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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. BDNF GENE EFFECTS ON BRAIN CIRCUITRY REPLICATED IN 455 TWINS

    PubMed Central

    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.

    2011-01-01

    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. The BDNF gene may affect intellectual performance by modulating 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. PMID:21195196

  3. Family-based study of brain-derived neurotrophic factor (BDNF) gene polymorphism in alcohol dependence.

    PubMed

    Grzywacz, Anna; Samochowiec, Agnieszka; Ciechanowicz, Andrzej; Samochowiec, Jerzy

    2010-01-01

    Brain-derived neurotrophic factor (BDNF) belongs to a family of proteins related to the nerve growth factor family, which are responsible for the proliferation, survival and differentiation of neurons. BDNF is thought to be involved in the pathogenesis of bipolar disorder, schizophrenia, eating disorders and addiction. We hypothesize that a functionally relevant polymorphism of the BDNF gene promoter may be associated with the pathogenesis of alcohol dependence. We performed an association study of 141 families with alcohol dependence. One hundred and thirty-eight healthy control subjects were matched based on ethnicity and gender. An association between the BDNF Val66Met gene polymorphism and alcoholism was not found. PMID:21098877

  4. BDNF genetic variants are associated with onset age of familial Parkinson disease: GenePD Study.

    PubMed

    Karamohamed, S; Latourelle, J C; Racette, B A; Perlmutter, J S; Wooten, G F; Lew, M; Klein, C; Shill, H; Golbe, L I; Mark, M H; Guttman, M; Nicholson, G; Wilk, J B; Saint-Hilaire, M; DeStefano, A L; Prakash, R; Tobin, S; Williamson, J; Suchowersky, O; Labell, N; Growdon, B N J; Singer, C; Watts, R; Goldwurm, S; Pezzoli, G; Baker, K B; Giroux, M L; Pramstaller, P P; Burn, D J; Chinnery, P; Sherman, S; Vieregge, P; Litvan, I; Gusella, J F; Myers, R H; Parsian, A

    2005-12-13

    Brain-derived neurotrophic factor (BDNF) stimulates neuronal growth and protects nigral dopamine neurons in animal models of Parkinson disease (PD). Therefore, BDNF is a candidate gene for PD. The authors investigated five single-nucleotide polymorphisms in 597 cases of familial PD. Homozygosity for the rare allele of the functional BDNF G196A (Val66Met) variant was associated with a 5.3-year older onset age (p = 0.0001). These findings suggest that BDNF may influence PD onset age. PMID:16344533

  5. 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

  6. Population genetic study of the brain-derived neurotrophic factor (BDNF) gene

    PubMed Central

    Petryshen, TL; Sabeti, PC; Aldinger, KA; Fry, B; Fan, JB; Schaffner, SF; Waggoner, SG; Tahl, AR; Sklar, P

    2009-01-01

    Genetic variants in the brain-derived neurotrophic factor (BDNF) gene, predominantly the functional Val66Met polymorphism, have been associated with risk of bipolar disorder and other psychiatric disorders. However, not all studies support these findings, and overall the evidence for BDNF association with disease risk is weak. As differences in population genetic structure between patient samples could cause discrepant or spurious association results, we investigated this possibility by carrying out population genetic analyses of the BDNF genomic region. Substantial variation was detected in BDNF coding region SNP allele and haplotype frequencies between 58 global populations, with the derived Met allele of Val66Met ranging from 0–72% frequency across populations. FST analyses to assess diversity in the HapMap populations determined that the Val66Met FST value was at the 99.8th percentile among all SNPs in the genome. As the BDNF population genetic differences may be due to local selection, we performed the long-range haplotype (LRH) test for selection using 68 SNPs spanning the BDNF genomic region in 12 European-derived pedigrees. Evidence for positive selection was found for a high frequency Val-carrying haplotype, with a relative extended haplotype homozygosity (REHH) value above the 99th percentile compared to HapMap data (P=4.6 ×10−4). In conclusion, we observed considerable BDNF allele and haplotype diversity among global populations and evidence for positive selection at the BDNF locus. These phenomena can have a profound impact on detection of disease susceptibility genes and must be considered in gene association studies of BDNF. PMID:19255578

