a gene reporter system based on hippocampal and cortical neuronal cultures, in which the transcription of luciferase is regulated by BDNF promoters I, II, IV or by cAMP response element (CRE), to investigate the activation of selected promoters induced by monoaminergic antidepressants and by serotonin or noradrenaline agonists. We found that incubation with fluoxetine or reboxetine failed to induce any activation of BDNF promoters or CRE. On the other hand, the incubation of cultures with selective agonists of serotonin or noradrenaline receptors induced a specific and distinct profile of activation of BDNF promoters I, II, IV and CRE, suggesting that the monoaminergic input, absent in dissociated cultures, is essential for the modulation of BDNF expression. In summary, we applied a rapidly detectable and highly sensitive reporter gene assay to characterize the selective activation profile of BDNF and CRE promoters, through specific and different pharmacological stimuli.

  1. BDNF — a key transducer of antidepressant effects

    PubMed Central

    Björkholm, Carl; Monteggia, Lisa M.

    2016-01-01

    How do antidepressants elicit an antidepressant response? Here, we review accumulating evidence that the neurotrophin brain-derived neurotrophic factor (BDNF) serves as a transducer, acting as the link between the antidepressant drug and the neuroplastic changes that result in the improvement of the depressive symptoms. Over the last decade several studies have consistently highlighted BDNF as a key player in antidepressant action. An increase in hippocampal and cortical expression of BDNF mRNA parallels the antidepressant-like response of conventional antidepressants such as SSRIs. Subsequent studies showed that a single bilateral infusion of BDNF into the ventricles or directly into the hippocampus is sufficient to induce a relatively rapid and sustained antidepressant-like effect. Importantly, the antidepressant-like response to conventional antidepressants is attenuated in mice where the BDNF signaling has been disrupted by genetic manipulations. Low dose ketamine, which has been found to induce a rapid antidepressant effect in patients with treatment-resistant depression, is also dependent on increased BDNF signaling. Ketamine transiently increases BDNF translation in hippocampus, leading to enhanced synaptic plasticity and synaptic strength. Ketamine has been shown to increase BDNF translation by blocking NMDA receptor activity at rest, thereby inhibiting calcium influx and subsequently halting eukaryotic elongation factor 2 (eEF2) kinase leading to a desuppression of protein translation, including BDNF translation. The antidepressant-like response of ketamine is abolished in BDNF and TrkB conditional knockout mice, eEF2 kinase knockout mice, in mice carrying the BDNF met/met allele, and by intra-cortical infusions of BDNF-neutralizing antibodies. In summary, current data suggests that conventional antidepressants and ketamine mediate their antidepressant-like effects by increasing BDNF in forebrain regions, in particular the hippocampus, making BDNF an

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

    PubMed

    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.

  3. NPY modulates miR-30a-5p and BDNF in opposite direction in an in vitro model of Alzheimer disease: a possible role in neuroprotection?

    PubMed

    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.

  4. Adenoviral astrocyte-specific expression of BDNF in the striata of mice transgenic for Huntington's disease delays the onset of the motor phenotype.

    PubMed

    Arregui, Leticia; Benítez, Jorge A; Razgado, Luis F; Vergara, Paula; Segovia, Jose

    2011-11-01

    Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms. The most characteristic structural feature of this disease is neurodegeneration accompanied by gliosis in the striatum. BDNF has been proposed to protect striatal neurons from degeneration, because it is an important survival factor for these neurons from development to adulthood. Considering the extensive gliosis and the survival effects of BDNF, we constructed an adenovirus to express a BDNF cDNA in astrocyte cells using a promoter of the glial fibrillary acidic protein gene. Cells stably transfected in vitro with a BDNF cDNA driven by this promoter expressed BDNF and responded to external stimuli increasing BDNF production. When the vector was applied into the striata of mice transgenic for HD, long-term expression of the transgene was observed, associated with a delay of onset of the motor phenotype of the R6/2 HD transgenic mice. The present data indicate that the striatal expression of BDNF is a potential adjuvant for the treatment of HD.

  5. Val66Met Polymorphism of BDNF Alters Prodomain Structure to Induce Neuronal Growth Cone Retraction

    PubMed Central

    Anastasia, Agustin; Deinhardt, Katrin; Chao, Moses V.; Will, Nathan E.; Irmady, Krithi; Lee, Francis S.; Hempstead, Barbara L.; Bracken, Clay

    2013-01-01

    A common single-nucleotide polymorphism in the human brain-derived neurotrophic factor (BDNF) gene results in a Val66Met substitution in the BDNF prodomain region. This single-nucleotide polymorphism is associated with alterations in memory and with enhanced risk to develop depression and anxiety disorders in humans. Here we show that the isolated BDNF prodomain is detected in the hippocampus and that it can be secreted from neurons in an activity-dependent manner. Using nuclear magnetic resonance spectroscopy and circular dichroism we find that the prodomain is intrinsically disordered, and the Val66Met substitution induces structural changes. Surprisingly, application of Met66 (but not Val66) BDNF prodomain induces acute growth cone retraction and a decrease in Rac activity in hippocampal neurons. Expression of p75NTR and differential engagement of the Met66 prodomain to the SorCS2 receptor are required for this effect. These results identify the Met66 prodomain as a new active ligand which modulates neuronal morphology. PMID:24048383

  6. BDNF Val66Met, stress, and positive mothering: Differential susceptibility model of adolescent trait anxiety.

    PubMed

    Chen, Jie; Yu, Jing; Liu, Yujie; Zhang, Leilei; Zhang, Jianxin

    2015-08-01

    Etiological research has indicated the gene-environment interaction (G × E) on adolescent anxiety. This study aimed to examine how the BDNF Val66Met polymorphism interacted with stressful life events and positive mothering to influence youth trait anxiety. The study sample included 780 community adolescents of Chinese Han ethnicity (M = 13.6, 51.3% females). Participants' trait anxiety, exposure to stressful life events, and mother's warmth-reasoning were assessed by self-reported questionnaires. We found that BDNF Val66Met polymorphism significantly moderated the influences of stressful life events and mother's warmth-reasoning on adolescent anxiety. The influences were significantly greater in adolescents carrying one or two Val allele than those with Met/Met genotype. Moreover, the G × E interactions were more consistent with the differential susceptibility than the diathesis-stress model. Adolescents carrying Val allele who were more susceptible to adversity were also more likely to benefit from supportive experiences. These findings provide novel evidence for the role of BDNF Val66Met as a genetic susceptibility modulating the influences of stressful life events and mother's warmth-reasoning on adolescent anxiety. We speculate that BDNF Val66Met may moderate anxious youths' responses to mindfulness-based stress reduction program and family-based treatment targeting the enhancement of positive parenting. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Interaction between 5-HTTLPR and BDNF Val66Met polymorphisms on HPA axis reactivity in preschoolers.

    PubMed

    Dougherty, Lea R; Klein, Daniel N; Congdon, Eliza; Canli, Turhan; Hayden, Elizabeth P

    2010-02-01

    This study examined whether the interaction between the serotonin transporter promoter region (5-HTTLPR) and brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms was associated with hypothalamic-pituitary-adrenal (HPA) axis reactivity to stress. A community sample of 144 preschool-aged children was genotyped and exposed to stress-inducing laboratory tasks. Salivary cortisol was obtained at four time points during a standardized laboratory assessment before and after stressors involving separation from a parent and frustrating tasks. Children homozygous for the short-5-HTTLPR allele and carrying the Met-BDNF allele evidenced a significantly lower initial level of cortisol, followed by a positive increase in cortisol in response to the laboratory stressors. In contrast, children who were homozygous for the short-5-HTTLPR and the Val-BDNF alleles evidenced a greater decline in cortisol in response to the laboratory stressors. Findings indicated that the BDNF gene moderated the association between 5-HTTLPR and children's biological stress responses, suggesting that epistatic effects play a role in individual differences in stress regulation, and possibly genetic vulnerability to stress-related disorders. Copyright 2009 Elsevier B.V. All rights reserved.

  8. BDNF-Treated Retinal Progenitor Sheets Transplanted to Degenerate Rats

    PubMed Central

    Seiler, Magdalene J.; Thomas, Biju B.; Chen, Zhenhai; Arai, Shinichi; Chadalavada, Sridhar; Mahoney, Melissa J.; Sadda, Srinivas R.; Aramant, Robert B.

    2011-01-01

    The aim of this study was to evaluate the functional efficacy of retinal progenitor cell (RPC) containing sheets with BDNF microspheres following subretinal transplantation in a rat model of retinal degeneration. Sheets of E19 RPCs derived from human placental alkaline phosphatase (hPAP) expressing transgenic rats were coated with PLGA (Poly-lactide-co-glycolide) microspheres containing brain-derived neurotrophic factor (BDNF) and transplanted into the subretinal space of S334ter-line-3 rhodopsin retinal degenerate rats. Controls received transplants without BDNF or BDNF microspheres alone. Visual function was monitored using optokinetic head-tracking behavior. Visually evoked responses to varying light intensities were recorded from the superior colliculus (SC) by electrophysiology at 60 days after surgery. Frozen sections were studied by immunohistochemistry for photoreceptor and synaptic markers. Visual head tracking was significantly improved in rats that received BDNF-coated RPC sheets. Relatively more BDNF treated transplanted rats (80%) compared to non-BDNF transplants (57%) responded to a “low light” intensity of 1 cd/m2in a confined SC area. With bright light, the onset latency of SC responses was restored to a nearly normal level in BDNF treated transplants. No significant improvement was observed in the BDNF-only and no surgery transgenic control rats. The bipolar synaptic markers mGluR6 and PSD-95 showed normal distribution in transplants and abnormal distribution of the host retina, both with or without BDNF-treatment. Red-green cones were significantly reduced in the host retina overlying the transplant in the BDNF -treated group. In summary, BDNF coating improved the functional efficacy of RPC grafts. The mechanism of the BDNF effects - either promoting functional integration between the transplant and the host retina and/or synergistic action with other putative humoral factors released by the RPCs - still needs to be elucidated. PMID:17983616

  9. No effect of 5HTTLPR or BDNF Val66Met polymorphism on hippocampal morphology in major depression.

    PubMed

    Cole, J; Weinberger, D R; Mattay, V S; Cheng, X; Toga, A W; Thompson, P M; Powell-Smith, G; Cohen-Woods, S; Simmons, A; McGuffin, P; Fu, C H Y

    2011-10-01

    Neuroimaging research implicates the hippocampus in the aetiology of major depressive disorder (MDD). Imaging genetics studies have investigated the influence of the serotonin transporter-linked polymorphic region (5HTTLPR) and brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on the hippocampus in healthy individuals and patients with depression (MDD). However, conflicting results have led to inconclusive evidence about the effect of 5HTTLPR or BDNF on hippocampal volume (HCV). We hypothesized that analysis methods based on three-dimensional (3D) hippocampal shape mapping could offer improved sensitivity to clarify these effects. Magnetic resonance imaging data were collected in parallel samples of 111 healthy individuals and 84 MDD patients. Manual hippocampal segmentation was conducted and the resulting data used to investigate the influence of 5HTTLPR and BDNF Val66Met genotypes on HCV and 3D shape within each sample. Hippocampal volume normalized by intracranial volume (ICV) showed no significant difference between 5HTTLPR S allele carriers and L/L homozygotes or between BDNF Met allele carriers and Val/Val homozygotes in the group of healthy individuals. Moreover, there was no significant difference in normalized HCV between 5HTTLPR diallelic and triallelic classifications or between the BDNF Val66Met genotypes in MDD patients, although there was a relationship between BDNF Val66Met and ICV. Shape analysis detected dispersed between-group differences, but these effects did not survive multiple testing correction. In this study, there was no evidence of a genetic effect for 5HTTLPR or BDNF Val66Met on hippocampal morphology in either healthy individuals or MDD patients despite the relatively large sample sizes and sensitive methodology. © 2011 The Authors. Genes, Brain and Behavior © 2011 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

  10. Pilot Study and Review: Physiological Differences in BDNF, a Potential Biomarker in Males and Females with Autistic Disorder.

    PubMed

    Spratt, Eve G; Granholm, Ann-Charlotte; Carpenter, Laura A; Boger, Heather A; Papa, Carrie E; Logan, Sarah; Chaudhary, Humera; Boatwright, Sarah-Wade; Brady, Kathleen T

    There is a need for more biologic research in autistic disorder (AD) to determine if biomarkers exist that would be useful for correlating to symptom severity and/or clinical improvement during treatment. Given the fact that AD is 4 times more common in males than females, gender differences in physiological biomarkers may be present. One potential biomarker that has begun to be studied is brain-derived neurotropic factor (BDNF), a peptide involved in the regulation of neuronal cell survival, differentiation, and plasticity, and possessing an ability to influence neurotransmitter systems by modulating gene expression. This pilot study examined whether serum BDNF differed according to gender in children with AD and whether differences were associated with a behavioral phenotype or severity of illness. Data for this investigation were collected during the participants' baseline visit of an intervention study. Participants were males (n=29) and females (n=7), aged 5 to 12 years diagnosed with AD. Baseline serum BDNF concentration was determined for comparison to clinical ratings using an autism severity measure and the Pervasive Developmental Disorder-Behavior Inventory (PDD-BI). BDNF serum concentrations were higher in females (p<0.049). The baseline BDNF value corresponded significantly to hyperactivity in females (p<0.0002) but not in males. BDNF did not correlate with severity of disease in either gender. Although this is a small study, a better understanding of the central role of BDNF may provide insight into the pathophysiology of the disease and elucidate why gender differences exist in prevalence and behavioral phenotype of AD.

  11. The CB1 cannabinoid receptor signals striatal neuroprotection via a PI3K/Akt/mTORC1/BDNF pathway

    PubMed Central

    Blázquez, C; Chiarlone, A; Bellocchio, L; Resel, E; Pruunsild, P; García-Rincón, D; Sendtner, M; Timmusk, T; Lutz, B; Galve-Roperh, I; Guzmán, M

    2015-01-01

    The CB1 cannabinoid receptor, the main molecular target of endocannabinoids and cannabis active components, is the most abundant G protein-coupled receptor in the mammalian brain. In particular, the CB1 receptor is highly expressed in the basal ganglia, mostly on terminals of medium-sized spiny neurons, where it plays a key neuromodulatory function. The CB1 receptor also confers neuroprotection in various experimental models of striatal damage. However, the assessment of the physiological relevance and therapeutic potential of the CB1 receptor in basal ganglia-related diseases is hampered, at least in part, by the lack of knowledge of the precise mechanism of CB1 receptor neuroprotective activity. Here, by using an array of pharmacological, genetic and pharmacogenetic (designer receptor exclusively activated by designer drug) approaches, we show that (1) CB1 receptor engagement protects striatal cells from excitotoxic death via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin complex 1 pathway, which, in turn, (2) induces brain-derived neurotrophic factor (BDNF) expression through the selective activation of BDNF gene promoter IV, an effect that is mediated by multiple transcription factors. To assess the possible functional impact of the CB1/BDNF axis in a neurodegenerative-disease context in vivo, we conducted experiments in the R6/2 mouse, a well-established model of Huntington's disease, in which the CB1 receptor and BDNF are known to be severely downregulated in the dorsolateral striatum. Adeno-associated viral vector-enforced re-expression of the CB1 receptor in the dorsolateral striatum of R6/2 mice allowed the re-expression of BDNF and the concerted rescue of the neuropathological deficits in these animals. Collectively, these findings unravel a molecular link between CB1 receptor activation and BDNF expression, and support the relevance of the CB1/BDNF axis in promoting striatal neuron survival. PMID:25698444

  12. Tet1-dependent epigenetic modification of BDNF expression in dorsal horn neurons mediates neuropathic pain in rats

    PubMed Central

    Hsieh, Ming-Chun; Lai, Cheng-Yuan; Ho, Yu-Cheng; Wang, Hsueh-Hsiao; Cheng, Jen-Kun; Chau, Yat-Pang; Peng, Hsien-Yu

    2016-01-01

    Ten-eleven translocation methylcytosine dioxygenase 1 (Tet1) mediates the conversion of 5-methylcytosine (5 mC) to 5-hydroxymethylcytosine (5 hmC), hence promoting DNA demethylation. Although recent studies have linked the DNA demethylation of specific genes to pain hypersensitivity, the role of spinal Tet1-dependent DNA demethylation in nociception hypersensitivity development remains elusive. Here, we report correlated with behavioral allodynia, spinal nerve ligation (SNL) upregulated Tet1 expression in dorsal horn neurons that hydroxylate 5 mC to 5 hmC at CpG dinucleotides in the bdnf promoter to promote spinal BDNF expression at day 7 after operation. Focal knockdown of spinal Tet1 expression decreased Tet1 binding and 5 hmC enrichment, further increased 5 mC enrichment at CpG sites in the bdnf promoter and decreased spinal BDNF expression accompanied by the alleviation of the developed allodynia. Moreover, at day 7 after operation, SNL-enhanced Tet1 expression also inhibited the binding of DNA methyltransferases (DNMTs, i.e., DNMT1, DNMT3a, and DNMT3b) to the bdnf promoter, a requirement for transcriptional silencing by catalysing 5-cytosine (5C) to 5 mC. Together, these data suggest at CpG sites of the bdnf promoter, SNL-enhanced Tet1 expression promotes DNA demethylation both by converting 5 mC to 5 hmC and inhibiting DNMT binding to regulate spinal BDNF expression, hence contributing to behavioral allodynia development. PMID:27857218

  13. Valence-specific effects of BDNF Val66Met polymorphism on dopaminergic stress and reward processing in humans.

    PubMed

    Peciña, Marta; Martínez-Jauand, Mercedes; Love, Tiffany; Heffernan, Joseph; Montoya, Pedro; Hodgkinson, Colin; Stohler, Christian S; Goldman, David; Zubieta, Jon-Kar

    2014-04-23

    Brain-derived neurotrophic factor (BDNF) levels in dopaminergic (DA) cells within the ventral tegmental area (VTA)/nucleus accumbens (NAc) circuitry appear to be a candidate mechanism for the neuroadaptive changes that follow stress and reward responses in animal models. However, the role of the BDNF gene variants in responses to salient cues through DA neurotransmission in humans remains unexplored. Here, we studied the effect of the common functional BDNF Val(66)Met (rs6265) polymorphism on rewarding experiences in the striatum and DA-mediated responses to stress. Seventy-two healthy controls were genotyped for the BDNF Val(66)Met polymorphism and underwent the monetary incentive delay task during an functional magnetic resonance imaging (fMRI) session. Forty-nine of them also underwent a sustained pain challenge with and without placebo administration with potential analgesic properties during PET measures of DA D2/3-receptor-mediated neurotransmission. Neuroimaging results revealed a significant effect of BDNF (Met(66) carriers > Val/Val) on brain responses during the anticipation of monetary losses, baseline D2/3 receptor availability, and pain-stress-induced DA release in the NAc. Conversely, BDNF Met(66) carriers showed no activation in response to monetary gains and a blunted DA response to the analgesic placebo in the NAc. These results provide initial human evidence regarding the effect of the BDNF Val(66)Met polymorphism on DA-mediated responses to stress, its cognitive regulation by positive expectations, and the anticipatory responses to monetary gains and losses in the VTA-NAc pathway. Our results are of relevance to the neurobiology of stress and reward interactions and the pathophysiology of stress-related disorders.

  14. BDNF Val66Met modifies the risk of childhood trauma on obsessive-compulsive disorder.

    PubMed

    Hemmings, Sian Megan Joanna; Lochner, Christine; van der Merwe, Lize; Cath, Danielle C; Seedat, Soraya; Stein, Dan J

    2013-12-01

    Childhood trauma has been linked to the development of later psychopathology, including obsessive-compulsive disorder (OCD). Although evidence exists to suggest that genetic and environmental factors are involved in the aetiology of OCD, little attention has been paid to the interactions that exist between genes and environment. The aim of this study was to investigate gene-by-environment interactions between childhood trauma and the BDNF Val66Met variant in patients with OCD. Childhood trauma was assessed in 134 OCD patients and 188 controls using the Childhood Trauma Questionnaire (CTQ). Linear regression models were used for statistical analyses. Gene-environment interactions were estimated by including a combined genotype and CTQ score in the models as interaction terms. All analyses were adjusted for age, gender, CTQ minimisation-denial score and home language by including them in the logistic regression models as covariates. Childhood trauma, specifically emotional abuse and neglect, increased the odds of having OCD significantly (p < 0.001). Although no significant association was observed between BDNF Val66Met and the development of OCD, interaction analysis indicated that the BDNF Met-allele interacted with childhood emotional abuse to increase the risk of OCD significantly in a dose-dependent manner (p = 0.024). To our knowledge, this is one of the first studies to investigate gene-environment interactions in OCD, and the findings indicate the importance of collating genetic and environmental variables in future studies.

  15. ProBDNF and mature BDNF as punishment and reward signals for synapse elimination at mouse neuromuscular junctions.

    PubMed

    Je, H Shawn; Yang, Feng; Ji, Yuanyuan; Potluri, Srilatha; Fu, Xiu-Qing; Luo, Zhen-Ge; Nagappan, Guhan; Chan, Jia Pei; Hempstead, Barbara; Son, Young-Jin; Lu, Bai

    2013-06-12

    During development, mammalian neuromuscular junctions (NMJs) transit from multiple-innervation to single-innervation through axonal competition via unknown molecular mechanisms. Previously, using an in vitro model system, we demonstrated that the postsynaptic secretion of pro-brain-derived neurotrophic factor (proBDNF) stabilizes or eliminates presynaptic axon terminals, depending on its proteolytic conversion at synapses. Here, using developing mouse NMJs, we obtained in vivo evidence that proBDNF and mature BDNF (mBDNF) play roles in synapse elimination. We observed that exogenous proBDNF promoted synapse elimination, whereas mBDNF infusion substantially delayed synapse elimination. In addition, pharmacological inhibition of the proteolytic conversion of proBDNF to mBDNF accelerated synapse elimination via activation of p75 neurotrophin receptor (p75(NTR)). Furthermore, the inhibition of both p75(NTR) and sortilin signaling attenuated synapse elimination. We propose a model in which proBDNF and mBDNF serve as potential "punishment" and "reward" signals for inactive and active terminals, respectively, in vivo.

  16. BDNF mRNA abundance regulated by antidromic action potentials and AP-LTD in hippocampus.

    PubMed

    Bukalo, Olena; Lee, Philip R; Fields, R Douglas

    2016-12-02

    Action-potential-induced LTD (AP-LTD) is a form of synaptic plasticity that reduces synaptic strength in CA1 hippocampal neurons firing antidromically during sharp-wave ripples. This firing occurs during slow-wave sleep and quiet moments of wakefulness, which are periods of offline replay of neural sequences learned during encoding sensory information. Here we report that rapid and persistent down-regulation of different mRNA transcripts of the BDNF gene accompanies AP-LTD, and that AP-LTD is abolished in mice with the BDNF gene knocked out in CA1 hippocampal neurons. These findings increase understanding of the mechanism of AP-LTD and the cellular mechanisms of memory consolidation.

  17. Epigenetic Modification of Hippocampal Bdnf DNA in Adult Rats in an Animal Model of Post-Traumatic Stress Disorder

    PubMed Central

    Roth, Tania L.; Zoladz, Phillip R.; Sweatt, J. David; Diamond, David M.

    2011-01-01

    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 BdnfDNA 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 BdnfDNA methylation patterns (at exon IV) and gene expression. We have found here that the psychosocial stress regimen significantly increased BdnfDNA 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 BdnfDNA methylation were detected in the medial prefrontal cortex or basolateral amygdala. In addition, there were decreased levels of BdnfmRNA 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 Bdnfgene may underlie hippocampal dysfunction in response to traumatic stress. Furthermore, this work provides support for the speculative notion that altered hippocampal BdnfDNA methylation is a cellular mechanism underlying the persistent cognitive deficits which are prominent features of the pathophysiology of PTSD. PMID:21306736

  18. Exercise induces BDNF and synapsin I to specific hippocampal subfields.

    PubMed

    Vaynman, Shoshanna; Ying, Zhe; Gómez-Pinilla, Fernando

    2004-05-01

    To assess the relationship between brain-derived neurotrophic factor (BDNF) and synapsin I in the hippocampus during exercise, we employed a novel microsphere injection method to block the action of BDNF through its tyrosine kinase (Trk) receptor and subsequently measure the mRNA levels of synapsin I, using real-time TaqMan RT-PCR for RNA quantification. After establishing a causal link between BDNF and exercise-induced synapsin I mRNA levels, we studied the exercise-induced distribution of BDNF and synapsin I in the rodent hippocampus. Quantitative immunohistochemical analysis revealed increases of BDNF and synapsin I in CA3 stratum lucidum and dentate gyrus, and synapsin I alone in CA1 stratum radiatum and stratum laconosum moleculare. These results indicate that exercise induces plasticity of select hippocampal transsynaptic circuitry, possibly comprising a spatial restriction on synapsin I regulation by BDNF.

  19. BDNF Mediates Adaptive Brain and Body Responses to Energetic Challenges

    PubMed Central

    Marosi, Krisztina; Mattson, Mark P.

    2014-01-01

    Emerging findings suggest that brain-derived neurotrophic factor (BDNF) serves widespread roles in regulating energy homeostasis by controlling patterns of feeding and physical activity, and by modulating glucose metabolism in peripheral tissues. BDNF mediates beneficial effects of energetic challenges such as vigorous exercise and fasting on cognition, mood, cardiovascular function and peripheral metabolism. By stimulating glucose transport and mitochondrial biogenesis BDNF bolsters cellular bioenergetics and protects neurons against injury and disease. By acting in the brain and periphery, BDNF increases insulin sensitivity and parasympathetic tone. Genetic factors, a ‘couch potato’ lifestyle and chronic stress impair BDNF signaling, which may contribute to the pathogenesis of metabolic syndrome. Novel BDNF-focused interventions are being developed for obesity, diabetes and neurological disorders. PMID:24361004

  20. A simple role for BDNF in learning and memory?

    PubMed

    Cunha, Carla; Brambilla, Riccardo; Thomas, Kerrie L

    2010-01-01

    Since its discovery almost three decades ago, the secreted neurotrophin brain-derived neurotrophic factor (BDNF) has been firmly implicated in the differentiation and survival of neurons of the CNS. More recently, BDNF has also emerged as an important regulator of synaptogenesis and synaptic plasticity mechanisms underlying learning and memory in the adult CNS. In this review we will discuss our knowledge about the multiple intracellular signalling pathways activated by BDNF, and the role of this neurotrophin in long-term synaptic plasticity and memory formation as well as in synaptogenesis. We will show that maturation of BDNF, its cellular localization and its ability to regulate both excitatory and inhibitory synapses in the CNS may result in conflicting alterations in synaptic plasticity and memory formation. Lack of a precise knowledge about the mechanisms by which BDNF influences higher cognitive functions and complex behaviours may constitute a severe limitation in the possibility to devise BDNF-based therapeutics for human disorders of the CNS.

  1. 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.

    PubMed

    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.

  2. Reduced cortical BDNF expression and aberrant memory in Carf knockout mice

    PubMed Central

    McDowell, Kelli A.; Hutchinson, Ashley N.; Wong-Goodrich, Sarah J.E.; Presby, Matthew M.; Su, Dan; Rodriguiz, Ramona M.; Law, Krystal C.; Williams, Christina L.; Wetsel, William C.; West, Anne E.

    2010-01-01

    Transcription factors are a key point of convergence between the cell-intrinsic and extracellular signals that guide synaptic development and brain plasticity. Calcium-Response Factor (CaRF) is a unique transcription factor first identified as a binding protein for a calcium-response element in the gene encoding Brain-Derived Neurotrophic Factor (Bdnf). We have now generated Carf knockout (KO) mice to characterize the function of this factor in vivo. Intriguingly, Carf KO mice have selectively reduced expression of Bdnf exon IV-containing mRNA transcripts and BDNF protein in the cerebral cortex while BDNF levels in the hippocampus and striatum remain unchanged, implicating CaRF as a brain region-selective regulator of BDNF expression. At the cellular level, Carf KO mice show altered expression of GABAergic proteins at striatal synapses, raising the possibility that CaRF may contribute to aspects of inhibitory synapse development. Carf KO mice show normal spatial learning in the Morris water maze and normal context-dependent fear conditioning. However they have an enhanced ability to find a new platform location on the first day of reversal training in the water maze and they extinguish conditioned fear more slowly than their wildtype (WT) littermates. Finally, Carf KO mice show normal short-term and long-term memory in a novel object recognition task, but exhibit impairments during the remote memory phase of testing. Taken together these data reveal novel roles for CaRF in the organization and/or function of neural circuits that underlie essential aspects of learning and memory. PMID:20519520

  3. Reduced cortical BDNF expression and aberrant memory in Carf knock-out mice.

    PubMed

    McDowell, Kelli A; Hutchinson, Ashley N; Wong-Goodrich, Sarah J E; Presby, Matthew M; Su, Dan; Rodriguiz, Ramona M; Law, Krystal C; Williams, Christina L; Wetsel, William C; West, Anne E

    2010-06-02

    Transcription factors are a key point of convergence between the cell-intrinsic and extracellular signals that guide synaptic development and brain plasticity. Calcium-response factor (CaRF) is a unique transcription factor first identified as a binding protein for a calcium-response element in the gene encoding brain-derived neurotrophic factor (Bdnf). We have now generated Carf knock-out (KO) mice to characterize the function of this factor in vivo. Intriguingly, Carf KO mice have selectively reduced expression of Bdnf exon IV-containing mRNA transcripts and BDNF protein in the cerebral cortex, whereas BDNF levels in the hippocampus and striatum remain unchanged, implicating CaRF as a brain region-selective regulator of BDNF expression. At the cellular level, Carf KO mice show altered expression of GABAergic proteins at striatal synapses, raising the possibility that CaRF may contribute to aspects of inhibitory synapse development. Carf KO mice show normal spatial learning in the Morris water maze and normal context-dependent fear conditioning. However they have an enhanced ability to find a new platform location on the first day of reversal training in the water maze and they extinguish conditioned fear more slowly than their wild-type littermates. Finally, Carf KO mice show normal short-term (STM) and long-term memory (LTM) in a novel object recognition task, but exhibit impairments during the remote memory phase of testing. Together, these data reveal novel roles for CaRF in the organization and/or function of neural circuits that underlie essential aspects of learning and memory.

  4. Merkel Cell-Driven BDNF Signaling Specifies SAI Neuron Molecular and Electrophysiological Phenotypes

    PubMed Central

    Reed-Geaghan, Erin G.; Wright, Margaret C.; See, Lauren A.; Adelman, Peter C.; Lee, Kuan Hsien; Koerber, H. Richard

    2016-01-01

    The extent to which the skin instructs peripheral somatosensory neuron maturation is unknown. We studied this question in Merkel cell–neurite complexes, where slowly adapting type I (SAI) neurons innervate skin-derived Merkel cells. Transgenic mice lacking Merkel cells had normal dorsal root ganglion (DRG) neuron numbers, but fewer DRG neurons expressed the SAI markers TrkB, TrkC, and Ret. Merkel cell ablation also decreased downstream TrkB signaling in DRGs, and altered the expression of genes associated with SAI development and function. Skin- and Merkel cell-specific deletion of Bdnf during embryogenesis, but not postnatal Bdnf deletion or Ntf3 deletion, reproduced these results. Furthermore, prototypical SAI electrophysiological signatures were absent from skin regions where Bdnf was deleted in embryonic Merkel cells. We conclude that BDNF produced by Merkel cells during a precise embryonic period guides SAI neuron development, providing the first direct evidence that the skin instructs sensory neuron molecular and functional maturation. SIGNIFICANCE STATEMENT Peripheral sensory neurons show incredible phenotypic and functional diversity that is initiated early by cell-autonomous and local environmental factors found within the DRG. However, the contribution of target tissues to subsequent sensory neuron development remains unknown. We show that Merkel cells are required for the molecular and functional maturation of the SAI neurons that innervate them. We also show that this process is controlled by BDNF signaling. These findings provide new insights into the regulation of somatosensory neuron development and reveal a novel way in which Merkel cells participate in mechanosensation. PMID:27076431

  5. The BDNF Val66Met Polymorphism Modulates Sleep Intensity: EEG Frequency- and State-Specificity

    PubMed Central

    Bachmann, Valérie; Klein, Carina; Bodenmann, Sereina; Schäfer, Nikolaus; Berger, Wolfgang; Brugger, Peter; Landolt, Hans-Peter

    2012-01-01

    Study Objectives: EEG slow waves are the hallmark of deep NREM sleep and may reflect the restorative functions of sleep. Evidence suggests that increased sleep slow waves after sleep deprivation reflect plastic synaptic processes, and that brain-derived neurotrophic factor (BDNF) is causally involved in their homeostatic regulation. The functional Val66Met polymorphism of the gene encoding pro-BDNF causes impaired activity-dependent secretion of mature BDNF protein. We investigated whether this polymorphism contributes to the pronounced inter-individual variation in sleep slow wave activity (SWA) in humans. Setting: Sleep laboratory in temporal isolation unit. Participants: Eleven heterozygous Met allele carriers and 11 individually sex- and age-matched Val/Val homozygotes. Interventions: Forty hours prolonged wakefulness. Measurements and Results: Cognitive performance, subjective state, and waking and sleep EEG in baseline and after sleep deprivation were studied. Val/Val homozygotes showed better response accuracy than Met allele carriers on a verbal 2-back working memory task. This difference did not reflect genotype-dependent differences in sleepiness, well-being, or sustained attention. In baseline and recovery nights, deep stage 4 sleep and NREM sleep intensity as quantified by EEG SWA (0.75-4.5 Hz) were higher in Val/Val compared to Val/Met genotype. Similar to sleep deprivation, the difference was most pronounced in the first NREM sleep episode. By contrast, increased activity in higher EEG frequencies (> 6 Hz) in wakefulness and REM sleep was distinct from the effects of prolonged wakefulness. Conclusion: BDNF contributes to the regulation of sleep slow wave oscillations, suggesting that genetically determined variation in neuronal plasticity modulates NREM sleep intensity in humans. Citation: Bachmann V; Klein C; Bodenmann S; Schäfer N; Berger W; Brugger P; Landolt HP. The BDNF Val66Met polymorphism modulates sleep intensity: EEG frequency- and state

  6. SorCS2 is required for BDNF-dependent plasticity in the hippocampus.

    PubMed

    Glerup, S; Bolcho, U; Mølgaard, S; Bøggild, S; Vaegter, C B; Smith, A H; Nieto-Gonzalez, J L; Ovesen, P L; Pedersen, L F; Fjorback, A N; Kjolby, M; Login, H; Holm, M M; Andersen, O M; Nyengaard, J R; Willnow, T E; Jensen, K; Nykjaer, A

    2016-12-01

    SorCS2 is a member of the Vps10p-domain receptor gene family receptors with critical roles in the control of neuronal viability and function. Several genetic studies have suggested SORCS2 to confer risk of bipolar disorder, schizophrenia and attention deficit-hyperactivity disorder. Here we report that hippocampal N-methyl-d-aspartate receptor-dependent synaptic plasticity is eliminated in SorCS2-deficient mice. This defect was traced to the ability of SorCS2 to form complexes with the neurotrophin receptor p75(NTR), required for pro-brain-derived neurotrophic factor (BDNF) to induce long-term depression, and with the BDNF receptor tyrosine kinase TrkB to elicit long-term potentiation. Although the interaction with p75(NTR) was static, SorCS2 bound to TrkB in an activity-dependent manner to facilitate its translocation to postsynaptic densities for synaptic tagging and maintenance of synaptic potentiation. Neurons lacking SorCS2 failed to respond to BDNF by TrkB autophosphorylation, and activation of downstream signaling cascades, impacting neurite outgrowth and spine formation. Accordingly, Sorcs2(-/-) mice displayed impaired formation of long-term memory, increased risk taking and stimulus seeking behavior, enhanced susceptibility to stress and impaired prepulse inhibition. Our results identify SorCS2 as an indispensable coreceptor for p75(NTR) and TrkB in hippocampal neurons and suggest SORCS2 as the link between proBDNF/BDNF signaling and mental disorders.

  7. Merkel Cell-Driven BDNF Signaling Specifies SAI Neuron Molecular and Electrophysiological Phenotypes.

    PubMed

    Reed-Geaghan, Erin G; Wright, Margaret C; See, Lauren A; Adelman, Peter C; Lee, Kuan Hsien; Koerber, H Richard; Maricich, Stephen M

    2016-04-13

    The extent to which the skin instructs peripheral somatosensory neuron maturation is unknown. We studied this question in Merkel cell-neurite complexes, where slowly adapting type I (SAI) neurons innervate skin-derived Merkel cells. Transgenic mice lacking Merkel cells had normal dorsal root ganglion (DRG) neuron numbers, but fewer DRG neurons expressed the SAI markers TrkB, TrkC, and Ret. Merkel cell ablation also decreased downstream TrkB signaling in DRGs, and altered the expression of genes associated with SAI development and function. Skin- and Merkel cell-specific deletion of Bdnf during embryogenesis, but not postnatal Bdnf deletion or Ntf3 deletion, reproduced these results. Furthermore, prototypical SAI electrophysiological signatures were absent from skin regions where Bdnf was deleted in embryonic Merkel cells. We conclude that BDNF produced by Merkel cells during a precise embryonic period guides SAI neuron development, providing the first direct evidence that the skin instructs sensory neuron molecular and functional maturation. Peripheral sensory neurons show incredible phenotypic and functional diversity that is initiated early by cell-autonomous and local environmental factors found within the DRG. However, the contribution of target tissues to subsequent sensory neuron development remains unknown. We show that Merkel cells are required for the molecular and functional maturation of the SAI neurons that innervate them. We also show that this process is controlled by BDNF signaling. These findings provide new insights into the regulation of somatosensory neuron development and reveal a novel way in which Merkel cells participate in mechanosensation. Copyright © 2016 the authors 0270-6474/16/364362-15$15.00/0.

  8. The BDNF Val66Met Polymorphism Affects the Vulnerability of the Brain Structural Network.

    PubMed

    Park, Chang-Hyun; Kim, Jungyoon; Namgung, Eun; Lee, Do-Wan; Kim, Geon Ha; Kim, Myeongju; Kim, Nayeon; Kim, Tammy D; Kim, Seunghee; Lyoo, In Kyoon; Yoon, Sujung

    2017-01-01

    Val66Met, a naturally occurring polymorphism in the human brain-derived neurotrophic factor (BDNF) gene resulting in a valine (Val) to methionine (Met) substitution at codon 66, plays an important role in neuroplasticity. While the effect of the BDNF Val66Met polymorphism on local brain structures has previously been examined, its impact on the configuration of the graph-based white matter structural networks is yet to be investigated. In the current study, we assessed the effect of the BDNF polymorphism on the network properties and robustness of the graph-based white matter structural networks. Graph theory was employed to investigate the structural connectivity derived from white matter tractography in two groups, Val homozygotes (n = 18) and Met-allele carriers (n = 55). Although there were no differences in the global network measures including global efficiency, local efficiency, and modularity between the two genotype groups, we found the effect of the BDNF Val66Met polymorphism on the robustness properties of the white matter structural networks. Specifically, the white matter structural networks of the Met-allele carrier group showed higher vulnerability to targeted removal of central nodes as compared with those of the Val homozygote group. These findings suggest that the central role of the BDNF Val66Met polymorphism in regards to neuroplasticity may be associated with inherent differences in the robustness of the white matter structural network according to the genetic variants. Furthermore, greater susceptibility to brain disorders in Met-allele carriers may be understood as being due to their limited stability in white matter structural connectivity.