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

    PubMed

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

    2012-08-01

    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 h 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

  8. BDNF gene polymorphisms and haplotypes in relation to cognitive performance in Polish healthy subjects.

    PubMed

    Wiłkość, Monika; Szałkowska, Agnieszka; Skibińska, Maria; Zając-Lamparska, Ludmiła; Maciukiewicz, Małgorzata; Araszkiewicz, Aleksander

    2016-01-01

    The brain derived neurotrophic factor (BDNF) is a neurotrophin that plays an important role in the cell survival, axonal and dendritic growth, and synaptic plasticity. BDNF gene polymorphisms, 'functional Val66Met mainly, were shown to influence human brain structure and cognition. The aim of the study was to assess the relationship between twelve BDNF gene variants and their haplotypes and cognitive performance measured using the Wisconsin Card Sorting Test (WCST), the Trail Making Test (TMT), the Stroop Test which are to a large extent connected with prefrontal cortex activity. Our sample consisted of 460 healthy participants from Polish population. We detected possible association between five BDNF polymorphisms (rs11030101, rs10835210, rs2049046, rs2030324, rs2883187) and TMT_A. Additionally, one haplotype block made from eleven BDNF variants (rs2883187, rs1401635, rs2049046, rs2030324, rs11030101, rs10835210, rs1013402, rs1401635, rs1013402), as significant linkage disequilibrium appeared. We discovered possible relationships of CACCGCGTACG and CACCGCGTACG haplotypes with TMT_A and TMT_B performance respectively. Our results confirmed the involvement of BDNF in the regulation of psychomotor speed, working memory and executive function in healthy subjects measured by a task engaging visuoperceptual abilities. PMID:27102917

  9. 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

  10. 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. PMID:26977770

  11. Gene Transfer of Brain-derived Neurotrophic Factor (BDNF) Prevents Neurodegeneration Triggered by FXN Deficiency.

    PubMed

    Katsu-Jiménez, Yurika; Loría, Frida; Corona, Juan Carlos; Díaz-Nido, Javier

    2016-05-01

    Friedreich's ataxia is a predominantly neurodegenerative disease caused by recessive mutations that produce a deficiency of frataxin (FXN). Here, we have used a herpesviral amplicon vector carrying a gene encoding for brain-derived neurotrophic factor (BDNF) to drive its overexpression in neuronal cells and test for its effect on FXN-deficient neurons both in culture and in the mouse cerebellum in vivo. Gene transfer of BDNF to primary cultures of mouse neurons prevents the apoptosis which is triggered by the knockdown of FXN gene expression. This neuroprotective effect of BDNF is also observed in vivo in a viral vector-based knockdown mouse cerebellar model. The injection of a lentiviral vector carrying a minigene encoding for a FXN-specific short hairpin ribonucleic acid (shRNA) into the mouse cerebellar cortex triggers a FXN deficit which is accompanied by significant apoptosis of granule neurons as well as loss of calbindin in Purkinje cells. These pathological changes are accompanied by a loss of motor coordination of mice as assayed by the rota-rod test. Coinjection of a herpesviral vector encoding for BDNF efficiently prevents both the development of cerebellar neuropathology and the ataxic phenotype. These data demonstrate the potential therapeutic usefulness of neurotrophins like BDNF to protect FXN-deficient neurons from degeneration. PMID:26849417

  12. 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

  13. Cognitive dysfunction and epigenetic alterations of the BDNF gene are induced by social isolation during early adolescence.

    PubMed

    Li, Man; Du, Wei; Shao, Feng; Wang, Weiwen

    2016-10-15

    Early life adversity, such as social isolation, causes a variety of changes to the development of cognitive abilities and the nervous system. Increasing evidence has shown that epigenetic modifications mediate gene-environment interactions throughout the lifespan. In this study, we investigated the effect of adolescent social isolation on cognitive behaviours and epigenetic alterations of the brain-derived neurotrophic factor (BDNF) gene. Male Sprague Dawley rats were randomly assigned to either group-reared or isolation-reared conditions during post-natal days (PNDs) 21-34. On PND 56, all rats underwent behavioural testing and were then sacrificed for biochemical testing. Adolescent social isolation induced impaired PPI. Regarding BDNF, the isolation-reared rats demonstrated increased BDNF mRNA levels, H3 acetylation at the BDNF gene and BDNF protein expression in the medial prefrontal cortex (mPFC). In contrast, the BDNF mRNA levels, H3 acetylation of the BDNF gene and BDNF protein expression were decreased in the hippocampus of the isolation-reared rats. The present study indicated that epigenetic regulation of BDNF may be one of the molecular mechanisms that mediated the cognitive dysfunction. Moreover, the interaction between the mPFC and hippocampus might play an important role in the regulation of cognitive behaviour. PMID:27435421

  14. 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

  15. 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

  16. 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

    2016-01-01

    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

  17. Early life stress increases stress vulnerability through BDNF gene epigenetic changes in the rat hippocampus.

    PubMed

    Seo, Mi Kyoung; Ly, Nguyen Ngoc; Lee, Chan Hong; Cho, Hye Yeon; Choi, Cheol Min; Nhu, Le Hoa; Lee, Jung Goo; Lee, Bong Ju; Kim, Gyung-Mee; Yoon, Bong June; Park, Sung Woo; Kim, Young Hoon

    2016-06-01

    Early life stress (ELS) exerts long-lasting epigenetic influences on the brain and makes an individual susceptible to later depression. It is poorly understood whether ELS and subsequent adult chronic stress modulate epigenetic mechanisms. We examined the epigenetic mechanisms of the BDNF gene in the hippocampus, which may underlie stress vulnerability to postnatal maternal separation (MS) and adult restraint stress (RS). Rat pups were separated from their dams (3 h/day from P1-P21). When the pups reached adulthood (8 weeks old), we introduced RS (2 h/day for 3 weeks) followed by escitalopram treatment. We showed that both the MS and RS groups expressed reduced levels of total and exon IV BDNF mRNA. Furthermore, RS potentiated MS-induced decreases in these expression levels. Similarly, both the MS and RS groups showed decreased levels of acetylated histone H3 and H4 at BDNF promoter IV, and RS exacerbated MS-induced decreases of H3 and H4 acetylation. Both the MS and RS groups had increased MeCP2 levels at BDNF promoter IV, as well as increased HDAC5 mRNA, and the combination of MS and RS exerted a greater effect on these parameters than did RS alone. In the forced swimming test, the immobility time of the MS + RS group was significantly higher than that of the RS group. Additionally, chronic escitalopram treatment recovered these alterations. Our results suggest that postnatal MS and subsequent adult RS modulate epigenetic changes in the BDNF gene, and that these changes may be related to behavioral phenotype. These epigenetic mechanisms are involved in escitalopram action. PMID:26877199

  18. Histone modifications around individual BDNF gene promoters in prefrontal cortex are associated with extinction of conditioned fear.

    PubMed

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

    2007-04-01

    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, in these studies, we have investigated whether epigenetic regulation of gene expression contributes to fear extinction. Since brain-derived neurotrophic factor (BDNF) is crucial for synaptic plasticity and for the maintenance of long-term memory, we examined histone modifications around two BDNF gene promoters after extinction of cued fear, as potential targets of learning-induced epigenetic regulation of gene expression. Valproic acid (VPA), used for some time as an anticonvulsant and a mood stabilizer, modulates the expression of BDNF, and is a histone deacetylase (HDAC) inhibitor. Here, we report that extinction of conditioned fear is accompanied by a significant increase in histone H4 acetylation around the BDNF P4 gene promoter and increases in BDNF exon I and IV mRNA expression in prefrontal cortex, that VPA enhances long-term memory for extinction because of its HDAC inhibitor effects, and that VPA potentiates the effect of weak extinction training on histone H4 acetylation around both the BDNF P1 and P4 gene promoters and on BDNF exon IV mRNA expression. These results suggest a relationship between histone H4 modification, epigenetic regulation of BDNF gene expression, and long-term memory for extinction of conditioned fear. In addition, they suggest that HDAC inhibitors may become a useful pharmacological adjunct to psychotherapy for human anxiety disorders. PMID:17522015