  9. Activity-dependent BDNF release and TRPC signaling is impaired in hippocampal neurons of Mecp2 mutant mice.

    PubMed

    Li, Wei; Calfa, Gaston; Larimore, Jennifer; Pozzo-Miller, Lucas

    2012-10-16

    Dysfunction of the neurotrophin brain-derived neurotrophic factor (BDNF) is implicated in Rett syndrome (RTT), but the state of its releasable pool and downstream signaling in mice lacking methyl-CpG-binding protein-2 (Mecp2) is unknown. Here, we show that membrane currents and dendritic Ca(2+) signals evoked by recombinant BDNF or an activator of diacylglycerol (DAG)-sensitive transient receptor potential canonical (TRPC) channels are impaired in CA3 pyramidal neurons of symptomatic Mecp2 mutant mice. TRPC3 and TRPC6 mRNA and protein levels are lower in Mecp2 mutant hippocampus, and chromatin immunoprecipitation (ChIP) identified Trpc3 as a target of MeCP2 transcriptional regulation. BDNF mRNA and protein levels are also lower in Mecp2 mutant hippocampus and dentate gyrus granule cells, which is reflected in impaired activity-dependent release of endogenous BDNF estimated from TRPC currents and dendritic Ca(2+) signals in CA3 pyramidal neurons. These results identify the gene encoding TRPC3 channels as a MeCP2 target and suggest a potential therapeutic strategy to boost impaired BDNF signaling in RTT.

  10. Anodal transcranial direct current stimulation boosts synaptic plasticity and memory in mice via epigenetic regulation of Bdnf expression

    PubMed Central

    Podda, Maria Vittoria; Cocco, Sara; Mastrodonato, Alessia; Fusco, Salvatore; Leone, Lucia; Barbati, Saviana Antonella; Colussi, Claudia; Ripoli, Cristian; Grassi, Claudio

    2016-01-01

    The effects of transcranial direct current stimulation (tDCS) on brain functions and the underlying molecular mechanisms are yet largely unknown. Here we report that mice subjected to 20-min anodal tDCS exhibited one-week lasting increases in hippocampal LTP, learning and memory. These effects were associated with enhanced: i) acetylation of brain-derived neurotrophic factor (Bdnf) promoter I; ii) expression of Bdnf exons I and IX; iii) Bdnf protein levels. The hippocampi of stimulated mice also exhibited enhanced CREB phosphorylation, pCREB binding to Bdnf promoter I and recruitment of CBP on the same regulatory sequence. Inhibition of acetylation and blockade of TrkB receptors hindered tDCS effects at molecular, electrophysiological and behavioral levels. Collectively, our findings suggest that anodal tDCS increases hippocampal LTP and memory via chromatin remodeling of Bdnf regulatory sequences leading to increased expression of this gene, and support the therapeutic potential of tDCS for brain diseases associated with impaired neuroplasticity. PMID:26908001

  11. A biological function for the neuronal activity-dependent component of Bdnf transcription in the development of cortical inhibition.

    PubMed

    Hong, Elizabeth J; McCord, Alejandra E; Greenberg, Michael E

    2008-11-26

    Neuronal activity-regulated gene expression has been suggested to be an important mediator of long-lasting, experience-dependent changes in the nervous system, but the activity-dependent component of gene transcription has never been selectively isolated and tested for its functional significance. Here, we demonstrate that introduction of a subtle knockin mutation into the mouse Bdnf gene that blocks the ability of the activity-regulated factor CREB to bind Bdnf promoter IV results in an animal in which the sensory experience-dependent induction of Bdnf expression is disrupted in the cortex. Neurons from these animals form fewer inhibitory synapses, have fewer spontaneous inhibitory quantal events, and exhibit reduced expression of inhibitory presynaptic markers in the cortex. These results indicate a specific requirement for activity-dependent Bdnf expression in the development of inhibition in the cortex and demonstrate that the activation of gene expression in response to experience-driven neuronal activity has important biological consequences in the nervous system.

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

    PubMed

    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.

  13. Up-regulation of dorsal root ganglia BDNF and trkB receptor in inflammatory pain: an in vivo and in vitro study

    PubMed Central

    2011-01-01

    Background During inflammation, immune cells accumulate in damaged areas and release pro-inflammatory cytokines and neurotrophins. Brain-derived neurotrophic factor (BDNF) plays a neuromodulatory role in spinal cord dorsal horn via the post-synaptic tyrosine protein kinase B (trkB) receptor to facilitate pain transmission. However, the precise role of BDNF and trkB receptor in the primary sensory neurons of dorsal root ganglia (DRG) during inflammation remains to be clarified. The aim of this study was to investigate whether and how BDNF-trkB signaling in the DRG is involved in the process of inflammatory pain. Methods We used complete Freund's adjuvant- (CFA-) induced and tumor necrosis factor-α- (TNF-α-) induced inflammation in rat hindpaw as animal models of inflammatory pain. Quantification of protein and/or mRNA levels of pain mediators was performed in separate lumbar L3-L5 DRGs. The cellular mechanism of TNF-α-induced BDNF and/or trkB receptor expression was examined in primary DRG cultures collected from pooled L1-L6 DRGs. Calcitonin gene-related peptide (CGRP), BDNF and substance P release were also evaluated by enzyme immunoassay. Results CFA injection into rat hindpaw resulted in mechanical hyperalgesia and significant increases in levels of TNF-α in the inflamed tissues, along with enhancement of BDNF and trkB receptor as well as the pain mediators CGRP and transient receptor potential vanilloid receptor subtype 1 (TRPV1) in DRG. Direct injection of TNF-α into rat hindpaw resulted in similar effects with retrograde transport of TNF-α along the saphenous nerve to DRG during CFA-induced inflammation. Primary DRG cultures chronically treated with TNF-α showed significant enhancement of mRNA and protein levels of BDNF and trkB receptor, BDNF release and trkB-induced phospho-ERK1/2 signal. Moreover, CGRP and substance P release were enhanced in DRG cultures after chronic TNF-α treatment or acute BDNF stimulation. In addition, we found that BDNF up

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

    PubMed

    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

  15. The BDNF Val66Met Polymorphism Influences Reading Ability and Patterns of Neural Activation in Children

    PubMed Central

    Jasińska, Kaja K.; Molfese, Peter J.; Kornilov, Sergey A.; Mencl, W. Einar; Frost, Stephen J.; Lee, Maria; Pugh, Kenneth R.; Grigorenko, Elena L.; Landi, Nicole

    2016-01-01

    Understanding how genes impact the brain’s functional activation for learning and cognition during development remains limited. We asked whether a common genetic variant in the BDNF gene (the Val66Met polymorphism) modulates neural activation in the young brain during a critical period for the emergence and maturation of the neural circuitry for reading. In animal models, the bdnf variation has been shown to be associated with the structure and function of the developing brain and in humans it has been associated with multiple aspects of cognition, particularly memory, which are relevant for the development of skilled reading. Yet, little is known about the impact of the Val66Met polymorphism on functional brain activation in development, either in animal models or in humans. Here, we examined whether the BDNF Val66Met polymorphism (dbSNP rs6265) is associated with children’s (age 6–10) neural activation patterns during a reading task (n = 81) using functional magnetic resonance imaging (fMRI), genotyping, and standardized behavioral assessments of cognitive and reading development. Children homozygous for the Val allele at the SNP rs6265 of the BDNF gene outperformed Met allele carriers on reading comprehension and phonological memory, tasks that have a strong memory component. Consistent with these behavioral findings, Met allele carriers showed greater activation in reading–related brain regions including the fusiform gyrus, the left inferior frontal gyrus and left superior temporal gyrus as well as greater activation in the hippocampus during a word and pseudoword reading task. Increased engagement of memory and spoken language regions for Met allele carriers relative to Val/Val homozygotes during reading suggests that Met carriers have to exert greater effort required to retrieve phonological codes. PMID:27551971

  16. The BDNF Val66Met Polymorphism Influences Reading Ability and Patterns of Neural Activation in Children.

    PubMed

    Jasińska, Kaja K; Molfese, Peter J; Kornilov, Sergey A; Mencl, W Einar; Frost, Stephen J; Lee, Maria; Pugh, Kenneth R; Grigorenko, Elena L; Landi, Nicole

    2016-01-01

    Understanding how genes impact the brain's functional activation for learning and cognition during development remains limited. We asked whether a common genetic variant in the BDNF gene (the Val66Met polymorphism) modulates neural activation in the young brain during a critical period for the emergence and maturation of the neural circuitry for reading. In animal models, the bdnf variation has been shown to be associated with the structure and function of the developing brain and in humans it has been associated with multiple aspects of cognition, particularly memory, which are relevant for the development of skilled reading. Yet, little is known about the impact of the Val66Met polymorphism on functional brain activation in development, either in animal models or in humans. Here, we examined whether the BDNF Val66Met polymorphism (dbSNP rs6265) is associated with children's (age 6-10) neural activation patterns during a reading task (n = 81) using functional magnetic resonance imaging (fMRI), genotyping, and standardized behavioral assessments of cognitive and reading development. Children homozygous for the Val allele at the SNP rs6265 of the BDNF gene outperformed Met allele carriers on reading comprehension and phonological memory, tasks that have a strong memory component. Consistent with these behavioral findings, Met allele carriers showed greater activation in reading-related brain regions including the fusiform gyrus, the left inferior frontal gyrus and left superior temporal gyrus as well as greater activation in the hippocampus during a word and pseudoword reading task. Increased engagement of memory and spoken language regions for Met allele carriers relative to Val/Val homozygotes during reading suggests that Met carriers have to exert greater effort required to retrieve phonological codes.

  17. Rare Syndromes and Common Variants of the Brain-Derived Neurotrophic Factor Gene in Human Obesity.

    PubMed

    Han, J C

    2016-01-01

    Rare genetic disorders that cause BDNF haploinsufficiency, such as WAGR syndrome, 11p deletion, and 11p inversion, serve as models for understanding the role of BDNF in human energy balance and neurocognition. Patients with BDNF haploinsufficiency or inactivating mutations of the BDNF receptor exhibit hyperphagia, childhood-onset obesity, intellectual disability, and impaired nociception. Prader-Willi, Smith-Magenis, and ROHHAD syndromes are separate genetic disorders that do not directly affect the BDNF locus but share many similar clinical features with BDNF haploinsufficiency, and BDNF insufficiency is believed to possibly contribute to the pathophysiology of each of these conditions. In the general population, common variants of BDNF that affect BDNF gene expression or BDNF protein processing have also been associated with modest alterations in energy balance and cognitive functioning. Thus, variable degrees of BDNF insufficiency appear to contribute to a spectrum of excess weight gain and cognitive impairment that ranges in phenotypic severity. In this modern era of precision medicine, genotype-specific therapies aimed at increasing BDNF signaling in patients with rare and common disorders associated with BDNF insufficiency could serve as useful approaches for treating obesity and neurodevelopmental disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. The Combination of Long-term Ketamine and Extinction Training Contributes to Fear Erasure by Bdnf Methylation

    PubMed Central

    Ju, Ling-Sha; Yang, Jiao-Jiao; Lei, Lei; Xia, Jiang-Yan; Luo, Dan; Ji, Mu-Huo; Martynyuk, Anatoly E.; Yang, Jian-Jun

    2017-01-01

    A combination of antidepressant drugs and psychotherapy exhibits more promising efficacy in treating fear disorders than either treatment alone, but underlying mechanisms of such treatments remain largely unknown. Here we investigated the role of DNA methylation of the brain-derived neurotrophic factor (Bdnf) gene in the therapeutic effects of ketamine in combination with extinction training in a mouse model of post-traumatic stress disorder (PTSD) induced by inescapable electric foot shocks (IFS). Male mice received ketamine for 22 consecutive days starting 1 h after the IFS (long-term ketamine treatment) or 2 h prior to the extinction training on days 15 and 16 after the IFS (short-term ketamine treatment). The Open Field (OF) and Elevated Plus Maze (EPM) tests were conducted on days 18 and 20. The spontaneous recovery and fear renewal tests were performed on day 23. Mice, subjected to IFS, exhibited anxiety-like behavior and fear relapse, accompanied by the increased levels of DNA methyltransferases, hyper-methylation of Bdnf gene, and decreased BDNF mRNA expression in the medial prefrontal cortex (mPFC) and hippocampus (HIP). Long-term treatment with ketamine combined with extinction training alleviated the IFS-induced abnormalities. These results suggest that long-term ketamine treatment in combination with extinction training may ameliorate fear relapse in the murine model of PTSD, at least in part, by normalizing DNA methylation of Bdnf gene. PMID:28473755

  19. Hdac Activity is Required for Bdnf to Increase Quantal Neurotransmitter Release and Dendritic Spine Density in CA1 Pyramidal Neurons

    PubMed Central

    Calfa, Gaston; Chapleau, Christopher A.; Campbell, Susan; Inoue, Takafumi; Morse, Sarah J.; Lubin, Farah D.; Pozzo-Miller, Lucas

    2012-01-01

    Molecular mechanisms involved in the strengthening and formation of synapses include the activation and repression of specific genes or subsets of genes by epigenetic modifications that do not alter the genetic code itself. Chromatin modifications mediated by histone acetylation have been shown to be critical for synaptic plasticity at hippocampal excitatory synapses and hippocampal-dependent memory formation. Considering that brain-derived neurotrophic factor (BDNF) plays an important role in synaptic plasticity and behavioral adaptations, it is not surprising that regulation of this gene is subject to histone acetylation changes during synaptic plasticity and hippocampal-dependent memory formation. Whether the effects of BDNF on dendritic spines and quantal transmitter release require histone modifications remains less known. By using two different inhibitors of histone deacetylases (HDAC), we describe here that their activity is required for BDNF to increase dendritic spine density and excitatory quantal transmitter release onto CA1 pyramidal neurons in hippocampal slice cultures. These results suggest that histone acetylation/deacetylation is a critical step in the modulation of hippocampal synapses by BDNF. Thus, mechanisms of epigenetic modulation of synapse formation and function are novel targets to consider for the amelioration of symptoms of intellectual disabilities and neurodegenerative disorders associated with cognitive and memory deficits. PMID:22161912

  20. Effect of antidepressants on brain-derived neurotrophic factor (BDNF) release from platelets in the rats.

    PubMed

    Watanabe, Kimihiko; Hashimoto, Eri; Ukai, Wataru; Ishii, Takao; Yoshinaga, Toshihiro; Ono, Takafumi; Tateno, Masaru; Watanabe, Ippei; Shirasaka, Tomohiro; Saito, Satoshi; Saito, Toshikazu

    2010-12-01

    Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family, and enhances the growth and maintenance of several neuronal systems. In addition, BDNF may promote neurogenesis and protect against hippocampal volume loss in depressive disorders. Although first detected in brain, BDNF also exists in peripheral tissues and is mainly stored in platelets and circulates in blood. Recent reports indicate that serum BDNF levels in depressive patients are lower than in control subjects, and antidepressant treatment increases serum BDNF levels in responders. A single report suggests that decreased serum BDNF in major depression is related to mechanisms of platelet BDNF release; however, the mechanisms of changes in BDNF blood levels are still poorly understood. In the present study, we investigated the direct influence of antidepressants on BDNF release from platelets and their effects on serum levels. We used samples of washed platelets prepared from rat blood, and investigated the platelet BDNF release and serum BDNF concentration changes in response to adding antidepressants. We found that BDNF was dose-dependently released from platelets by direct treatment with various kinds of antidepressants in vitro, and serum BDNF concentration was also increased by intravenous antidepressant treatment. These results confirm that BDNF release from platelets is affected by antidepressants, which may relate to the circulating BDNF level change in peripheral blood. The response of BDNF release differs depending on the type and amount of antidepressants, making BDNF a serious candidate as a predictor of antidepressant treatment response. Copyright © 2010 Elsevier Inc. All rights reserved.

  1. The BDNF Val(66)Met polymorphism is associated with escitalopram response in depressed patients.

    PubMed

    El-Hage, Wissam; Vourc'h, Patrick; Gaillard, Philippe; Léger, Julie; Belzung, Catherine; Ibarguen-Vargas, Yadira; Andres, Christian R; Camus, Vincent

    2015-02-01

    The brain-derived neurotrophic factor (BDNF) gene is a candidate gene in therapeutic responses to antidepressants. The aim of the study was to determine the effects of BDNF allelic variability on responses to escitalopram treatment at 3 weeks after treatment initiation and at a 6-week endpoint. We included 187 Caucasian subjects with depression; 153 completed the 6-week study. Clinical evaluation was performed using the Montgomery and Asberg Depression Rating Scale (MADRS) before and after 3-6 weeks of treatment. After 3 weeks of treatment, we saw significantly better treatment responses in the Met carriers and greater antidepressant resistance among the Val/Val homozygotes. Relative to Val/Val homozygous (59.78 %), a significantly greater proportion of subjects Met-carriers (77.94 %) responded to escitalopram treatment (χ (2) = 5.88, p = 0.015). After 6 weeks, we found the same pattern of results but this effect did not reach statistical significance (χ (2) = 2.07, p = 0.15). These findings highlight a significant association between the BDNF valine to methionine substitution (Val(66)Met) polymorphism and the treatment response to escitalopram in a Caucasian population of severely depressed inpatients.

  2. The Association Between Peer and own Aggression is Moderated by the BDNF Val-met Polymorphism.

    PubMed

    Kretschmer, Tina; Vitaro, Frank; Barker, Edward D

    2014-03-01

    Peer antisocial behavior robustly predicts adolescents' own behavior but not all adolescents are equally vulnerable to their peers' influence and genetic factors may confer vulnerability. This study used data of n = 3081 adolescents from the Avon Longitudinal Study of Parents and Children (ALSPAC) to examine whether BDNF, a polymorphism that affects psychological functioning, moderates the association between affiliation with aggressive peers at age 10 and own aggression at age 15. A significant gene-environment interaction was found, where those who affiliated with aggressive peers in childhood showed increased risk for being aggressive in adolescence if they carried the BDNF met-met variant compared to val-val carriers. Our findings underline the importance of both biological and social factors for adolescent development.

  3. The Association Between Peer and own Aggression is Moderated by the BDNF Val-met Polymorphism

    PubMed Central

    Kretschmer, Tina; Vitaro, Frank; Barker, Edward D.

    2013-01-01

    Peer antisocial behavior robustly predicts adolescents’ own behavior but not all adolescents are equally vulnerable to their peers’ influence and genetic factors may confer vulnerability. This study used data of n = 3081 adolescents from the Avon Longitudinal Study of Parents and Children (ALSPAC) to examine whether BDNF, a polymorphism that affects psychological functioning, moderates the association between affiliation with aggressive peers at age 10 and own aggression at age 15. A significant gene-environment interaction was found, where those who affiliated with aggressive peers in childhood showed increased risk for being aggressive in adolescence if they carried the BDNF met-met variant compared to val-val carriers. Our findings underline the importance of both biological and social factors for adolescent development. PMID:25061266

  4. The function of BDNF in the adult auditory system.

    PubMed

    Singer, Wibke; Panford-Walsh, Rama; Knipper, Marlies

    2014-01-01

    The inner ear of vertebrates is specialized to perceive sound, gravity and movements. Each of the specialized sensory organs within the cochlea (sound) and vestibular system (gravity, head movements) transmits information to specific areas of the brain. During development, brain-derived neurotrophic factor (BDNF) orchestrates the survival and outgrowth of afferent fibers connecting the vestibular organ and those regions in the cochlea that map information for low frequency sound to central auditory nuclei and higher-auditory centers. The role of BDNF in the mature inner ear is less understood. This is mainly due to the fact that constitutive BDNF mutant mice are postnatally lethal. Only in the last few years has the improved technology of performing conditional cell specific deletion of BDNF in vivo allowed the study of the function of BDNF in the mature developed organ. This review provides an overview of the current knowledge of the expression pattern and function of BDNF in the peripheral and central auditory system from just prior to the first auditory experience onwards. A special focus will be put on the differential mechanisms in which BDNF drives refinement of auditory circuitries during the onset of sensory experience and in the adult brain. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'.