  19. Correlation of 5-HTT, BDNF and NPSR1 gene polymorphisms with anxiety and depression in asthmatic patients

    PubMed Central

    YANG, YUAN; ZHAO, MINGZHE; ZHANG, YUQUN; SHEN, XINHUA; YUAN, YONGGUI

    2016-01-01

    Asthmatic patients are known to have a higher risk of anxiety and depression. In the present study, we aimed to explore the association of serotonin transporter (5-HTT), brain-derived neurotrophic factor (BDNF) and neuropeptide S receptor 1 (NPSR1) gene polymorphisms with anxiety and depression in asthmatic patients. This was a cross-sectional study conducted on 143 asthmatic patients and 175 healthy volunteers. Of the asthmatic patients, 49 suffered from anxiety and 12 exhibited signs of depression. Patients with a lower level of education were more prone to depression. Both anxiety and depression were associated with poor asthma control as evaluated by the Asthma Control Test (ACT) score. The association of single nucleotide polymorphisms of BDNF, NPSR1 and 5-HTT with anxiety and depression in asthamtic patients was evaluated. The distribution of 5-HTT gene polymorphisms in the healthy group, the group with asthma but without anxiety, and the group with asthma and anxiety had significant differences. Females with asthma and anxiety were more prone to BDNF polymorphism. Also, BDNF gene distribution exhibited significant differences among those in the healthy group, the group with asthma but no depression, and the group with asthma and depression; however, NPSR1 gene distribution did not vary greatly between the groups. The anxiety score was significantly affected by the interaction between 5-HTT (LL, S+) and BDNF (A+, GG) (H=5.99, P=0.015). The depression score was significantly affected by the interaction between BDNF (A+, GG) and NPSR1 (AA, T+). We noted that both anxiety and depression led to poor asthma control. The interaction between 5-HTT (LL) and BDNF (A+) increased the risk of anxiety, and the interaction between BDNF (A+, GG) and NPSR1 (AA, T+) increased the risk of depression in asthmatic patients. PMID:27176146

  20. 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…

  1. 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

    2015-01-01

    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. PMID:25132151

  2. Demethylation regulation of BDNF gene expression in dorsal root ganglion neurons is implicated in opioid-induced pain hypersensitivity in rats.

    PubMed

    Chao, Yu-Chieh; Xie, Fang; Li, Xueyang; Guo, Ruijuan; Yang, Ning; Zhang, Chen; Shi, Rong; Guan, Yun; Yue, Yun; Wang, Yun

    2016-07-01

    Repeated administration of morphine may result in opioid-induced hypersensitivity (OIH), which involves altered expression of numerous genes, including brain-derived neurotrophic factor (BDNF) in dorsal root ganglion (DRG) neurons. Yet, it remains unclear how BDNF expression is increased in DRG neurons after repeated morphine treatment. DNA methylation is an important mechanism of epigenetic control of gene expression. In the current study, we hypothesized that the demethylation regulation of certain BDNF gene promoters in DRG neurons may contribute to the development of OIH. Real-time RT-PCR was used to assess changes in the mRNA transcription levels of major BDNF exons including exon I, II, IV, VI, as well as total BDNF mRNA in DRGs from rats after repeated morphine administration. The levels of exon IV and total BDNF mRNA were significantly upregulated by repeated morphine administration, as compared to that in saline control group. Further, ELISA array and immunocytochemistry study revealed a robust upregulation of BDNF protein expression in DRG neurons after repeated morphine exposure. Correspondingly, the methylation levels of BDNF exon IV promoter showed a significant downregulation by morphine treatment. Importantly, intrathecal administration of a BDNF antibody, but not control IgG, significantly inhibited mechanical hypersensitivity that developed in rats after repeated morphine treatment. Conversely, intrathecal administration of an inhibitor of DNA methylation, 5-aza-2'-deoxycytidine (5-aza-dC) markedly upregulated the BDNF protein expression in DRG neurons and enhanced the mechanical allodynia after repeated morphine exposure. Together, our findings suggest that demethylation regulation of BDNF gene promoter may be implicated in the development of OIH through epigenetic control of BDNF expression in DRG neurons. PMID:26970395

  3. [Anxiety and polymorphism Val66Met of BDNF gene--predictors of depression severity in ischemic heart disease].