  5. Plasma BDNF levels following weight recovery in anorexia nervosa.

    PubMed

    Phillips, Kathryn E; Jimerson, David C; Pillai, Anilkumar; Wolfe, Barbara E

    2016-10-15

    Preclinical studies have implicated brain-derived neurotrophic factor (BDNF) in the regulation of eating behavior and body weight. As reviewed in this report, prior studies of BDNF levels in anorexia nervosa have yielded variable results, perhaps reflecting effects of malnutrition and psychiatric comorbidity. The goal of the current report was to assess plasma BDNF as a biomarker in weight-recovered individuals with a history of anorexia nervosa (ANWR). Study groups included women meeting criteria for ANWR and healthy female controls. Participants were in a normal weight range, free of current major psychiatric disorder, and free of medication. Self-ratings included eating disorder symptoms, depression and anxiety. Plasma BDNF levels were measured by enzyme linked immunoassay. Plasma BDNF levels were not significantly different for ANWR and control groups. Plasma BDNF levels were inversely correlated with anxiety ratings in controls (p<0.02) but not in the ANWR group. This report provides new evidence that circulating BDNF concentrations do not differ in healthy controls and ANWR free of psychiatric comorbidity. Additionally, the data provide new information on the relationship between plasma BDNF and anxiety in these two study groups. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Glioactive ATP controls BDNF recycling in cortical astrocytes

    PubMed Central

    Vignoli, Beatrice; Canossa, Marco

    2017-01-01

    ABSTRACT We have recently reported that long-term memory retention requires synaptic glia for proBDNF uptake and recycling. Through the recycling course, glial cells release endocytic BDNF, a mechanism that is activated in response to glutamate via AMPA and mGluRI/II receptors. Cortical astrocytes express receptors for many different transmitters suggesting for a complex signaling controlling endocytic BDNF secretion. Here, we demonstrated that the extracellular nucleotide ATP, activating P2X and P2Y receptors, regulates endocytic BDNF secretion in cultured astrocytes. Our data indicate that distinct glioactive molecules can participate in BDNF glial recycling and suggest that cortical astrocytes contributing to neuronal plasticity can be influenced by neurotransmitters in tune with synaptic needs. PMID:28289489

  7. BDNF Met66 modulates the cumulative effect of psychosocial childhood adversities on major depression in adolescents

    PubMed Central

    Cruz-Fuentes, Carlos S; Benjet, Corina; Martínez-Levy, Gabriela A; Pérez-Molina, Amado; Briones-Velasco, Magdalena; Suárez-González, Jesús

    2014-01-01

    Background The interplay among lifetime adversities and the genetic background has been previously examined on a variety of measures of depression; however, only few studies have focused on major depression disorder (MDD) in adolescence. Methods Using clinical data and DNA samples from mouthwash gathered from an epidemiological study on the prevalence of mental disorders in youths between 12 and 17 years old, we tested the statistical interaction between a set of psychosocial adversities experienced during childhood (CAs) with two common polymorphisms in the brain-derived neurotrophic factor (BDNF) (Val66Met) and SLC6A4 (L/S) genes on the probability of suffering MDD in adolescence. Results Genotype or allele frequencies for both polymorphisms were similar between groups of comparison (MDD N = 246; controls N = 270). The CAs factors: Abuse, neglect, and family dysfunctions; parental maladjustment, parental death, and to have experienced a life-threatening physical illness were predictors of clinical depression in adolescents. Remarkably, the cumulative number of psychosocial adversities was distinctly associated with an increase in the prevalence of depression but only in those Val/Val BDNF individuals; while the possession of at least a copy of the BDNF Met allele (i.e., Met +) was statistically linked with a “refractory” or resilient phenotype to the noticeable influence of CAs. Conclusion Liability or resilience to develop MDD in adolescence is dependent of a complex interplay between particular environmental exposures and a set of plasticity genes including BDNF. A better understanding of these factors is important for developing better prevention and early intervention measures. PMID:24683520

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

    PubMed

    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.

  9. TrkB/BDNF-Dependent Striatal Plasticity and Behavior in a Genetic Model of Epilepsy: Modulation by Valproic Acid

    PubMed Central

    Ghiglieri, Veronica; Sgobio, Carmelo; Patassini, Stefano; Bagetta, Vincenza; Fejtova, Anna; Giampà, Carmela; Marinucci, Silvia; Heyden, Alexandra; Gundelfinger, Eckart D; Fusco, Francesca R; Calabresi, Paolo; Picconi, Barbara

    2010-01-01

    In mice lacking the central domain of the presynaptic scaffold Bassoon the occurrence of repeated cortical seizures induces cell-type-specific plasticity changes resulting in a general enhancement of the feedforward inhibition within the striatal microcircuit. Early antiepileptic treatment with valproic acid (VPA) reduces epileptic attacks, inhibits the emergence of pathological form of plasticity in fast-spiking (FS) interneurons and restores physiological striatal synaptic plasticity in medium spiny (MS) neurons. Brain-derived neurotrophic factor (BDNF) is a key factor for the induction and maintenance of synaptic plasticity and it is also implicated in the mechanisms underlying epilepsy-induced adaptive changes. In this study, we explore the possibility that the TrkB/BDNF system is involved in the striatal modifications associated with the Bassoon gene (Bsn) mutation. In epileptic mice abnormal striatum-dependent learning was paralleled by higher TrkB levels and an altered distribution of BDNF. Accordingly, subchronic intrastriatal administration of k252a, an inhibitor of TrkB receptor tyrosine kinase activity, reversed behavioral alterations in Bsn mutant mice. In addition, in vitro manipulations of the TrkB/BDNF complex by k252a, prevented the emergence of pathological plasticity in FS interneurons. Chronic treatment with VPA, by reducing seizures, was able to rebalance TrkB to control levels favoring a physiological redistribution of BDNF between MS neurons and FS interneurons with a concomitant recovery of striatal plasticity. Our results provide the first indication that BDNF is involved in determining the striatal alterations occurring in the early-onset epileptic syndrome associated with the absence of presynaptic protein Bassoon. PMID:20200504

  10. TrkB/BDNF-dependent striatal plasticity and behavior in a genetic model of epilepsy: modulation by valproic acid.

    PubMed

    Ghiglieri, Veronica; Sgobio, Carmelo; Patassini, Stefano; Bagetta, Vincenza; Fejtova, Anna; Giampà, Carmela; Marinucci, Silvia; Heyden, Alexandra; Gundelfinger, Eckart D; Fusco, Francesca R; Calabresi, Paolo; Picconi, Barbara

    2010-06-01

    In mice lacking the central domain of the presynaptic scaffold Bassoon the occurrence of repeated cortical seizures induces cell-type-specific plasticity changes resulting in a general enhancement of the feedforward inhibition within the striatal microcircuit. Early antiepileptic treatment with valproic acid (VPA) reduces epileptic attacks, inhibits the emergence of pathological form of plasticity in fast-spiking (FS) interneurons and restores physiological striatal synaptic plasticity in medium spiny (MS) neurons. Brain-derived neurotrophic factor (BDNF) is a key factor for the induction and maintenance of synaptic plasticity and it is also implicated in the mechanisms underlying epilepsy-induced adaptive changes. In this study, we explore the possibility that the TrkB/BDNF system is involved in the striatal modifications associated with the Bassoon gene (Bsn) mutation. In epileptic mice abnormal striatum-dependent learning was paralleled by higher TrkB levels and an altered distribution of BDNF. Accordingly, subchronic intrastriatal administration of k252a, an inhibitor of TrkB receptor tyrosine kinase activity, reversed behavioral alterations in Bsn mutant mice. In addition, in vitro manipulations of the TrkB/BDNF complex by k252a, prevented the emergence of pathological plasticity in FS interneurons. Chronic treatment with VPA, by reducing seizures, was able to rebalance TrkB to control levels favoring a physiological redistribution of BDNF between MS neurons and FS interneurons with a concomitant recovery of striatal plasticity. Our results provide the first indication that BDNF is involved in determining the striatal alterations occurring in the early-onset epileptic syndrome associated with the absence of presynaptic protein Bassoon.

  11. BDNF Val66Met polymorphism significantly affects d' in verbal recognition memory at short and long delays.

    PubMed

    Goldberg, Terry E; Iudicello, Jennifer; Russo, Christine; Elvevåg, Brita; Straub, Richard; Egan, Michael F; Weinberger, Daniel R

    2008-01-01

    A functional polymorphism at the val66met locus in the BDNF gene has significant effects on the pro-form of the protein in intracellular trafficking and activity-dependent, but not constitutive, secretion. These differences are thought to underlie several findings in humans related to this polymorphism, including markers of neuronal viability, BOLD activation in medial temporal lobe regions, and some aspects of behavior. However, many important questions remain about the impact of BDNF on various mnemonic subprocesses at the behavioral level. In this study, we examined the impact of the val/met polymorphism in a verbal recognition memory paradigm involving manipulation of depth of encoding and differential delays for recall and analyses of hits for previously presented target words and correct rejections of foils. Twenty-four human val homozygous individuals and 24 met carrier individuals comprised the sample. All were healthy controls. IQ between the groups was equivalent. In the encoding phase of the study, words were presented and encoded either by a decision as to whether they were living or nonliving ("deep") or if they contained the letter "A" (shallow). After this phase, recognition was tested immediately, half an hour, and 24h later. BDNF genotype had significant effects on hits and discriminability (d'), accounting for at least 10% of the variance, but not on correct rejections or beta. BDNF did not interact with level of encoding, nor did it interact with delay. In sum, BDNF genotypes impacted "hits" in a recognition memory paradigm, findings consistent with the general notion that BDNF plays a prominent role in memory subprocesses thought to engage the medial temporal lobe.

  12. Selective DNA methylation of BDNF promoter in bipolar disorder: differences among patients with BDI and BDII.

    PubMed

    D'Addario, Claudio; Dell'Osso, Bernardo; Palazzo, Maria Carlotta; Benatti, Beatrice; Lietti, Licia; Cattaneo, Elisabetta; Galimberti, Daniela; Fenoglio, Chiara; Cortini, Francesca; Scarpini, Elio; Arosio, Beatrice; Di Francesco, Andrea; Di Benedetto, Manuela; Romualdi, Patrizia; Candeletti, Sanzio; Mari, Daniela; Bergamaschini, Luigi; Bresolin, Nereo; Maccarrone, Mauro; Altamura, A Carlo

    2012-06-01

    The etiology of bipolar disorder (BD) is still poorly understood, involving genetic and epigenetic mechanisms as well as environmental contributions. This study aimed to investigate the degree of DNA methylation at the promoter region of the brain-derived neurotrophic factor (BDNF) gene, as one of the candidate genes associated with major psychoses, in peripheral blood mononuclear cells isolated from 94 patients with BD (BD I=49, BD II=45) and 52 healthy controls. A significant BDNF gene expression downregulation was observed in BD II 0.53±0.11%; P<0.05), but not in BD I (1.13±0.19%) patients compared with controls (CONT: 1±0.2%). Consistently, an hypermethylation of the BDNF promoter region was specifically found in BD II patients (CONT: 24.0±2.1%; BDI: 20.4±1.7%; BDII: 33.3±3.5%, P<0.05). Of note, higher levels of DNA methylation were observed in BD subjects on pharmacological treatment with mood stabilizers plus antidepressants (34.6±4.2%, predominantly BD II) compared with those exclusively on mood-stabilizing agents (21.7±1.8%; P<0.01, predominantly BD I). Moreover, among the different pharmacological therapies, lithium (20.1±3.8%, P<0.05) and valproate (23.6±2.9%, P<0.05) were associated with a significant reduction of DNA methylation compared with other drugs (35.6±4.6%). Present findings suggest selective changes in DNA methylation of BDNF promoter in subjects with BD type II and highlight the importance of epigenetic factors in mediating the onset and/or susceptibility to BD, providing new insight into the mechanisms of gene expression. Moreover, they shed light on possible mechanisms of action of mood-stabilizing compounds vs antidepressants in the treatment of BD, pointing out that BDNF regulation might be a key target for their effects.

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

    PubMed

    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.

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

    PubMed Central

    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

    2015-01-01

    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 p75NTR. 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. PMID:26015580

  15. Age-dependent deficits in fear learning in heterozygous BDNF knock-out mice.

    PubMed

    Endres, Thomas; Lessmann, Volkmar

    2012-11-15

    Beyond its trophic function, the neurotrophin BDNF (brain-derived neurotrophic factor) is well known to crucially mediate synaptic plasticity and memory formation. Whereas recent studies suggested that acute BDNF/TrkB signaling regulates amygdala-dependent fear learning, no impairments of cued fear learning were reported in heterozygous BDNF knock-out mice (BDNF(+/-)). Since brain BDNF levels are known to decline with aging, we hypothesized that BDNF(+/-) mice might show reduced fear learning at older ages. Indeed, BDNF(+/-) animals revealed an age-dependent deficit in fear learning 3 mo after birth and beyond. Since there were no alterations between the two genotypes during the conditioning training and when testing short-term memory, this learning deficit most likely reflects a deficit in memory consolidation. Importantly, there were no differences in spontaneous motor behavior and baseline anxiety in BDNF(+/-) animals at any age tested. Following behavioral testing quantification of BDNF levels in the basolateral amygdala with a sensitive BDNF ELISA revealed a positive correlation between the levels of BDNF in the amygdala and the individual learning performance. However, the age-dependent decline in the efficiency of fear conditioning in BDNF(+/-) mice was not accompanied by reduced BDNF expression in the amygdala. Thus, while reduced BDNF levels in general correlate with less efficient fear learning, this lack of BDNF can be compensated in young but not in older animals, suggesting that the cellular mechanisms responsible for fear learning consolidation become BDNF-dependent 3 mo after birth.

  16. Working Memory Deficits, Increased Anxiety-Like Traits, and Seizure Susceptibility in BDNF Overexpressing Mice

    ERIC Educational Resources Information Center

    Papaleo, Francesco; Silverman, Jill L.; Aney, Jordan; Tian, Qingjun; Barkan, Charlotte L.; Chadman, Kathryn K.; Crawley, Jacqueline N.

    2011-01-01

    BDNF regulates components of cognitive processes and has been implicated in psychiatric disorders. Here we report that genetic overexpression of the BDNF mature isoform (BDNF-tg) in female mice impaired working memory functions while sparing components of fear conditioning. BDNF-tg mice also displayed reduced breeding efficiency, higher…

  17. Working Memory Deficits, Increased Anxiety-Like Traits, and Seizure Susceptibility in BDNF Overexpressing Mice

    ERIC Educational Resources Information Center

    Papaleo, Francesco; Silverman, Jill L.; Aney, Jordan; Tian, Qingjun; Barkan, Charlotte L.; Chadman, Kathryn K.; Crawley, Jacqueline N.

    2011-01-01

    BDNF regulates components of cognitive processes and has been implicated in psychiatric disorders. Here we report that genetic overexpression of the BDNF mature isoform (BDNF-tg) in female mice impaired working memory functions while sparing components of fear conditioning. BDNF-tg mice also displayed reduced breeding efficiency, higher…

  18. Acute Administration of Branched-Chain Amino Acids Increases the Pro-BDNF/Total-BDNF Ratio in the Rat Brain.

    PubMed

    Scaini, Giselli; Morais, Meline O S; Furlanetto, Camila B; Kist, Luiza W; Pereira, Talita C B; Schuck, Patrícia F; Ferreira, Gustavo C; Pasquali, Matheus A B; Gelain, Daniel P; Moreira, José Cláudio F; Bogo, Maurício R; Streck, Emilio L

    2015-05-01

    Maple syrup urine disease (MSUD) is caused by an inborn error in metabolism resulting from a deficiency in the branched-chain α-keto acid dehydrogenase complex activity. This blockage leads to accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine and valine, as well as their corresponding α-keto acids and α-hydroxy acids. High levels of BCAAs are associated with neurological dysfunction and the role of pro- and mature brain-derived neurotrophic factor (BDNF) in the neurological dysfunction of MSUD is still unclear. Thus, in the present study we investigated the effect of an acute BCAA pool administration on BDNF levels and on the pro-BDNF cleavage-related proteins S100A10 and tissue plasminogen activator (tPA) in rat brains. Our results demonstrated that acute Hyper-BCAA (H-BCAA) exposure during the early postnatal period increases pro-BDNF and total-BDNF levels in the hippocampus and striatum. Moreover, tPA levels were significantly decreased, without modifications in the tPA transcript levels in the hippocampus and striatum. On the other hand, the S100A10 mRNA and S100A10 protein levels were not changed in the hippocampus and striatum. In the 30-day-old rats, we observed increased pro-BDNF, total-BDNF and tPA levels only in the striatum, whereas the tPA and S100A10 mRNA expression and the immunocontent of S100A10 were not altered. In conclusion, we demonstrated that acute H-BCAA administration increases the pro-BDNF/total-BDNF ratio and decreases the tPA levels in animals, suggesting that the BCAA effect may depend, at least in part, on changes in BDNF post-translational processing.

  19. Ratio of mBDNF to proBDNF for Differential Diagnosis of Major Depressive Disorder and Bipolar Depression.

    PubMed

    Zhao, Guoqing; Zhang, Chen; Chen, Jun; Su, Yousong; Zhou, Rubai; Wang, Fan; Xia, Weiping; Huang, Jia; Wang, Zuowei; Hu, Yingyan; Cao, Lan; Guo, Xiaoyun; Yuan, Chengmei; Wang, Yong; Yi, Zhenghui; Lu, Weihong; Wu, Yan; Wu, Zhiguo; Hong, Wu; Peng, Daihui; Fang, Yiru

    2017-09-01

    There is a high rate of misdiagnosis between major depressive disorder (MDD) and bipolar disorder (BD) in clinical practice. Our previous work provided suggestive evidence for brain-derived neurotrophic factor (BDNF) in differentiating BD from MDD. In this study, we aimed to investigate the role of mature BDNF (mBDNF) and its precursor (proBDNF) in distinguishing bipolar depression (BP) from MDD during acute depressive episode. A total of 105 participants, including 44 healthy controls, 37 MDD patients and 24 BP patients, were recruited. Enzyme-linked immunosorbent assay kits were applied to measure plasma mBDNF levels and proBDNF levels of all participants. Plasma mBDNF levels were significantly decreased in BP group than those in MDD group (P = 0.001) and healthy controls (P = 0.002). Significantly higher ratio of mBDNF to proBDNF (M/P) at baseline was showed in MDD group than those in BP group as well as in healthy controls (P = 0.000 and P = 0.000, respectively). The optimal model for discriminating BP was the M/P ratio (area under the ROC curve = 0.858, 95 % CI 0.753-0.963). Furthermore, the M/P ratio was restored to normal levels after antidepressants treatment in MDD group. In summary, our data demonstrated that both plasma mBDNF levels and M/P ratio were lower in BP compared with MDD. These findings further support M/P ratio as a potential differential diagnostic biomarker for BP among patients in depressive episodes.

  20. The risk for major depression conferred by childhood maltreatment is multiplied by BDNF and SERT genetic vulnerability: a replication study

    PubMed Central

    Gutiérrez, Blanca; Bellón, Juan Ángel; Rivera, Margarita; Molina, Esther; King, Michael; Marston, Louise; Torres-González, Francisco; Moreno-Küstner, Berta; Moreno-Peral, Patricia; Motrico, Emma; Montón-Franco, Carmen; GildeGómez-Barragán, María Josefa; Sánchez-Celaya, Marta; Díaz-Barreiros, Miguel Ángel; Vicens, Catalina; de Dios Luna, Juan; Nazareth, Irwin; Cervilla, Jorge

    2015-01-01

    Background There is limited evidence for a moderating role of both serotonin transporter (SERT) and brain-derived neurotrophic factor (BDNF) genes on the risk for major depression (MD) developing after childhood maltreatment. However, research on this topic remains inconclusive, and there is a lack of data from longitudinal studies with large and representative population samples. Our study aimed to clarify whether, in the presence of previous childhood maltreatment, individuals carrying low functional alleles for both SERT 5-HTTLPR and BDNF Val66Met polymorphisms had a higher risk for MD. Methods We explored 2- and 3-way gene (SERT and BDNF) × environment (childhood maltreatment) interactions in a large sample of Spanish adults who were followed up over a 3-year period and assessed in person for both DSM-IV MD and exposure to childhood maltreatment. Results Our study included 2679 participants. Those with both the 5-HTTLPR s allele and the BDNF Met allele showed the highest risk of MD if they had previously experienced emotional (z = 2.08, p = 0.037), sexual (z = 2.19, p = 0.029) or any kind of childhood abuse (z = 2.37, p = 0.018). These 3-way interactions remained significant regardless of whether the 5-HTTLPR triallelic or the 5-HTTLPR biallelic polymorphisms were included in the analyses. Limitations Retrospective assessment of childhood maltreatment may have resulted in a moderate degree of recall bias. Conclusion Our results confirm that the risk of depression conferred by childhood maltreatment is modified by variation at both SERT and BDNF genes. PMID:25510949

  1. The risk for major depression conferred by childhood maltreatment is multiplied by BDNF and SERT genetic vulnerability: a replication study.

    PubMed

    Gutiérrez, Blanca; Bellón, Juan Á; Rivera, Margarita; Molina, Esther; King, Michael; Marston, Louise; Torres-González, Francisco; Moreno-Küstner, Berta; Moreno-Peral, Patricia; Motrico, Emma; Montón-Franco, Carmen; GildeGómez-Barragán, María J; Sánchez-Celaya, Marta; Díaz-Barreiros, Miguel Á; Vicens, Catalina; de Dios Luna, Juan; Nazareth, Irwin; Cervilla, Jorge

    2015-05-01

    There is limited evidence for a moderating role of both serotonin transporter (SERT) and brain-derived neurotrophic factor (BDNF) genes on the risk for major depression (MD) developing after childhood maltreatment. However, research on this topic remains inconclusive, and there is a lack of data from longitudinal studies with large and representative population samples. Our study aimed to clarify whether, in the presence of previous childhood maltreatment, individuals carrying low functional alleles for both SERT 5-HTTLPR and BDNF Val66Met polymorphisms had a higher risk for MD. We explored 2- and 3-way gene (SERT and BDNF) × environment (childhood maltreatment) interactions in a large sample of Spanish adults who were followed up over a 3-year period and assessed in person for both DSM-IV MD and exposure to childhood maltreatment. Our study included 2679 participants. Those with both the 5-HTTLPR s allele and the BDNF Met allele showed the highest risk of MD if they had previously experienced emotional (z = 2.08, p = 0.037), sexual (z = 2.19, p = 0.029) or any kind of childhood abuse (z = 2.37, p = 0.018). These 3-way interactions remained significant regardless of whether the 5-HTTLPR triallelic or the 5-HTTLPR biallelic polymorphisms were included in the analyses. Retrospective assessment of childhood maltreatment may have resulted in a moderate degree of recall bias. Our results confirm that the risk of depression conferred by childhood maltreatment is modified by variation at both SERT and BDNF genes.

  2. New insights in the biology of BDNF synthesis and release: implications in CNS function.

    PubMed

    Greenberg, Michael E; Xu, Baoji; Lu, Bai; Hempstead, Barbara L

    2009-10-14

    BDNF has pleiotropic effects on neuronal development and synaptic plasticity that underlie circuit formation and cognitive function. Recent breakthroughs reveal that neuronal activity regulates BDNF cell biology, including Bdnf transcription, dendritic targeting and trafficking of BDNF mRNA and protein, and secretion and extracellular conversion of proBDNF to mature BDNF. Defects in these mechanisms contribute differentially to cognitive dysfunction and anxiety-like behaviors. Here we review recent studies, presented at a symposium at Neuroscience 2009, that describe regulatory mechanisms that permit rapid and dynamic refinement of BDNF actions in neurons.

  3. BDNF, produced by a TPO-stimulated megakaryocytic cell line, regulates autocrine proliferation

    SciTech Connect

    Tamura, Shogo; Nagasawa, Ayumi; Masuda, Yuya; Tsunematsu, Tetsuya; Hayasaka, Koji; Matsuno, Kazuhiko; Shimizu, Chikara; Ozaki, Yukio; Moriyama, Takanori

    2012-10-26

    Highlights: Black-Right-Pointing-Pointer It has been thought that BDNF is not produced in the megakaryocytic lineage. Black-Right-Pointing-Pointer MEG-01 produces BDNF upon TPO stimulation and regulates its proliferation. Black-Right-Pointing-Pointer BDNF accelerates proliferation of MEG-01 in an autocrine manner. Black-Right-Pointing-Pointer BDNF may be an autocrine MEG-CSF, which regulates megakaryopoiesis. -- Abstract: While human platelets release endogenous brain-derived neurotrophic factor (BDNF) upon activation, a previous report on MEG-01, a megakaryocytic cell line, found no trace of BDNF production, and the pathophysiological function of platelet BDNF has remained elusive. In the present study, we demonstrate that MEG-01 produces BDNF in the presence of TPO and that this serves to potentiate cell proliferation. Our in vitro findings suggest that BDNF regulates MEG-01 proliferation in an autocrine manner, and we suggest that BDNF may be a physiological autocrine regulator of megakaryocyte progenitors.

  4. A common variant near BDNF is associated with dietary calcium intake in adolescents.

    PubMed

    Dušátková, Lenka; Zamrazilová, Hana; Aldhoon-Hainerová, Irena; Sedláčková, Barbora; Včelák, Josef; Hlavatý, Petr; Bendlová, Běla; Kunešová, Marie; Hainer, Vojtěch

    2015-09-01

    Specific targets for most obesity candidate genes discovered by genomewide association studies remain unknown. Such genes are often highly expressed in the hypothalamus, indicating their role in energy homeostasis. We aimed to evaluate the associations of selected gene variants with adiposity and dietary traits. Anthropometric parameters, fat mass, dietary intake (total energy, fat, protein, carbohydrate, fiber, and calcium) and 10 gene variants (in/near TMEM18, SH2B1, KCTD15, PCSK1, BDNF, SEC16B, MC4R and FTO) were analyzed in 1953 Czech individuals aged 10.0 to 18.0 years (1035 nonoverweight and 918 overweight: body mass index [BMI] ≥90th percentile). Obesity risk alleles of TMEM18 rs7561317, SEC16B rs10913469, and FTO rs9939609 were related to increased body weight and BMI (P < .005). The FTO variant also showed a significant positive association with waist circumference and fat mass (P < .001). Overweight adolescents had a lower total energy intake (P < .001) but a higher percentage of fat (P = .009) and protein intake (P < .001) than the nonoverweight subjects. There was also a lower calcium intake in the overweight group (P < .001). An association with at least one component of dietary intake was found in 3 of 10 studied gene variants. The MC4R rs17782313 was associated negatively with protein (P = .012) and positively associated with fiber (P = .032) intakes. The obesity risk alleles of BDNF rs925946 and FTO rs9939609 were related to a lower calcium intake (P = .001 and .037). The effects of FTO and MC4R variants, however, disappeared after corrections for multiple testing. Our results suggest that the common BDNF variant may influence dietary calcium intake independent of BMI.

  5. BDNF Val(66)Met polymorphism tunes frontolimbic circuitry during affective contextual learning.

    PubMed

    Jabbi, Mbemba; Cropp, Brett; Nash, Tiffany; Kohn, Philip; Kippenhan, J Shane; Masdeu, Joseph C; Mattay, Raghav; Kolachana, Bhaskar; Berman, Karen F

    2017-08-31

    Adaptive learning impairments are common in cognitive and behavioral disorders, but the neurogenetic mechanisms supporting human affective learning are poorly understood. We designed a higher-order contextual learning task in which healthy participants genotyped for the Val(66)Met polymorphism of the brain derived neurotropic factor gene (BDNF) were required to choose the member of a picture pair most congruent with the emotion in a previously-viewed facial expression video in order to produce an advantageous monetary outcome. Functional magnetic resonance imaging (fMRI) identified frontolimbic blood oxygenation level dependent (BOLD) reactivity that was associated with BDNF Val(66)Met genotype during all three phases of the learning task: aversive and reward-predictive learning, contextually-challenging decision-making, and choice-related monetary loss-avoidance and gain outcomes. Relative to Val homozygotes, Met carriers showed attenuated ventromedial prefrontal response to predictive affective cues, dorsolateral prefrontal signaling that depended on decision difficulty, and enhanced ventromedial prefrontal reactivity that was specific to loss-avoidance. These findings indicate that the BDNF Val(66)Met polymorphism is associated with functional tuning of behaviorally-relevant frontolimbic circuitry, particularly involving the ventromedial prefrontal cortex, during higher-order learning. Copyright © 2017. Published by Elsevier Inc.

  6. BDNF Polymorphism–Dependent OFC and DLPFC Plasticity Differentially Moderates Implicit and Explicit Bias

    PubMed Central

    Poore, Joshua C.; Barbey, Aron K.; Krueger, Frank; Solomon, Jeffrey; Lipsky, Robert H.; Hodgkinson, Colin A.; Goldman, David; Grafman, Jordan

    2012-01-01

    This study examined the role of orbitofrontal cortex (OFC) and dorsolateral prefrontal cortex (DLPFC) plasticity in controlling implicit and explicit social biases. Normal controls and patients with varied OFC and DLPFC lesion size and single nucleotide polymorphisms (SNPs) in the brain-derived neurotrophic factor (BDNF) gene, which promotes (methionine–valine [Met/Val] SNP) or stifles (valine–valine [Val/Val] SNP) plasticity in damaged PFC regions, completed measures of implicit and explicit social bias. Patients and controls demonstrated comparable levels of implicit bias, but patients with Met/Val SNPs exhibited less implicit bias when they had smaller OFC lesions compared with Val/Val patients with similar size lesions and those with large OFC lesions. Both patients and controls demonstrated patterns of explicit bias consistent with hypotheses. Patients with Met/Val SNPs exhibited less explicit bias when they had smaller DLPFC lesions sizes compared with Val/Val patients with similar size lesions and those with large DLPFC lesions. OFC lesion size and BDNF SNP type did not moderate explicit bias; DLPFC lesion size and BDNF SNP type did not moderate implicit bias (nor did other medial or lateral regions). Findings suggest that plasticity within specific PFC regions modulates the type and degree of social bias that individuals’ exhibit. PMID:22123938

  7. Decreased Plasma BDNF Levels of Patients with Somatization Disorder

    PubMed Central

    Kang, Nam-In; Park, Jong-Il

    2016-01-01

    Objective Brain-derived neurotrophic factor (BDNF), one of the most abundant and important neurotrophins, is known to be involved in the development, survival, maintenance, and plasticity of neurons in the nervous system. Some studies have suggested that BDNF may play a role in the pathophysiology of several psychiatric illnesses such as depression and schizophrenia. Similarly, it is likely that the alteration of BDNF may be associated with the neuro-modulation that contributes to the development of somatization disorder. Methods The purpose of this study was to determine whether there is an abnormality of plasma BDNF levels in patients with somatization disorder, and to analyze the nature of the alteration after pharmacotherapy using an enzyme-linked immunosorbent assay (ELISA). Results The plasma BDNF levels of the patients with a somatization disorder were significantly lower compared with those of the control volunteers (83.61±89.97 pg/mL vs. 771.36±562.14 pg/mL); moreover, the plasma BDNF levels of those patients who received an antidepressant were significantly increased after the treatment (118.13±91.45 pg/mL vs. 72.92±88.21 pg/mL). Conclusion These results suggest that BDNF may play a role in the pathophysiology of somatization disorder. PMID:27757131

  8. Adolescent testosterone influences BDNF and TrkB mRNA and neurotrophin-interneuron marker relationships in mammalian frontal cortex.

    PubMed

    Purves-Tyson, Tertia D; Allen, Katherine; Fung, Samantha; Rothmond, Debora; Noble, Pam L; Handelsman, David J; Shannon Weickert, Cynthia

    2015-11-01

    Late adolescence in males is a period of increased susceptibility for the onset of schizophrenia, coinciding with increased circulating testosterone. The cognitive deficits prevalent in schizophrenia may be related to unhealthy cortical interneurons, which are trophically dependent on brain derived neurotrophic factor. We investigated, under conditions of depleted (monkey and rat) and replaced (rat) testosterone over adolescence, changes in gene expression of cortical BDNF and TrkB transcripts and interneuron markers and the relationships between these mRNAs and circulating testosterone. Testosterone removal by gonadectomy reduced gene expression of some BDNF transcripts in monkey and rat frontal cortices and the BDNF mRNA reduction was prevented by testosterone replacement. In rat, testosterone replacement increased the potential for classical TrkB signalling by increasing the full length to truncated TrkB mRNA ratio, whereas in the monkey cortex, circulating testosterone was negatively correlated with the TrkB full length/truncated mRNA ratio. We did not identify changes in interneuron gene expression in monkey frontal cortex in response to gonadectomy, and in rat, we showed that only somatostatin mRNA was decreased by gonadectomy but not restored by testosterone replacement. We identified complex and possibly species-specific, relationships between BDNF/TrkB gene expression and interneuron marker gene expression that appear to be dependent on the presence of testosterone at adolescence in rat and monkey frontal cortices. Taken together, our findings suggest there are dynamic relationships between BDNF/TrkB and interneuron markers that are dependent on the presence of testosterone but that this may not be a straightforward increase in testosterone leading to changes in BDNF/TrkB that contributes to interneuron health.

  9. Curcumin confers neuroprotection against alcohol-induced hippocampal neurodegeneration via CREB-BDNF pathway in rats.

    PubMed

    Motaghinejad, Majid; Motevalian, Manijeh; Fatima, Sulail; Hashemi, Hajar; Gholami, Mina

    2017-03-01

    Alcohol abuse causes severe damage to the brain neurons. Studies have reported the neuroprotective effects of curcumin against alcohol-induced neurodegeneration. However, the precise mechanism of action remains unclear. Seventy rats were equally divided into 7 groups (10 rats per group). Group 1 received normal saline (0.7ml/rat) and group 2 received alcohol (2g/kg/day) for 21days. Groups 3, 4, 5 and 6 concurrently received alcohol (2g/kg/day) and curcumin (10, 20, 40 and 60mg/kg, respectively) for 21days. Animals in group 7 self- administered alcohol for 21days. Group 8 treated with curcumin (60mg/kg, i.p.) alone for 21days. Open Field Test (OFT) was used to investigate motor activity in rats. Hippocampal oxidative, antioxidative and inflammatory factors were evaluated. Furthermore, brain cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) and brain derived neurotrophic factor (BDNF) levels were studied at gene level by reverse transcriptase polymerase chain reaction (RT-PCR). In addition, protein expression for BDNF, CREB, phosphorylated CREB (CREB-P), Bax and Bcl-2 was determined by western blotting. Voluntary and involuntary administration of alcohol altered motor activity in OFT, and curcumin treatment inhibited this alcohol-induced motor disturbance. Also, alcohol administration augmented lipid peroxidation, mitochondrial oxidized glutathione (GSSG), interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α) and Bax levels in isolated hippocampal tissues. Furthermore, alcohol-induced significant reduction were observed in reduced form of glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR) activities and CREB, BDNF and Bcl-2 levels. Also curcumin alone did not change the behavior and biochemical and molecular parameters. Curcumin can act as a neuroprotective agent against neurodegenerative effects of alcohol abuse, probably via activation of CREB-BDNF signaling pathway

  10. BDNF signaling contributes to oral cancer pain in a preclinical orthotopic rodent model

    PubMed Central

    Chodroff, Leah; Bendele, Michelle; Valenzuela, Vanessa; Henry, Michael

    2016-01-01

    The majority of patients with oral cancer report intense pain that is only partially managed by current analgesics. Thus, there is a strong need to study mechanisms as well as develop novel analgesics for oral cancer pain. Current study employed an orthotopic tongue cancer model with molecular and non-reflexive behavioral assays to determine possible mechanisms of oral cancer pain. Human oral squamous cell carcinoma cells line, HSC2, was injected into the tongue of male athymic mice and tumor growth was observed by day 6. Immunohistological analyses revealed a well-differentiated tumor with a localized immune response and pronounced sensory and sympathetic innervation and vascularization. The tumor expressed TMPRSS2, a protein previously reported with oral squamous cell carcinoma. ATF3 expression in trigeminal ganglia was not altered by tumor growth. Molecular characterization of the model demonstrated altered expression of several pain-related genes, out of which up-regulation of BDNF was most striking. Moreover, BDNF protein expression in trigeminal ganglia neurons was increased and inhibition of BDNF signaling with a tyrosine kinase B antagonist, ANA-12, reversed pain-like behaviors induced by the oral tumor. Oral squamous cell carcinoma tumor growth was also associated with a reduction in feeding, mechanical hypersensitivity in the face, as well as spontaneous pain behaviors as measured by the conditioned place preference test, all of which were reversed by analgesics. Interestingly, injection of HSC2 into the hindpaw did not reproduce this spectrum of pain behaviors; nor did injection of a colonic cancer cell line into the tongue. Taken together, this orthotopic oral cancer pain model reproduces the spectrum of pain reported by oral cancer patients, including higher order cognitive changes, and demonstrates that BDNF signaling constitutes a novel mechanism by which oral squamous cell carcinoma induces pain. Identification of the key role of tyrosine kinase B

  11. Interaction between stress and the BDNF Val66Met polymorphism in depression: a systematic review and meta-analysis

    PubMed Central

    2014-01-01

    Background Major depression is a disabling psychiatric illness with complex origins. Life stress (childhood adversity and recent stressful events) is a robust risk factor for depression. The relationship between life stress and Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene has received much attention. The aim of the present work was to review and conduct a meta-analysis on the results from published studies examining this interaction. Methods A literature search was conducted using PsychINFO and PubMed databases until 22 November 2013. A total of 22 studies with a pooled total of 14,233 participants met the inclusion criteria, the results of which were combined and a meta-analysis performed using the Liptak-Stouffer z-score method. Results The results suggest that the Met allele of BDNF Val66Met significantly moderates the relationship between life stress and depression (P = 0.03). When the studies were stratified by type of environmental stressor, the evidence was stronger for an interaction with stressful life events (P = 0.01) and weaker for interaction of BDNF Val66Met with childhood adversity (P = 0.051). Conclusions The interaction between BDNF and life stress in depression is stronger for stressful life events rather than childhood adversity. Methodological limitations of existing studies include poor measurement of life stress. PMID:24433458

  12. Predicting change in symptoms of depression during the transition to university: the roles of BDNF and working memory capacity.

    PubMed

    LeMoult, Joelle; Carver, Charles S; Johnson, Sheri L; Joormann, Jutta

    2015-03-01

    Studies on depression risk emphasize the importance of both cognitive and genetic vulnerability factors. The present study has provided the first examination of whether working memory capacity, the BDNF Val66Met polymorphism, and their interaction predict changes in symptoms of depression during the transition to university. Early in the semester, students completed a self-report measure of depressive symptoms and a modified version of the reading span task to assess working memory capacity in the presence of both neutral and negative distractors. Whole blood was genotyped for the BDNF Val66Met polymorphism. Students returned at the end of the semester to complete additional self-report questionnaires. Neither working memory capacity nor the BDNF Val66Met polymorphism predicted change in depressive symptoms either independently or in interaction with self-reported semester difficulty. The BDNF Val66Met polymorphism, however, moderated the association between working memory capacity and symptom change. Among met carriers, lower working memory capacity in the presence of negative-but not neutral-distractors was associated with increased symptoms of depression over the semester. For the val/val group, working memory capacity did not predict symptom change. These findings contribute directly to biological and cognitive models of depression and highlight the importance of examining Gene × Cognition interactions when investigating risk for depression.

  13. Time-dependent effects of escitalopram on brain derived neurotrophic factor (BDNF) and neuroplasticity related targets in the central nervous system of rats.

    PubMed

    Alboni, Silvia; Benatti, Cristina; Capone, Giacomo; Corsini, Daniela; Caggia, Federica; Tascedda, Fabio; Mendlewicz, Julien; Brunello, Nicoletta

    2010-09-25

    Chronic treatment with antidepressants affects several proteins linked to neuroplasticity, particularly brain derived neurotrophic factor (BDNF): this leads eventually to their therapeutic effects. It is possible that also for putative early therapeutic onset, antidepressants may act by promoting cellular adaptations linked to neuroplasticity. Escitalopram, known to be already effective in preclinical models of depression after 7 days, allowed us to investigate whether two effective treatment regimens (7 and 21 days) may contribute to synaptic plasticity by acting on BDNF signalling. We focused our attention on two regulators of BDNF transcription, CREB and CaRF (calcium responsive factor), and on kinases, CaMKII, ERK1/2 and p38 MAPK, linked to BDNF that play a distinctive role in synaptic plasticity. We evaluated whether the effects of escitalopram on these targets may be different in brain areas involved in the depressive symptomatology (hippocampus, frontal and prefrontal cortex). Here we demonstrate that escitalopram regulates intracellular pathways linked to neuroplasticity at both the time points evaluated in an area-specific manner. While the two escitalopram-treatment regimens failed to affect gene expression in the rat frontal cortex, 7days of treatment with escitalopram activated intracellular pathways linked to BDNF and increased the levels of Pro-BDNF in the rat prefrontal cortex. Moreover, 21 days of treatment with escitalopram decreased CREB/BDNF signalling while increasing p38 levels in the rat hippocampus. Even if further experiments with different antidepressant strategies will be needed, our data suggest that escitalopram efficacy may be mediated by early and late effects on synaptic plasticity in selective brain areas.