    PubMed

    Golimbet, V E; Volel', B A; Kopylov, F Iu; Dolzhikov, A V; Korovaitseva, G I; Kasparov, S V; Isaeva, M I

    2015-01-01

    In a framework of search for early predictors of depression in patients with ischemic heart disease (IHD) we studied effect of molecular-genetic factors (polymorphism of brain-derived neirotrophic factor--BDNF), personality traits (anxiety, neuroticism), IHD severity, and psychosocial stressors on manifestations of depression in men with verified diagnosis of IHD. Severity of depression was assessed by Hamilton Depression Rating Scale 21-item (HAMD 21), anxiety and neuroticism were evaluated by the Spielberger State-Trait Anxiety Inventory and "Big Five" questionnaire, respectively. It wa shown that personal anxiety and ValVal genotype of BDNF gene appeared to be predictors of moderate and severe depression. PMID:26050483

  4. Serum Brain-Derived Neurotrophic Factor is Related to Platelet Reactivity but not to Genetic Polymorphisms within BDNF Encoding Gene in Patients with Type 2 Diabetes

    PubMed Central

    Eyileten, Ceren; Zaremba, Małgorzata; Janicki, Piotr K.; Rosiak, Marek; Cudna, Agnieszka; Kapłon-Cieślicka, Agnieszka; Opolski, Grzegorz; Filipiak, Krzysztof J.; Kosior, Dariusz A.; Mirowska-Guzel, Dagmara; Postula, Marek

    2016-01-01

    Background The aim of this study was to investigate the association between serum concentrations of the brain-derived neurotrophic factor (BDNF), platelet reactivity and inflammatory markers, as well as its association with BDNF encoding gene variants in type 2 diabetic patients (T2DM) during acetylsalicylic acid (ASA) therapy. Material/Methods This retrospective, open-label study enrolled 91 patients. Serum BDNF, genotype variants, hematological, biochemical, and inflammatory markers were measured. Blood samples were taken in the morning 2–3 h after the last ASA dose. The BDNF genotypes for selected variants were analyzed by use of the iPLEX Sequenom assay. Results In multivariate linear regression analysis, CADP-CT >74 sec (p<0.001) and sP-selectin concentration (p=0.03) were predictive of high serum BDNF. In multivariate logistic regression analysis, CADP-CT >74 sec (p=0.02) and IL-6 concentration (p=0.03) were risk factors for serum BDNF above the median. Non-significant differences were observed between intronic SNP rs925946, missense SNP rs6265, and intronic SNP rs4923463 allelic groups and BDNF concentrations in the investigated cohort. Conclusions Chronic inflammatory condition and enhanced immune system are associated with the production of BDNF, which may be why the serum BDNF level in T2DM patients with high platelet reactivity was higher compared to subjects with normal platelet reactivity in this study. PMID:26739449