  14. Regulation of the spatial code for BDNF mRNA isoforms in the rat hippocampus following pilocarpine-treatment: a systematic analysis using laser microdissection and quantitative real-time PCR.

    PubMed

    Baj, Gabriele; Del Turco, Domenico; Schlaudraff, Jessica; Torelli, Lucio; Deller, Thomas; Tongiorgi, Enrico

    2013-05-01

    Brain-derived neurotrophic factor (BDNF) is essential for neuronal survival, differentiation, and plasticity and is one of those genes that generate multiple mRNAs with different alternatively spliced 5'UTRs. The functional significance of many BDNF transcripts, each producing the same protein, is emerging. On the basis of the analysis of the four most abundant brain BDNF transcripts, we recently proposed the "spatial code hypothesis of BDNF splice variants" according to which the BDNF transcripts, through their differential subcellular localization in soma or dendrites, represent a mechanism to synthesize the protein at distinct locations and produce local effects. In this study, using laser microdissection of hippocampal laminae and reverse transcription-quantitative real-time PCR (RT-qPCR), we analyzed all known BDNF mRNA variants at resting conditions or following 3 h pilocarpine-induced status epilepticus. In untreated rats, we found dendritic enrichment of BDNF transcripts encoding exons 6 and 7 in CA1; exons 1, 6, and 9a in CA3; and exons 5, 6, 7, and 8 in DG. Considering the low abundance of the other transcripts, exon 6 was the main transcript in dendrites under resting conditions. Pilocarpine treatment induced an increase of BDNF transcripts encoding exons 4 and 6 in all dendritic laminae and, additionally, of exon 2 in CA1 stratum radiatum and exons 2, 3, 9a in DG molecular layer while the other transcripts were decreased in dendrites, suggesting restriction to the soma. These results support the hypothesis of a spatial code to differentially regulate BDNF in the somatic or dendritic compartment under conditions of pilocarpine-induced status epilepticus and, furthermore, highlight the existence of subfield-specific differences.

  15. Glucocorticoid affects dendritic transport of BDNF-containing vesicles.

    PubMed

    Adachi, Naoki; Numakawa, Tadahiro; Nakajima, Shingo; Fukuoka, Masashi; Odaka, Haruki; Katanuma, Yusuke; Ooshima, Yoshiko; Hohjoh, Hirohiko; Kunugi, Hiroshi

    2015-08-04

    Brain-derived neurotrophic factor (BDNF) is essential for neuronal survival, differentiation, and functions in the central nervous system (CNS). Because BDNF protein is sorted into secretory vesicles at the trans-Golgi network in the cell body after translation, transport of BDNF-containing vesicles to the secretion sites is an important process for its function. Here we examined the effect of dexamethasone (DEX), a synthetic glucocorticoid, on BDNF-containing vesicle transport and found that DEX decreased the proportion of stationary vesicles and increased velocity of the microtubule-based vesicle transport in dendrites of cortical neurons. Furthermore, DEX increased huntingtin (Htt) protein levels via glucocorticoid receptor (GR) activation, and reduction in the amount of Htt by a specific shRNA reversed the action of DEX on BDNF vesicle transport. Given that Htt protein is a positive regulator for the microtubule-dependent vesicular transport in neurons, our data suggest that glucocorticoid stimulates BDNF vesicle transport through upregulation of Htt protein levels.

  16. Glucocorticoid affects dendritic transport of BDNF-containing vesicles

    PubMed Central

    Adachi, Naoki; Numakawa, Tadahiro; Nakajima, Shingo; Fukuoka, Masashi; Odaka, Haruki; Katanuma, Yusuke; Ooshima, Yoshiko; Hohjoh, Hirohiko; Kunugi, Hiroshi

    2015-01-01

    Brain-derived neurotrophic factor (BDNF) is essential for neuronal survival, differentiation, and functions in the central nervous system (CNS). Because BDNF protein is sorted into secretory vesicles at the trans-Golgi network in the cell body after translation, transport of BDNF-containing vesicles to the secretion sites is an important process for its function. Here we examined the effect of dexamethasone (DEX), a synthetic glucocorticoid, on BDNF-containing vesicle transport and found that DEX decreased the proportion of stationary vesicles and increased velocity of the microtubule-based vesicle transport in dendrites of cortical neurons. Furthermore, DEX increased huntingtin (Htt) protein levels via glucocorticoid receptor (GR) activation, and reduction in the amount of Htt by a specific shRNA reversed the action of DEX on BDNF vesicle transport. Given that Htt protein is a positive regulator for the microtubule-dependent vesicular transport in neurons, our data suggest that glucocorticoid stimulates BDNF vesicle transport through upregulation of Htt protein levels. PMID:26239075

  17. Interaction of BDNF with cytokines in chronic schizophrenia.

    PubMed

    Zhang, Xiang Yang; Tan, Yun-Long; Chen, Da-Chun; Tan, Shu-Ping; Yang, Fu-De; Wu, Hanjing Emily; Zunta-Soares, Giovana B; Huang, Xu-Feng; Kosten, Thomas R; Soares, Jair C

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) interacts with cytokines. Although both BDNF and cytokines occur at abnormal levels in schizophrenia patients, their interactions have not yet been examined. We therefore compared serum BDNF, TNF-α, interleukin (IL)-2, IL-6, and IL-8 levels in 92 chronically medicated schizophrenia patients and 60 healthy controls. We correlated these serum levels within these subject groups with each other and with clinical symptoms assessed according to the Positive and Negative Syndrome Scale (PANSS). Compared to the control group, the schizophrenia patients had significantly lower BDNF and TNF-α levels, and higher IL-2, IL-6, and IL-8 levels. The patients also showed a significant positive correlation between BDNF and both IL-2 and IL-8 levels, and low BDNF and TNF-α levels together were associated with poor performance on the PANSS cognitive factor. Thus, an interaction between cytokines and neurotrophic factors may be implicated in the pathophysiology of chronic schizophrenia. In particular, the cytokine TNF-α may interact with BNDF causing cognitive impairment.

  18. BDNF protects neurons following injury by modulation of caspase activity.

    PubMed

    Kim, Dong H; Zhao, Xiurong

    2005-01-01

    Neurotrophins can protect against apoptotic death following neuronal injury. In a previous article, we showed that activation of the trk receptor is required, but the subsequent mechanisms of action remain unclear. Because the caspase family of cysteine proteases plays a central role in the apoptotic process, we examined the effect of the neurotrophins on caspase activation. Primary neuronal cultures from the embryonic rat cortex were injured with radiation, oxygen deprivation, or oxygen-glucose deprivation. Neurons were treated with brain-derived growth factor (BDNF) or caspase inhibitors. The level of injury was assayed by measuring lactate dehydrogenase release. Western blots were used to note the presence and activation of the caspases 1, 2, 3, 8, and 9--with and without treatment with BDNF. Proenzymes for caspases 1, 2, and 3--but not for caspases 8 or 9 were expressed. With radiation or oxygen deprivation, but not oxygen-glucose deprivation, caspase 3 was activated. Treatment with BDNF was protective against radiation and oxygen deprivation only. Treatment with BDNF also blocked the activation of caspase 3. A similar effect was achieved by directly blocking caspase 1 or 3 activation using an inhibitor. In this study, we showed that BDNF treatment inhibits caspase 3 activation following neuronal injury. This is a central event: when injury did not lead to caspase 3 activation, BDNF treatment was not protective. These results suggest one mechanism by which the neurotrophins protect neurons following injury.

  19. Alteration in BDNF and its receptors, full-length and truncated TrkB and p75(NTR) following penetrating traumatic brain injury.

    PubMed

    Rostami, Elham; Krueger, Frank; Plantman, Stefan; Davidsson, Johan; Agoston, Denes; Grafman, Jordan; Risling, Mårten

    2014-01-13

    The evidence that BDNF is involved in neuroprotection, neuronal repair and recovery after traumatic brain injury (TBI) is substantial. We have previously shown that the polymorphism of the human BDNF gene predicts cognitive recovery and outcome following penetrating TBI. The distribution of expression of BDNF and its receptors after penetrating TBI has not been investigated. In this study we examined the expression of these genes in a rat model of penetrating TBI. The injury is produced by a controlled penetration of a 2mm thick needle-shaped object, which is accelerated with a pellet from an air gun. We used in situ hybridization and investigated the mRNA expression of BDNF and its receptors: the full-length and the truncated TrkB and p75(NTR), from 1 day to 8 weeks following penetrating TBI. In addition, the protein level of BDNF in frontal cortex and hippocampus was measured by reverse phase protein microarray (RPPM). The mRNA expression of BDNF and its receptors decreased in the hippocampus in the border zone ipsilateral to the injury while there was an increase in mRNA expression at the contralateral side. The increase in BDNF mRNA expression in the hippocampus was sustained for 2 weeks following injury, with the highest expression noted in the CA3 cell layer. Furthermore, the protein analysis by RPPM showed increased levels of BDNF in the frontal cortex and the hippocampus up to 2 weeks after TBI. At 8 weeks following injury there was an intense labeling of the truncated TrkB receptor and the p75(NTR) in the area surrounding the cavity. Our study is the first report on the expression of BDNF and its receptors following penetrating TBI and suggests that their expression is altered long after the acute phase of injury. Further studies are needed to investigate if the late expressions of these receptors are beneficial or deleterious. In either case it indicates the possibility to influence the recovery after brain injury during the chronic phase and the

  20. Antidepressant effects of crocin and its effects on transcript and protein levels of CREB, BDNF, and VGF in rat hippocampus

    PubMed Central

    2014-01-01

    Background Antidepressants have been shown to affect levels of brain-derived neurotrophic factor (BDNF) and VGF (non-acronymic) whose transcriptions are dependent on cAMP response element binding protein (CREB) in long term treatment. The aim of this study was to verify the subacute antidepressant effects of crocin, an active constituent of saffron (Crocus sativus L.), and its effects on CREB, BDNF, and VGF proteins, transcript levels and amount of active, phosphorylated CREB (P-CREB) protein in rat hippocampus. Methods Crocin (12.5, 25, and 50 mg/kg), imipramine (10 mg/kg; positive control) and saline (1 mL/kg; neutral control) were administered intraperitoneally (IP) to male Wistar rats for 21 days. The antidepressant effects were studied using the forced swimming test (FST) on day 21 after injection. Protein expression and transcript levels of genes in the rat hippocampus were evaluated using western blot and quantitative reverse transcription-polymerase chain reaction (qRT-PCR), respectively. Results Crocin significantly reduced the immobility time in the FST. Western blot analysis showed that 25 and 50 mg/kg of crocin increased the levels of CREB and BDNF significantly and dose dependently. All doses of crocin increased the VGF levels in a dose-dependent manner. Levels of p-CREB increased significantly by 50 mg/kg dose of crocin. Only 12.5 mg/kg crocin could significantly increase the transcript levels of BDNF. No changes in CREB and VGF transcript levels were observed in all groups. Conclusions These results suggest that crocin has antidepressant-like action by increasing CREB, BDNF and VGF levels in hippocampus. PMID:24401376

  1. Aerobic Fitness Linked to Cortical Brain Development in Adolescent Males: Preliminary Findings Suggest a Possible Role of BDNF Genotype

    PubMed Central

    Herting, Megan M.; Keenan, Madison F.; Nagel, Bonnie J.

    2016-01-01

    Aerobic exercise has been shown to impact brain structure and cognition in children and adults. Exercise-induced activation of a growth protein known as brain derived neurotrophic factor (BDNF) is thought to contribute to such relationships. To date, however, no study has examined how aerobic fitness relates to cortical brain structure during development and if BDNF genotype moderates these relationships. Using structural magnetic resonance imaging (MRI) and FreeSurfer, the current study examined how aerobic fitness relates to volume, thickness, and surface area in 34 male adolescents, 15 to 18 years old. Moreover, we examined if the val66met BDNF genotype moderated these relationships. We hypothesized that aerobic fitness would relate to greater thickness and volumes in frontal, parietal, and motor regions, and that these relationships would be less robust in individuals carrying a Met allele, since this genotype leads to lower BDNF expression. We found that aerobic fitness positively related to right rostral middle frontal cortical volume in all adolescents. However, results also showed BDNF genotype moderated the relationship between aerobic fitness and bilateral medial precuneus surface area, with a positive relationship seen in individuals with the Val/Val allele, but no relationship detected in those adolescents carrying a Met allele. Lastly, using self-reported levels of aerobic activity, we found that higher-fit adolescents showed larger right medial pericalcarine, right cuneus and left precuneus surface areas as compared to their low-fit peers. Our findings suggest that aerobic fitness is linked to cortical brain development in male adolescents, and that more research is warranted to determine how an individual’s genes may influence these relationships. PMID:27445764

  2. BDNF-TrkB Pathway Mediates Neuroprotection of Hydrogen Sulfide against Formaldehyde-Induced Toxicity to PC12 Cells

    PubMed Central

    Gao, Sheng-Lan; Tian, Ying; Wang, Chun-Yan; Wang, Li; Gu, Hong-Feng; Tang, Xiao-Qing

    2015-01-01

    Formaldehyde (FA) is a common environmental contaminant that has toxic effects on the central nervous system (CNS). Our previous data demonstrated that hydrogen sulfide (H2S), the third endogenous gaseous mediator, has protective effects against FA-induced neurotoxicity. As is known to all, Brain-derived neurotropic factor (BDNF), a member of the neurotrophin gene family, mediates its neuroprotective properties via various intracellular signaling pathways triggered by activating the tyrosine kinase receptor B (TrkB). Intriguingly, our previous data have illustrated the upregulatory role of H2S on BDNF protein expression in the hippocampus of rats. Therefore, in this study, we hypothesized that H2S provides neuroprotection against FA toxicity by regulating BDNF-TrkB pathway. In the present study, we found that NaHS, a donor of H2S, upregulated the level of BDNF protein in PC12 cells, and significantly rescued FA-induced downregulation of BDNF levels. Furthermore, we found that pretreatment of PC12 cells with K252a, an inhibitor of the BDNF receptor TrkB, markedly reversed the inhibition of NaHS on FA-induced cytotoxicity and ablated the protective effects of NaHS on FA-induced oxidative stress, including the accumulation of intracellular reactive oxygen species (ROS), 4-hydroxy-2-trans-nonenal (4-HNE), and malondialdehyde (MDA). We also showed that K252a abolished the inhibition of NaHS on FA-induced apoptosis, as well as the activation of caspase-3 in PC12 cells. In addition, K252a reversed the protection of H2S against FA-induced downregulation of Bcl-2 protein expression and upregulation of Bax protein expression in PC12 cells. These data indicate that the BDNF-TrkB pathway mediates the neuroprotection of H2S against FA-induced cytotoxicity, oxidative stress and apoptosis in PC12 cells. These findings provide a novel mechanism underlying the protection of H2S against FA-induced neurotoxicity. PMID:25749582

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

    PubMed

    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.

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

    PubMed Central

    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. PMID:28250730

  5. Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism influences the association of the methylome with maternal anxiety and neonatal brain volumes.

    PubMed

    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.

  6. PI3-kinase/Akt pathway-regulated membrane insertion of acid-sensing ion channel 1a underlies BDNF-induced pain hypersensitivity.

    PubMed

    Duan, Bo; Liu, Di-Shi; Huang, Yu; Zeng, Wei-Zheng; Wang, Xiang; Yu, Hui; Zhu, Michael X; Chen, Zhe-Yu; Xu, Tian-Le

    2012-05-02

    Central neural plasticity plays a key role in pain hypersensitivity. This process is modulated by brain-derived neurotrophic factor (BDNF) and also involves the type 1a acid-sensing ion channel (ASIC1a). However, the interactions between the BDNF receptor, tropomyosin-related kinase B (TrkB), and ASIC1a are unclear. Here, we show that deletion of ASIC1 gene suppressed the sustained mechanical hyperalgesia induced by intrathecal BDNF application in mice. In both rat spinal dorsal horn neurons and heterologous cell cultures, the BDNF/TrkB pathway enhanced ASIC1a currents via phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB/Akt) cascade and phosphorylation of cytoplasmic residue Ser-25 of ASIC1a, resulting in enhanced forward trafficking and increased surface expression. Moreover, in both rats and mice, this enhanced ASIC1a activity was required for BDNF-mediated hypersensitivity of spinal dorsal horn nociceptive neurons and central mechanical hyperalgesia, a process that was abolished by intrathecal application of a peptide representing the N-terminal region of ASIC1a encompassing Ser-25. Thus, our results reveal a novel mechanism underlying central sensitization and pain hypersensitivity, and reinforce the critical role of ASIC1a channels in these processes.

  7. Lack of neural compensatory mechanisms of BDNF val66met met carriers and APOE E4 carriers in healthy aging, mild cognitive impairment, and Alzheimer's disease.

    PubMed

    Gomar, Jesus J; Conejero-Goldberg, Concepcion; Huey, Edward D; Davies, Peter; Goldberg, Terry E

    2016-03-01

    Compromises in compensatory neurobiologic mechanisms due to aging and/or genetic factors (i.e., APOE gene) may influence brain-derived neurotrophic factor (BDNF) val66met polymorphism effects on temporal lobe morphometry and memory performance. We studied 2 cohorts from Alzheimer's Disease Neuroimaging Initiative: 175 healthy subjects and 222 with prodromal and established Alzheimer's disease. Yearly structural magnetic resonance imaging and cognitive performance assessments were carried out over 3 years of follow-up. Both cohorts had similar BDNF Val/Val and Met allele carriers' (including both Val/Met and Met/Met individuals) distribution. In healthy subjects, a significant trend for thinner posterior cingulate and precuneus cortices was detected in Met carriers compared to Val homozygotes in APOE E4 carriers, with large and medium effect sizes, respectively. The mild cognitive impairment/Alzheimer's disease cohort showed a longitudinal decline in entorhinal thickness in BDNF Met carriers compared to Val/Val in APOE E4 carriers, with effect sizes ranging from medium to large. In addition, an effect of BDNF genotype was found in APOE E4 carriers for episodic memory (logical memory and ADAS-Cog) and semantic fluency measures, with Met carriers performing worse in all cases. These findings suggest a lack of compensatory mechanisms in BDNF Met carriers and APOE E4 carriers in healthy and pathological aging. Copyright © 2016 Elsevier Inc. All rights reserved.

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

    PubMed

    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.

  9. The BDNF Val66Met Polymorphism Interacts with Maternal Parenting Influencing Adolescent Depressive Symptoms: Evidence of Differential Susceptibility Model.

    PubMed

    Zhang, Leilei; Li, Zhi; Chen, Jie; Li, Xinying; Zhang, Jianxin; Belsky, Jay

    2016-03-01

    Although depressive symptoms are common during adolescence, little research has examined gene-environment interaction on youth depression. This study chose the brain-derived neurotrophic factor (BDNF) gene, tested the interaction between a functional polymorphism resulting amino acid substitution of valine (Val) to methionine (Met) in the proBDNF protein at codon 66 (Val66Met), and maternal parenting on youth depressive symptoms in a sample of 780 community adolescents of Chinese Han ethnicity (aged 11-17, M = 13.6, 51.3 % females). Participants reported their depressive symptoms and perceived maternal parenting. Results indicated the BDNF Val66Met polymorphism significantly moderated the influence of maternal warmth-reasoning, but not harshness-hostility, on youth depressive symptoms. Confirmatory model evaluation indicated that the interaction effect involving warmth-reasoning conformed to the differential-susceptibility rather than diathesis-stress model of person-X-environment interaction. Thus, Val carriers experienced less depressive symptoms than Met homozygotes when mothering was more positive but more symptoms when mothering was less positive. The findings provided evidence in support of the differential susceptibility hypothesis of youth depressive symptoms and shed light on the importance of examining the gene-environment interaction from a developmental perspective.

  10. Activity-dependent BDNF release via endocytic pathways is regulated by synaptotagmin-6 and complexin.

    PubMed

    Wong, Yu-Hui; Lee, Chia-Ming; Xie, Wenjun; Cui, Bianxiao; Poo, Mu-ming

    2015-08-11

    Brain-derived neurotrophic factor (BDNF) is known to modulate synapse development and plasticity, but the source of synaptic BDNF and molecular mechanisms regulating BDNF release remain unclear. Using exogenous BDNF tagged with quantum dots (BDNF-QDs), we found that endocytosed BDNF-QDs were preferentially localized to postsynaptic sites in the dendrite of cultured hippocampal neurons. Repetitive neuronal spiking induced the release of BDNF-QDs at these sites, and this process required activation of glutamate receptors. Down-regulating complexin 1/2 (Cpx1/2) expression eliminated activity-induced BDNF-QD secretion, although the overall activity-independent secretion was elevated. Among eight synaptotagmin (Syt) isoforms examined, down-regulation of only Syt6 impaired activity-induced BDNF-QD secretion. In contrast, activity-induced release of endogenously synthesized BDNF did not depend on Syt6. Thus, neuronal activity could trigger the release of endosomal BDNF from postsynaptic dendrites in a Cpx- and Syt6-dependent manner, and endosomes containing BDNF may serve as a source of BDNF for activity-dependent synaptic modulation.

  11. Serum pro-BDNF/BDNF as a treatment biomarker for response to docosahexaenoic acid in traumatized people vulnerable to developing psychological distress: a randomized controlled trial

    PubMed Central

    Matsuoka, Y; Nishi, D; Tanima, Y; Itakura, M; Kojima, M; Hamazaki, K; Noguchi, H; Hamazaki, T

    2015-01-01

    Our open-label pilot study showed that supplementation with docosahexaenoic acid (DHA) increased serum brain-derived neurotrophic factor (BDNF) levels and that there might be an association between changes in serum BDNF levels and reduced psychological distress. Animal research has indicated that a DHA-enriched diet increases BDNF in the brain. In this randomized double-blind controlled trial of severely injured patients vulnerable to posttraumatic stress disorder (PTSD) and depression, we examined whether DHA increases serum BDNF levels and whether changes in BDNF levels are associated with subsequent symptoms of PTSD and depression. Patients received 1470 mg per day of DHA plus 147 mg per day of eicosapentaenoic acid (EPA; n=53) or placebo (n=57) for 12 weeks. Serum levels of mature BDNF and precursor pro-BDNF at baseline and 12-week follow-up were measured using enzyme-linked immunosorbent assay kits. At 12 weeks, we used the Clinician-Administered PTSD Scale to assess PTSD symptoms and depressive symptoms by the Montgomery–Åsberg Depression Rating Scale. We found a significant increase in serum BDNF levels during the trial in the DHA and placebo groups with no interaction between time and group. Changes in BDNF levels were not associated with PTSD severity but negatively associated with depression severity (Spearman's ρ=−0.257, P=0.012). Changes in pro-BDNF were also negatively associated with depression severity (Spearman's ρ=−0.253, P=0.013). We found no specific effects of DHA on increased serum levels of BDNF and pro-BDNF; however, evidence in this study suggests that increased BDNF and pro-BDNF have a protective effect by minimizing depression severity. PMID:26151924

  12. VGF and Its C-Terminal Peptide TLQP-62 Regulate Memory Formation in Hippocampus via a BDNF-TrkB-Dependent Mechanism.

    PubMed

    Lin, Wei-Jye; Jiang, Cheng; Sadahiro, Masato; Bozdagi, Ozlem; Vulchanova, Lucy; Alberini, Cristina M; Salton, Stephen R

    2015-07-15

    Regulated expression and secretion of BDNF, which activates TrkB receptor signaling, is known to play a critical role in cognition. Identification of additional modulators of cognitive behavior that regulate activity-dependent BDNF secretion and/or potentiate TrkB receptor signaling would therefore be of considerable interest. In this study, we show in the adult mouse hippocampus that expression of the granin family gene Vgf and secretion of its C-terminal VGF-derived peptide TLQP-62 are required for fear memory formation. We found that hippocampal VGF expression and TLQP-62 levels were transiently induced after fear memory training and that sequestering secreted TLQP-62 peptide in the hippocampus immediately after training impaired memory formation. Reduced VGF expression was found to impair learning-evoked Rac1 induction and phosphorylation of the synaptic plasticity markers cofilin and synapsin in the adult mouse hippocampus. Moreover, TLQP-62 induced acute, transient activation of the TrkB receptor and subsequent CREB phosphorylation in hippocampal slice preparations and its administration immediately after training enhanced long-term memory formation. A critical role of BDNF-TrkB signaling as a downstream effector in VGF/TLQP-62-mediated memory consolidation was further revealed by posttraining activation of BDNF-TrkB signaling, which rescued impaired fear memory resulting from hippocampal administration of anti-VGF antibodies or germline VGF ablation in mice. We propose that VGF is a critical component of a positive BDNF-TrkB regulatory loop and, upon its induced expression by memory training, the TLQP-62 peptide rapidly reinforces BDNF-TrkB signaling, regulating hippocampal memory consolidation. Identification of the cellular and molecular mechanisms that regulate long-term memory formation and storage may provide alternative treatment modalities for degenerative and neuropsychiatric memory disorders. The neurotrophin BDNF plays a prominent role in cognitive

  13. VGF and Its C-Terminal Peptide TLQP-62 Regulate Memory Formation in Hippocampus via a BDNF-TrkB-Dependent Mechanism

    PubMed Central

    Lin, Wei-Jye; Jiang, Cheng; Sadahiro, Masato; Bozdagi, Ozlem; Vulchanova, Lucy; Alberini, Cristina M.

    2015-01-01

    Regulated expression and secretion of BDNF, which activates TrkB receptor signaling, is known to play a critical role in cognition. Identification of additional modulators of cognitive behavior that regulate activity-dependent BDNF secretion and/or potentiate TrkB receptor signaling would therefore be of considerable interest. In this study, we show in the adult mouse hippocampus that expression of the granin family gene Vgf and secretion of its C-terminal VGF-derived peptide TLQP-62 are required for fear memory formation. We found that hippocampal VGF expression and TLQP-62 levels were transiently induced after fear memory training and that sequestering secreted TLQP-62 peptide in the hippocampus immediately after training impaired memory formation. Reduced VGF expression was found to impair learning-evoked Rac1 induction and phosphorylation of the synaptic plasticity markers cofilin and synapsin in the adult mouse hippocampus. Moreover, TLQP-62 induced acute, transient activation of the TrkB receptor and subsequent CREB phosphorylation in hippocampal slice preparations and its administration immediately after training enhanced long-term memory formation. A critical role of BDNF-TrkB signaling as a downstream effector in VGF/TLQP-62-mediated memory consolidation was further revealed by posttraining activation of BDNF-TrkB signaling, which rescued impaired fear memory resulting from hippocampal administration of anti-VGF antibodies or germline VGF ablation in mice. We propose that VGF is a critical component of a positive BDNF-TrkB regulatory loop and, upon its induced expression by memory training, the TLQP-62 peptide rapidly reinforces BDNF-TrkB signaling, regulating hippocampal memory consolidation. SIGNIFICANCE STATEMENT Identification of the cellular and molecular mechanisms that regulate long-term memory formation and storage may provide alternative treatment modalities for degenerative and neuropsychiatric memory disorders. The neurotrophin BDNF plays a

  14. BDNF - A key player in cardiovascular system.

    PubMed

    Pius-Sadowska, Ewa; Machaliński, Bogusław

    2017-09-01

    Neurotrophins (NTs) were first identified as target-derived survival factors for neurons of the central and peripheral nervous system (PNS). They are known to control neural cell fate, development and function. Independently of their neuronal properties, NTs exert unique cardiovascular activity. The heart is innervated by sensory, sympathetic and parasympathetic neurons, which require NTs during early development and in the establishment of mature properties, contributing to the maintenance of cardiovascular homeostasis. The identification of molecular mechanisms regulated by NTs and involved in the crosstalk between cardiac sympathetic nerves, cardiomyocytes, cardiac fibroblasts, and vascular cells, has a fundamental importance in both normal heart function and disease. The article aims to review the recent data on the effects of Brain-Derived Neurotrophic Factor (BDNF) on various cardiovascular neuronal and non-neuronal functions such as the modulation of synaptic properties of autonomic neurons, axonal outgrowth and sprouting, formation of the vascular and neural networks, smooth muscle migration, and control of endothelial cell survival and cardiomyocytes. Understanding these mechanisms may be crucial for developing novel therapeutic strategies, including stem cell-based therapies. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. BDNF Val66Met genotype and neuroticism predict life stress: A longitudinal study from childhood to adulthood.

    PubMed

    Lehto, Kelli; Mäestu, Jarek; Kiive, Evelyn; Veidebaum, Toomas; Harro, Jaanus

    2016-03-01

    The brain-derived neurotrophic factor gene (BDNF) Val66Met polymorphism and life stress have been associated with negative emotionality (e.g., neuroticism), but relevant evidence is far from unequivocal. Possible confounding factors include the type and timing of stressful events measured, such as childhood adversity vs. recent stressful events, and variable gene × environment interactions. The aim of this study was to longitudinally assess the BDNF Val66Met polymorphism and environment interaction effect on neuroticism in a population representative sample, depending upon the type of stress, gender and family relations. In the original older cohort of the Estonian Children Personality Behavior and Health Study (ECPBHS, n=593), neuroticism was measured at age 15 (parental assessment), 18 and 25 (self-assessments). Childhood stress was reported at age 15, quality of family relations was measured at age 18, and recent stressful life events at age 25. The BDNF Val66Met polymorphism interacted with recent stressful life events, but not with childhood adversities, to impact neuroticism. Interestingly, in female participants, neuroticism at age 18 predicted future stressful life events dependent upon genotype: individuals with Val/Val genotype and high neuroticism experienced higher, but Met-allele carriers with high neuroticism lower stress exposure at age 25. Similar tendencies were observed using parental assessments at age 15. The protective effect of Met-allele in the high stress exposure group could result from better early family environment. In conclusion, we herewith provide further evidence for a role of BDNF gene variance contributing to plasticity in response to environmental demands.

  16. Peripheral levels of BDNF and NGF in primary headaches.

    PubMed

    Blandini, F; Rinaldi, L; Tassorelli, C; Sances, G; Motta, M; Samuele, A; Fancellu, R; Nappi, G; Leon, A

    2006-02-01

    Neurotrophins, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), have been implicated in the generation and modulation of pain. To investigate whether alterations in neurotrophin levels can be detected in subjects suffering from nociceptive disorders, such as primary headaches, we determined the peripheral (platelet and plasma) levels of BDNF and NGF in patients suffering from migraine, with or without aura, or cluster headache (CH), in the interictal phase, and in healthy volunteers. All primary headaches patients studied showed significantly decreased platelet levels of BDNF (migraine vs. controls P<0.001; CH vs. controls P<0.01), while a selective reduction of platelet NGF was observed in migraine sufferers and not in CH patients compared with control subjects (migraine vs. controls P<0.001). These changes were not accompanied by significant modifications of neurotrophin plasma levels. Our findings show for the first time that changes in peripheral levels of neurotrophines (BDNF and NGF) occur in patients suffering from different types of primary headaches, suggesting a potential involvement of BDNF and NGF in the pathophysiology of these disorders, and raising the possibility that differences in peripheral neurotrophins may help to distinguish migraine biologically from CH.

  17. BDNF Boosts Spike Fidelity in Chaotic Neural Oscillations

    PubMed Central

    Fujisawa, Shigeyoshi; Yamada, Maki K.; Nishiyama, Nobuyoshi; Matsuki, Norio; Ikegaya, Yuji

    2004-01-01

    Oscillatory activity and its nonlinear dynamics are of fundamental importance for information processing in the central nervous system. Here we show that in aperiodic oscillations, brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, enhances the accuracy of action potentials in terms of spike reliability and temporal precision. Cultured hippocampal neurons displayed irregular oscillations of membrane potential in response to sinusoidal 20-Hz somatic current injection, yielding wobbly orbits in the phase space, i.e., a strange attractor. Brief application of BDNF suppressed this unpredictable dynamics and stabilized membrane potential fluctuations, leading to rhythmical firing. Even in complex oscillations induced by external stimuli of 40 Hz (γ) on a 5-Hz (θ) carrier, BDNF-treated neurons generated more precisely timed spikes, i.e., phase-locked firing, coupled with θ-phase precession. These phenomena were sensitive to K252a, an inhibitor of tyrosine receptor kinases and appeared attributable to BDNF-evoked Na+ current. The data are the first indication of pharmacological control of endogenous chaos. BDNF diminishes the ambiguity of spike time jitter and thereby might assure neural encoding, such as spike timing-dependent synaptic plasticity. PMID:14990508

  18. Genetic susceptibility to family environment: BDNF Val66met and 5-HTTLPR influence depressive symptoms.

    PubMed

    Dalton, Elizabeth D; Hammen, Constance L; Najman, Jake M; Brennan, Patricia A

    2014-12-01

    Functional genetic polymorphisms associated with Brain-Derived Neurotrophic Factor (BDNF) and serotonin (5-HTTLPR) have demonstrated associations with depression in interaction with environmental stressors. In light of evidence for biological connections between BDNF and serotonin, it is prudent to consider genetic epistasis between variants in these genes in the development of depressive symptoms. The current study examined the effects of val66met, 5-HTTLPR, and family environment quality on youth depressive symptoms in adolescence and young adulthood in a longitudinal sample oversampled for maternal depression history. A differential susceptibility model was tested, comparing the effects of family environment on depression scores across different levels of a cumulative plasticity genotype, defined as presence of both, either, or neither plasticity alleles (defined here as val66met Met and 5-HTTLPR 'S'). Cumulative plasticity genotype interacted with family environment quality to predict depression among males and females at age 15. After age 15, however, the interaction of cumulative plasticity genotype and early family environment quality was only predictive of depression among females. Results supported a differential susceptibility model at age 15, such that plasticity allele presence was associated with more or less depressive symptoms depending on valence of the family environment, and a diathesis-stress model of gene-environment interaction after age 15. These findings, although preliminary because of the small sample size, support prior results indicating interactive effects of 5-HTTLPR, val66met, and environmental stress, and suggest that family environment may have a stronger influence on genetically susceptible women than men.

  19. Loss of MeCP2 disrupts cell autonomous and autocrine BDNF signaling in mouse glutamatergic neurons

    PubMed Central

    Sampathkumar, Charanya; Wu, Yuan-Ju; Vadhvani, Mayur; Trimbuch, Thorsten; Eickholt, Britta; Rosenmund, Christian

    2016-01-01

    Mutations in the MECP2 gene cause the neurodevelopmental disorder Rett syndrome (RTT). Previous studies have shown that altered MeCP2 levels result in aberrant neurite outgrowth and glutamatergic synapse formation. However, causal molecular mechanisms are not well understood since MeCP2 is known to regulate transcription of a wide range of target genes. Here, we describe a key role for a constitutive BDNF feed forward signaling pathway in regulating synaptic response, general growth and differentiation of glutamatergic neurons. Chronic block of TrkB receptors mimics the MeCP2 deficiency in wildtype glutamatergic neurons, while re-expression of BDNF quantitatively rescues MeCP2 deficiency. We show that BDNF acts cell autonomous and autocrine, as wildtype neurons are not capable of rescuing growth deficits in neighboring MeCP2 deficient neurons in vitro and in vivo. These findings are relevant for understanding RTT pathophysiology, wherein wildtype and mutant neurons are intermixed throughout the nervous system. DOI: http://dx.doi.org/10.7554/eLife.19374.001 PMID:27782879

  20. Higher reward value of starvation imagery in anorexia nervosa and association with the Val66Met BDNF polymorphism

    PubMed Central

    Clarke, J; Ramoz, N; Fladung, A-K; Gorwood, P

    2016-01-01

    Recent studies support the idea that abnormalities of the reward system contribute to onset and maintenance of anorexia nervosa (AN). Next to cues coding for overweight, other research suggest cues triggering the proposed starvation dependence to be pivotally involved in the AN pathogenesis. We assessed the characteristics of the cognitive, emotional and physiologic response toward disease-specific pictures of female body shapes, in adult AN patients compared with healthy control (HC) women. Frequency and amplitude of skin conductance response (SCR) in 71 patients with AN and 20 HC were registered during processing of stimuli of three weight categories (over-, under- and normal weight). We then assessed the role of the Val66Met BDNF polymorphism as a potential intermediate factor. AN patients reported more positive feelings during processing of underweight stimuli and more negative feelings for normal- and overweight stimuli. The SCR showed a group effect (P=0.007), AN patients showing overall higher frequency of the response. SCR within patients was more frequent during processing of underweight stimuli compared with normal- and overweight stimuli. The Met allele of the BDNF gene was not more frequent in patients compared with controls, but was associated to an increased frequency of SCR (P=0.008) in response to cues for starvation. A higher positive value of starvation, rather than more negative one of overweight, might more accurately define females with AN. The Met allele of the BDNF gene could partly mediate the higher reward value of starvation observed in AN. PMID:27271855

  1. Fluvoxamine moderates reduced voluntary activity following chronic dexamethasone infusion in mice via recovery of BDNF signal cascades.

    PubMed

    Terada, Kazuki; Izumo, Nobuo; Suzuki, Biora; Karube, Yoshiharu; Morikawa, Tomomi; Ishibashi, Yukiko; Kameyama, Toshiki; Chiba, Koji; Sasaki, Noriko; Iwata, Keiko; Matsuzaki, Hideo; Manabe, Takayuki

    2014-04-01

    Major depression is a complex disorder characterized by genetic and environmental interactions. Selective serotonin reuptake inhibitors (SSRIs) effectively treat depression. Neurogenesis following chronic antidepressant treatment activates brain derived neurotrophic factor (BDNF) signaling. In this study, we analyzed the effects of the SSRI fluvoxamine (Flu) on locomotor activity and forced-swim behavior using chronic dexamethasone (cDEX) infusions in mice, which engenders depression-like behavior. Infusion of cDEX decreased body weight and produced a trend towards lower locomotor activity during darkness. In the forced-swim test, cDEX-mice exhibited increased immobility times compared with mice administered saline. Flu treatment reversed decreased locomotor activity and mitigated forced-swim test immobility. Real-time polymerase chain reactions using brain RNA samples yielded significantly lower BDNF mRNA levels in cDEX-mice compared with the saline group. Endoplasmic reticulum stress-associated X-box binding protein-1 (XBP1) gene expression was lower in cDEX-mice compared with the saline group. However, marked expression of the XBP1 gene was observed in cDEX-mice treated with Flu compared with mice given saline and untreated cDEX-mice. Expression of 5-HT2A and Sigma-1 receptors decreased after cDEX infusion compared with the saline group, and these decreases normalized to control levels upon Flu treatment. Our results indicate that the Flu moderates reductions in voluntary activity following chronic dexamethasone infusions in mice via recovery of BDNF signal cascades.

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

    PubMed

    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.

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

    PubMed Central

    Huie, J. Russell

    2016-01-01

    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. PMID:27721996

  4. [The role of BDNF in brain ischemia pulmonary edema].

    PubMed

    Zhang, Yun-Hui; Wang, Ting-Hua

    2012-11-01

    Brain ischemia pulmonary edema(BIPE)is a critical type of the neurogenic pulmonary edema (NPE), with acute development and progression and high mortality. The study on mechanism of BIPE has important scientific significance and substantial practice values. NPE, as a complicated physiopathology condition, is not resulted from single factor but systemic events including the changes in nervous system, body fluid regulation and endocrine involved in central nervous system after the injury. The studies on this topic in this current issue suggested that brain-derived neurotrophic factor (BDNF) could involve in the pathogenesis procedure of NPE following brain ischemia, which indicated that the crucial role of BDNF in the NPE after BIPE. The findings of these studies pave a way for the treatment of BIPE by using BDNF administration in future clinic trail.

  5. BDNF in schizophrenia, depression and corresponding animal models.

    PubMed

    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.

  6. The melatonin-MT1 receptor axis modulates mutant huntingtin-mediated toxicity

    PubMed Central

    Wang, Xin; Sirianni, Ana; Pei, Zhijuan; Cormier, Kerry; Smith, Karen; Jiang, Jiying; Zhou, Shuanhu; Wang, Hui; Zhao, Rong; Yano, Hiroko; Kim, Jeong Eun; Li, Wei; Kristal, Bruce S.; Ferrante, Robert J.; Friedlander, Robert M.