  5. Spirulina non-protein components induce BDNF gene transcription via HO-1 activity in C6 glioma cells.

    PubMed

    Morita, Kyoji; Itoh, Mari; Nishibori, Naoyoshi; Her, Song; Lee, Mi-Sook

    2015-01-01

    Blue-green algae are known to contain biologically active proteins and non-protein substances and considered as useful materials for manufacturing the nutritional supplements. Particularly, Spirulina has been reported to contain a variety of antioxidants, such as flavonoids, carotenoids, and vitamin C, thereby exerting their protective effects against the oxidative damage to the cells. In addition to their antioxidant actions, polyphenolic compounds have been speculated to cause the protection of neuronal cells and the recovery of neurologic function in the brain through the production of brain-derived neurotrophic factor (BDNF) in glial cells. Then, the protein-deprived extract was prepared by removing the most part of protein components from aqueous extract of Spirulina platensis, and the effect of this extract on BDNF gene transcription was examined in C6 glioma cells. Consequently, the protein-deprived extract was shown to cause the elevation of BDNF mRNA levels following the expression of heme oxygenase-1 (HO-1) in the glioma cells. Therefore, the non-protein components of S. platensis are considered to stimulate BDNF gene transcription through the HO-1 induction in glial cells, thus proposing a potential ability of the algae to indirectly modulate the brain function through the glial cell activity. PMID:25349086

  6. 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

  7. BDNF as a Model System for examining Gene by Environment Interactions across Development

    PubMed Central

    Casey, BJ; Glatt, Charles E.; Tottenham, Nim; Soliman, Fatima; Bath, Kevin; Amso, Dima; Altemus, Marty; Pattwell, Siobhan; Jones, Rebecca; Levita, Liat; McEwen, Bruce; Magariños, Ana M.; Gunnar, Megan; Thomas, Kathleen M.; Mezey, Jason; Clark, Andrew G.; Hempstead, Barbara L.; Lee, Francis S.

    2009-01-01

    There has been a dramatic rise in gene x environment studies of human behavior over the past decade that has moved the field beyond simple nature versus nurture debates. These studies offer promise in accounting for more variability in behavioral and biological phenotypes than studies that focus on genetic or experiential factors alone. They also provide clues into mechanisms of modifying genetic risk or resilience in neurodevelopmental disorders. Yet, it is rare that these studies consider how these interactions change over the course of development. In this paper, we describe research that focuses on the impact of a polymorphism in a brain-derived neurotrophic factor (BDNF) gene, known to be involved in learning and development. Specifically we present findings that assess the effects of genotypic and environmental loadings on neuroanatomic and behavioral phenotypes across development. The findings illustrate the use of a genetic mouse model that mimics the human polymorphism, to constrain the interpretation of gene-environment interactions across development in humans. PMID:19358879

  8. 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

  9. The Neurotrophin-Inducible Gene Vgf Regulates Hippocampal Function and Behavior Through a BDNF-Dependent Mechanism

    PubMed Central

    Bozdagi, Ozlem; Rich, Erin; Tronel, Sophie; Sadahiro, Masato; Patterson, Kamara; Shapiro, Matthew L.; Alberini, Cristina M.; Huntley, George W.; Salton, Stephen R. J.

    2009-01-01

    VGF is a neurotrophin-inducible, activity-regulated gene product that is expressed in CNS and PNS neurons, where it is processed into peptides and secreted. VGF synthesis is stimulated by BDNF, a critical regulator of hippocampal development and function, and two VGF C-terminal peptides increase synaptic activity in cultured hippocampal neurons. To assess VGF function in the hippocampus, we tested heterozygous and homozygous VGF knockout mice in two different learning tasks, assessed long-term potentiation (LTP) and depression (LTD) in hippocampal slices from VGF mutant mice, and investigated how VGF C-terminal peptides modulate synaptic plasticity. Treatment of rat hippocampal slices with the VGF-derived peptide TLQP62 resulted in transient potentiation through a mechanism that was selectively blocked by the BDNF scavenger TrkB-Fc, the Trk tyrosine kinase inhibitor K252a (100 nM), and by tPASTOP, an inhibitor of tissue plasminogen activator (tPA), an enzyme involved in pro-BDNF cleavage to BDNF, but was not blocked by the NMDA receptor antagonist APV, anti-p75NTR function-blocking antiserum, nor by prior tetanic stimulation. Although LTP was normal in slices from VGF knockout mice, LTD could not be induced, and VGF mutant mice were impaired in hippocampal-dependent spatial learning and contextual fear conditioning tasks. Our studies indicate that the VGF C-terminal peptide TLQP62 modulates hippocampal synaptic transmission through a BDNF-dependent mechanism, and that VGF deficiency in mice impacts synaptic plasticity and memory in addition to depressive behavior. PMID:18815270

  10. 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.