    2011-01-01

    Melatonin mediates neuroprotection in several experimental models of neurodegeneration. It is not yet known, however, whether melatonin provides neuroprotection in genetic models of Huntington’s disease (HD). We report that melatonin delays disease onset and mortality in a transgenic mouse model of HD. Moreover, mutant huntingtin (htt)-mediated toxicity in cells, mice, and humans is associated with loss of the type 1 melatonin receptor (MT1). We observe high levels of MT1 receptor in mitochondria from the brains of wild-type mice but much less in brains from HD mice. Moreover, we demonstrate that melatonin inhibits mutant htt-induced caspase activation and preserves MT1 receptor expression. This observation is critical, since melatonin-mediated protection is dependent upon the presence and activation of the MT1 receptor. In summary, we delineate a pathologic process whereby mutant htt-induced loss of the mitochondrial MT1 receptor enhances neuronal vulnerability and potentially accelerates the neurodegenerative process. PMID:21994366

  7. A huntingtin-mediated fast stress response halting endosomal trafficking is defective in Huntington's disease

    PubMed Central

    Nath, Siddharth; Munsie, Lise N.; Truant, Ray

    2015-01-01

    Cellular stress is a normal part of the aging process and is especially relevant in neurodegenerative disease. Canonical stress responses, such as the heat shock response, activate following exposure to stress and restore proteostasis through the action of isomerases and chaperones within the cytosol. Through live-cell imaging, we demonstrate involvement of the Huntington's disease (HD) protein, huntingtin, in a rapid cell stress response that lies temporally upstream of canonical stress responses. This response is characterized by the formation of distinct cytosolic puncta and reversible localization of huntingtin to early endosomes. The formation of these puncta, which we have termed huntingtin stress bodies (HSBs), is associated with arrest of early-to-recycling and early-to-late endosomal trafficking. The critical domains for this response have been mapped to two regions of huntingtin flanking the polyglutamine tract, and we observe polyglutamine-expanded huntingtin-expressing cells to be defective in their ability to recover from this stress response. We propose that HSB formation rapidly diverts high ATP use from vesicular trafficking during stress, thus mobilizing canonical stress responses without relying on increased energy metabolism, and that restoration from this response is defective in HD. PMID:25205111

  8. The transrepression arm of glucocorticoid receptor signaling is protective in mutant huntingtin-mediated neurodegeneration

    PubMed Central

    Varadarajan, S; Breda, C; Smalley, J L; Butterworth, M; Farrow, S N; Giorgini, F; Cohen, G M

    2015-01-01

    The unfolded protein response (UPR) occurs following the accumulation of unfolded proteins in the endoplasmic reticulum (ER) and orchestrates an intricate balance between its prosurvival and apoptotic arms to restore cellular homeostasis and integrity. However, in certain neurodegenerative diseases, the apoptotic arm of the UPR is enhanced, resulting in excessive neuronal cell death and disease progression, both of which can be overcome by modulating the UPR. Here, we describe a novel crosstalk between glucocorticoid receptor signaling and the apoptotic arm of the UPR, thus highlighting the potential of glucocorticoid therapy in treating neurodegenerative diseases. Several glucocorticoids, but not mineralocorticoids, selectively antagonize ER stress-induced apoptosis in a manner that is downstream of and/or independent of the conventional UPR pathways. Using GRT10, a novel selective pharmacological modulator of glucocorticoid signaling, we describe the importance of the transrepression arm of the glucocorticoid signaling pathway in protection against ER stress-induced apoptosis. Furthermore, we also observe the protective effects of glucocorticoids in vivo in a Drosophila model of Huntington's disease (HD), wherein treatment with different glucocorticoids diminished rhabdomere loss and conferred neuroprotection. Finally, we find that growth differentiation factor 15 has an important role downstream of glucocorticoid signaling in antagonizing ER stress-induced apoptosis in cells, as well as in preventing HD-mediated neurodegeneration in flies. Thus, our studies demonstrate that this novel crosstalk has the potential to be effectively exploited in alleviating several neurodegenerative disorders. PMID:25656655

  9. 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.

    PubMed

    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

  10. Occlusal disharmony induces BDNF level in rat submandibular gland.

    PubMed

    Irie, Koichiro; Ekuni, Daisuke; Tomofuji, Takaaki; Azuma, Tetsuji; Endo, Yasumasa; Kasuyama, Kenta; Morita, Manabu

    2011-01-01

    brain-derived neurotrophic factor (BDNF), which is produced in rat submandibular gland, is one of the most abundant neurotrophins in the central nervous system. It is generally accepted that occlusal disharmony causes stress. The purpose of the present study was to investigate whether occlusal disharmony-induced chronic stress affects BDNF levels and morphology in rat submandibular gland. eight wks old male Wistar rats (n=21) were randomly divided into three groups of 7 rats. In a control (C) group, the rats received no treatment for 8 wks. In a molar cusp-less (OD) group, maxillary molar cusps were cut off with a dental turbine at baseline and kept for 8 wks. In a molar cusp-less + recovered cusp (OR) group, maxillary molar cusps were cut off and then were recovered after 4 wks using resin material. After the experimental period, expression of BDNF mRNA and protein as well as histological findings were evaluated in the submandibular glands. The comparisons between the groups were made using the Mann-Whitney U test with Bonferroni correction. the OD group showed a significant increase in submandibular gland BDNF mRNA and protein expression after 8 wks, and plasma adrenocorticotropic hormone and corticosterone levels increased in a time-dependent manner. There were no significant differences in BDNF expression in the submandibular glands and in levels of plasma adrenocorticotropic hormone and corticosterone between the OR and C groups. these results indicate that psychological stress induced by occlusal disharmony reversibly induces BDNF expression in the rat submandibular gland. 2010 Elservier Ltd. All Rights reserved.

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

    PubMed

    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.

  12. MicroRNA-107 inhibits tumor growth and metastasis by targeting the BDNF-mediated PI3K/AKT pathway in human non-small lung cancer.

    PubMed

    Xia, Huan; Li, Yang; Lv, Xiaohong

    2016-10-01

    Abnormal expression of microRNA-107 (miR-107) was found in non-small cell lung cancer (NSCLC). However, little is known about its role and molecular mechanism in NSCLC progression and metastasis. Therefore, the aims of this study were to clarify the potential role of miR-107 and molecular mechanism in NSCLC progression and metastasis. Quantitative real-time polymerase chain reaction assay showed that miR-107 expression levels were significantly decreased in NSCLC tissue and cell lines. Low miR-107 levels in tumor tissue correlated with advanced TNM stage and lymph node metastasis. Function assays showed that overexpression of miR-107 suppressed cell proliferation, migration and invasion in A549 cells in vitro, and inhibited NSCLC tumor growth in vivo. Further mechanism assays suggested the brain-derived neurotrophic factor (BDNF) was identified as a target gene of miR-107 in NSCLC cells. In addition, BDNF expression was upregulated, and inversely correlated with miR-107 in NSCLC tissues. Enforced overexpression of BDNF effectively reversed the tumor suppressive functions of miR-107 on NSCLC proliferation, migration and invasion. miR-107 overexpression or downregulation of BDNF was able to inhibit activation of PI3K/AKT signaling pathway. Taken together, our findings present the first evidence that miR-107 could suppress NSCLC metastasis by targeting BDNF and indirectly regulating PI3K/AKT signaling pathway, which might lead to a potential therapeutic strategy focusing on miR-107 and BDNF for human NSCLC.

  13. Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety.

    PubMed

    Gatt, J M; Nemeroff, C B; Dobson-Stone, C; Paul, R H; Bryant, R A; Schofield, P R; Gordon, E; Kemp, A H; Williams, L M

    2009-07-01

    Individual risk markers for depression and anxiety disorders have been identified but the explicit pathways that link genes and environment to these markers remain unknown. Here we examined the explicit interactions between the brain-derived neurotrophic factor (BDNF) Val66Met gene and early life stress (ELS) exposure in brain (amygdala-hippocampal-prefrontal gray matter volume), body (heart rate), temperament and cognition in 374 healthy European volunteers assessed for depression and anxiety symptoms. Brain imaging data were based on a subset of 89 participants. Multiple regression analysis revealed main effects of ELS for body arousal (resting heart rate, P=0.005) and symptoms (depression and anxiety, P<0.001) in the absence of main effects for BDNF. In addition, significant BDNF-ELS interactions indicated that BDNF Met carriers exposed to greater ELS have smaller hippocampal and amygdala volumes (P=0.013), heart rate elevations (P=0.0002) and a decline in working memory (P=0.022). Structural equation path modeling was used to determine if this interaction predicts anxiety and depression by mediating effects on the brain, body and cognitive measures. The combination of Met carrier status and exposure to ELS predicted reduced gray matter in hippocampus (P<0.001), and associated lateral prefrontal cortex (P<0.001) and, in turn, higher depression (P=0.005). Higher depression was associated with poorer working memory (P=0.005), and slowed response speed. The BDNF Met-ELS interaction also predicted elevated neuroticism and higher depression and anxiety by elevations in body arousal (P<0.001). In contrast, the combination of BDNF V/V genotype and ELS predicted increases in gray matter of the amygdala (P=0.003) and associated medial prefrontal cortex (P<0.001), which in turn predicted startle-elicited heart rate variability (P=0.026) and higher anxiety (P=0.026). Higher anxiety was linked to verbal memory, and to impulsivity. These effects were specific to the BDNF

  14. The distribution of PGP9. 5, BDNF and NGF in the vallate papilla of adult and developing mice.

    PubMed

    Chou, H C; Chien, C L; Lu, K S

    2001-08-01

    The development and innervation of vallate papillae and taste buds in mice were studied using antibodies against the neuronal marker, protein gene product 9.5 (PGP 9.5), and against nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). PGP 9.5 immunohistochemical studies revealed that the earliest sign of median vallate papilla formation was an epithelial bulge at embryonic day 13 (E13), and at E14, a dense nerve plexus was found within the connective tissue core of the papilla. Thin nerve fibers penetrated the apical and medial trench wall epithelium of the papilla at E16 and a few of these began to invade the lateral trench wall epithelium at E17. At postnatal day 1 (P1), the newly formed taste buds were recognizable and a small number of PGP 9.5-immunoreactive (IR) cells appeared on the medial trench wall epithelium. The number of PGP 9.5-IR taste bud cells then increased gradually and reached the adult level at postnatal week 2. PGP 9.5 immunoreactivity increased systematically with age. NGF and BDNF immunoreactivity was first seen at the boundary between the columnar cells in the apical epithelium of the developing vallate papilla at E13, then in the medial and lateral trench walls at E15 (BDNF) or E18 (NGF). At P1, BDNF immunoreactivity was exclusively present in the newly formed taste buds of the medial trench wall. The number of BDNF-IR taste bud cells then increased gradually, reaching the adult level at P7. Similar degrees of NGF and BDNF immunoreactivity were seen in the developing vallate papilla. In the present study, we found that the vallate papilla was formed prior to its innervation, and we propose that initiation of papilla formation does not require any direct influence from the specific gustatory nerve. We also suggest that neurotrophins in the early developing vallate papillae might act as local tropic factors for the embryonic growth of nerve fibers to induce differentiation of the taste buds.

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

    PubMed

    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.

  16. Maternal prenatal anxiety and child brain-derived neurotrophic factor (BDNF) genotype: effects on internalizing symptoms from 4 to 15 years of age.

    PubMed

    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.

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

    PubMed Central

    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. PMID:26241953

  18. Performance-related increases in hippocampal N-acetylaspartate (NAA) induced by spatial navigation training are restricted to BDNF Val homozygotes.

    PubMed

    Lövdén, Martin; Schaefer, Sabine; Noack, Hannes; Kanowski, Martin; Kaufmann, Jörn; Tempelmann, Claus; Bodammer, Nils Christian; Kühn, Simone; Heinze, Hans-Jochen; Lindenberger, Ulman; Düzel, Emrah; Bäckman, Lars

    2011-06-01

    Recent evidence indicates experience-dependent brain volume changes in humans, but the functional and histological nature of such changes is unknown. Here, we report that adult men performing a cognitively demanding spatial navigation task every other day over 4 months display increases in hippocampal N-acetylaspartate (NAA) as measured with magnetic resonance spectroscopy. Unlike measures of brain volume, changes in NAA are sensitive to metabolic and functional aspects of neural and glia tissue and unlikely to reflect changes in microvasculature. Training-induced changes in NAA were, however, absent in carriers of the Met substitution in the brain-derived neurotrophic factor (BDNF) gene, which is known to reduce activity-dependent secretion of BDNF. Among BDNF Val homozygotes, increases in NAA were strongly related to the degree of practice-related improvement in navigation performance and normalized to pretraining levels 4 months after the last training session. We conclude that changes in demands on spatial navigation can alter hippocampal NAA concentrations, confirming epidemiological studies suggesting that mental experience may have direct effects on neural integrity and cognitive performance. BDNF genotype moderates these plastic changes, in line with the contention that gene-context interactions shape the ontogeny of complex phenotypes.

  19. Increased blood BDNF in healthy individuals with a family history of depression.

    PubMed

    Knorr, Ulla; Søndergaard, Mia H Greisen; Koefoed, Pernille; Jørgensen, Anders; Faurholt-Jepsen, Maria; Vinberg, Maj; Kessing, Lars Vedel

    2017-10-01

    The brain-derive neurotrophic factor (BDNF) may play an important role in the course of depression. We aimed to study the associations between peripheral whole blood BDNF levels in healthy individuals with and without a family history of depression. BDNF levels were significantly increased in healthy individuals with (n = 76), compared with healthy individuals without (n = 39) a family history of depression and persisted after adjustment for age and gender differences. Higher BDNF levels were associated with increasing age and seasonality. A family history of depression may contribute to an elevation of peripheral BDNF levels in healthy individuals. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Tobacco use is associated with increased plasma BDNF levels in depressed patients.

    PubMed

    Colle, Romain; Trabado, Séverine; Rotenberg, Samuel; Brailly-Tabard, Sylvie; Benyamina, Amine; Aubin, Henri-Jean; Hardy, Patrick; Falissard, Bruno; Becquemont, Laurent; Verstuyft, Céline; Fève, Bruno; Corruble, Emmanuelle

    2016-12-30

    Since serum Brain Derived Neurotrophic Factor (BDNF) levels are higher in tobacco smokers than in non-smokers and since Major Depressive Disorder (MDD) is associated with a 2-fold increased risk of smoking, we assessed the association of smoking and plasma BDNF levels in 359 depressed MDD patients. Plasma BDNF levels were positively correlated with the magnitude of tobacco consumption (current number of cigarettes/day and number of packs/year). Accordingly, current tobacco users had significantly higher plasma BDNF levels than non-users. In further studies of MDD, peripheral measures of BDNF should take into account tobacco use.

  1. Transient changes of brain-derived neurotrophic factor (BDNF) mRNA expression in hippocampus during moderate ischemia induced by chronic bilateral common carotid artery occlusions in the rat.

    PubMed

    Schmidt-Kastner, R; Truettner, J; Lin, B; Zhao, W; Saul, I; Busto, R; Ginsberg, M D

    2001-08-15

    Chronic bilateral common carotid artery occlusion (BCCAO) induces moderate ischemia (oligemia) in the rat forebrain in the absence of overt neuronal damage. In situ hybridization for brain-derived neurotrophic factor (BDNF) mRNA was used to search for a molecular response to moderate ischemia. BDNF mRNA was significantly increased in the hippocampal granule cells at 6 h of occlusion (ANOVA, Tukey test P<0.05). At 1, 7 and 14 days BDNF mRNA levels returned to control levels. The frequency of BDNF gene expression at 6 h was 83%, which was significantly higher than the 7% incidence of histological injury in the hippocampus (Fisher's exact test, P<0.002). Cerebral blood flow was reduced to 75% of control levels in the hippocampus after 1 week of BCCAO when measured with the autoradiographic method. Measurements of tissue flow with a microprobe for laser Doppler flow excluded decreases into the ischemic range during the period when elevated gene expression was observed. Prolonged moderate ischemia (oligemia) is a sufficient stimulus for BDNF gene expression in the hippocampus. These molecular studies provide direct evidence for an involvement of the hippocampus in the BCCAO model.

  2. Physical Exercise and Antidepressants Enhance BDNF Targeting in Hippocampal CA3 Dendrites: Further Evidence of a Spatial Code for BDNF Splice Variants

    PubMed Central

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

    2012-01-01

    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. PMID:22318196

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

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed Central

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

    2012-01-01

    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-p75NTR 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. PMID:23019376

  8. Epibranchial placode-derived neurons produce BDNF required for early sensory neuron development.

    PubMed

    Harlow, Danielle E; Yang, Hui; Williams, Trevor; Barlow, Linda A

    2011-02-01

    In mice, BDNF provided by the developing taste epithelium is required for gustatory neuron survival following target innervation. However, we find that expression of BDNF, as detected by BDNF-driven β-galactosidase, begins in the cranial ganglia before its expression in the central (hindbrain) or peripheral (taste papillae) targets of these sensory neurons, and before gustatory ganglion cells innervate either target. To test early BDNF function, we examined the ganglia of bdnf null mice before target innervation, and found that while initial neuron survival is unaltered, early neuron development is disrupted. In addition, fate mapping analysis in mice demonstrates that murine cranial ganglia arise from two embryonic populations, i.e., epibranchial placodes and neural crest, as has been described for these ganglia in non-mammalian vertebrates. Only placodal neurons produce BDNF, however, which indicates that prior to innervation, early ganglionic BDNF produced by placode-derived cells promotes gustatory neuron development.

  9. Polarized signaling endosomes coordinate BDNF-induced chemotaxis of cerebellar precursors

    PubMed Central

    Zhou, Pengcheng; Porcionatto, Marimelia; Pilapil, Mariecel; Chen, Yicheng; Choi, Yoojin; Tolias, Kimberley F.; Bikoff, Jay B.; Hong, Elizabeth J.; Greenberg, Michael E.; Segal, Rosalind A.

    2007-01-01

    Summary During development, neural precursors migrate in response to positional cues such as growth factor gradients. However, the mechanisms that enable precursors to sense and respond to such gradients are poorly understood. Here we show that cerebellar granule cell precursors (GCPs) migrate along a gradient of brain-derived neurotrophic factor (BDNF), and we demonstrate that vesicle trafficking is critical for this chemotactic process. Activation of TrkB, the BDNF receptor, stimulates GCPs to secrete BDNF, thereby amplifying the ambient gradient. The BDNF gradient stimulates endocytosis of TrkB and associated signaling molecules, causing asymmetric accumulation of signaling endosomes at the subcellular location where BDNF concentration is maximal. Thus regulated BDNF exocytosis and TrkB endocytosis enable precursors to polarize and migrate in a directed fashion along a shallow BDNF gradient. PMID:17610817

  10. Polarized signaling endosomes coordinate BDNF-induced chemotaxis of cerebellar precursors.

    PubMed

    Zhou, Pengcheng; Porcionatto, Marimelia; Pilapil, Mariecel; Chen, Yicheng; Choi, Yoojin; Tolias, Kimberley F; Bikoff, Jay B; Hong, Elizabeth J; Greenberg, Michael E; Segal, Rosalind A

    2007-07-05

    During development, neural precursors migrate in response to positional cues such as growth factor gradients. However, the mechanisms that enable precursors to sense and respond to such gradients are poorly understood. Here we show that cerebellar granule cell precursors (GCPs) migrate along a gradient of brain-derived neurotrophic factor (BDNF), and we demonstrate that vesicle trafficking is critical for this chemotactic process. Activation of TrkB, the BDNF receptor, stimulates GCPs to secrete BDNF, thereby amplifying the ambient gradient. The BDNF gradient stimulates endocytosis of TrkB and associated signaling molecules, causing asymmetric accumulation of signaling endosomes at the subcellular location where BDNF concentration is maximal. Thus, regulated BDNF exocytosis and TrkB endocytosis enable precursors to polarize and migrate in a directed fashion along a shallow BDNF gradient.

  11. TRPC Channels as Novel Effectors of BDNF Signaling: Potential Implications for Rett Syndrome

    PubMed Central

    Amaral, Michelle D.; Chapleau, Christopher A.; Pozzo-Miller, Lucas

    2007-01-01

    In addition to their prominent role as survival signals for neurons in the developing nervous system, neurotrophins have established their significance in the adult bra