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

    PubMed

    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

  12. 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

  13. BDNF and HSP gene polymorphisms and their influence on the progression of primary open-angle glaucoma in a Polish population

    PubMed Central

    Nowak, Alicja; Szaflik, Jacek P.; Gacek, Mira; Przybylowska-Sygut, Karolina; Kamińska, Anna; Szaflik, Jerzy

    2014-01-01

    Introduction Glaucoma is a neurodegenerative disease that is often associated with high intraocular pressure (IOP). One of the effects of elevated IOP is disorder of neurotrophic molecules transport, including brain-derived neurotrophic factor (BDNF) and recruit specific cellular proteins called “heat shock proteins” (HSPs). The aim of this study was to evaluate a relationship between the BDNF and HSP70-1 gene polymorphisms with risk occurrence of primary open-angle glaucoma (POAG). Material and methods The study consisted of 167 patients with POAG (mean age: 73 ±9) and 193 healthy subjects (mean age: 64 ±13). Genomic DNA was extracted from peripheral blood. Analysis of the gene polymorphisms was performed using PCR-RFLP, using the following restriction enzymes: NlaIII (rs6265) and BsrBI (rs1043618). The Heidelberg retinal tomography (HRT) clinical parameters were also analyzed. The odds ratios (ORs) and 95% confidence intervals (CIs) for each genotype and allele were calculated. Results Comparison of the distributions of genotypes and alleles of the 196G/A polymorphism of the BDNF gene as well as 190G/C polymorphism of the HSP70-1 gene and analysis of the odds ratio (OR) showed no statistically significant differences between POAG patients and controls (p > 0.05). However, there was a statistically significant association of the 196G/A of BDNF and 190G/C of HSP70-1 gene polymorphisms with progression of POAG depending on values of clinical parameters. 196G/A of BDNF correlated with the parameters GDx and RA (p = 0.03; p = 0.002, respectively), while 190G/C of HSP70-1 correlated with c/d and RA (p = 0.014, p = 0.024, respectively). Conclusions The BDNF 196G/A and HSP70-1 190G/C gene polymorphisms may be related to progression of POAG. PMID:25624860

  14. 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. PMID:26334786

  15. The Impact of Bdnf Gene Deficiency to the Memory Impairment and Brain Pathology of APPswe/PS1dE9 Mouse Model of Alzheimer’s Disease

    PubMed Central

    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

  16. Effect of actual long-term spaceflight on BDNF, TrkB, p75, BAX and BCL-XL genes expression in mouse brain regions.

    PubMed

    Naumenko, V S; Kulikov, A V; Kondaurova, E M; Tsybko, A S; Kulikova, E A; Krasnov, I B; Shenkman, B S; Sychev, V N; Bazhenova, E Y; Sinyakova, N A; Popova, N K

    2015-01-22

    Mice of C57BL/6J strain were exposed to 1-month spaceflight on Russian biosatellite Bion-M1 to determine the effect of long-term actual spaceflight on the expression of genes involved in the processes of neurogenesis and apoptosis. Specifically, we focused on the genes encoding proapoptotic factor BAX, antiapoptotic factor BCL-XL, brain-derived neurotrophic factor (BDNF) and BDNF receptors TrkB and p75. Spaceflight reduced the expression of the antiapoptotic BCL-XL gene in the striatum and hypothalamus, but increased it in the hippocampus. To estimate environmental stress contribution into spaceflight effects we analyzed spaceflight-responsive genes in mice housed for 1 month on Earth in the same shuttle cabins that were used for spaceflight, and in mice of the laboratory control group. It was shown that 1-month shuttle cabin housing decreased BCL-XL gene expression in the striatum but failed to alter BCL-XL mRNA levels in the hippocampus or hypothalamus. Spaceflight failed to alter the expression of the proapoptotic BAX gene in all investigated brain structures, although the insignificant increase of the BAX mRNA level in the hippocampus of spaceflight mice was found. At the same time, shuttle cabin housing produced insignificant decrease in BAX gene expression in the hippocampus. In contrast to the BCL-XL gene, genes encoding BAX, BDNF as well as TrkB and p75 receptors did not respond to 30-day spaceflight. Thus, long-term spaceflight (1) did not affect the expression of genes encoding BDNF as well as TrkB and p75 receptors, (2) produced dysregulation in genetic control of the neuronal apoptosis, (3) implicated BCL-XL as the risk factor for spaceflight-induced behavioral abnormalities. PMID:25451288

  17. Regulation of BDNF expression by cocaine.

    PubMed

    McCarthy, Deirdre M; Brown, Amber N; Bhide, Pradeep G

    2012-12-01

    Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors. It is expressed throughout the nervous system. A unique feature of the BDNF gene is the existence of multiple mRNA transcripts, all of which are translated into BDNF protein, suggesting a multilevel regulation of expression. In particular, the BDNF exon IV promoter region is a preferential target for epigenetic alterations, as it contains binding sites for CREB and MeCP2, two transcriptional regulators known to mediate epigenetic changes. Exposure to drugs of abuse is known to modulate epigenetic regulation of BDNF gene expression. This review will discuss how exposure to cocaine, one of the most addictive drugs known to mankind, can produce alterations in BDNF gene expression, especially in the mesolimbic dopaminergic system, which lead to alterations in the reward-mediated behaviors involved in addiction. PMID:23239946

  18. 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. PMID:25934485

  19. Association study of BDNF and DRD3 genes in schizophrenia diagnosis using matched case-control and family based study designs.

    PubMed

    Zai, Clement C; Manchia, Mirko; De Luca, Vincenzo; Tiwari, Arun K; Squassina, Alessio; Zai, Gwyneth C; Strauss, John; Shaikh, Sajid A; Freeman, Natalie; Meltzer, Herbert Y; Lieberman, Jeffrey; Le Foll, Bernard; Kennedy, James L

    2010-12-01

    Schizophrenia (SCZ) is a severe neuropsychiatric disorder with prominent genetic etiologic factors. The dopamine receptor DRD3 gene is a strong candidate in genetic studies of SCZ because of the dopamine hypothesis of SCZ and the selective expression of D(3) in areas of the limbic system implicated in the disease. We examined 15 single-nucleotide polymorphisms (SNPs) in DRD3 in our sample of European origin consisting of 95 small nuclear SCZ families and 167 case-control pairs. We also examined four BDNF SNPs in our samples because of evidence for BDNF regulation of DRD3 expression (Guillin et al., 2001). We found a nominally significant genotypic association with rs7633291 and allelic association with rs1025398 alleles. However, these observations did not survive correction for multiple testing. We did not find a statistically significant association with the other DRD3 and BDNF polymorphisms. Taken together, the results from the present study suggest that BDNF and DRD3 may not be involved in SCZ susceptibility. PMID:20667458

  20. Prenatal stress decreases Bdnf expression and increases methylation of Bdnf exon IV in rats

    PubMed Central

    Boersma, Gretha J; Lee, Richard S; Cordner, Zachary A; Ewald, Erin R; Purcell, Ryan H; Moghadam, Alexander A; Tamashiro, Kellie L

    2014-01-01

    There is ample evidence that exposure to stress during gestation increases the risk of the offspring to develop mood disorders. Brain-derived neurotrophic factor (Bdnf) plays a critical role during neuronal development and is therefore a prime candidate to modulate neuronal signaling in adult offspring of rat dams that were stressed during gestation. In the current study, we tested the hypothesis that alterations in Bdnf expression in prenatally stressed (PNS) offspring are mediated by changes in DNA methylation in exons IV and VI of the Bdnf gene. We observed decreased Bdnf expression in the amygdala and hippocampus of prenatally stressed rats both at weaning and in adulthood. This decrease in Bdnf expression was accompanied by increased DNA methylation in Bdnf exon IV in the amygdala and hippocampus, suggesting that PNS-induced reduction in Bdnf expression may, at least in part, be mediated by increased DNA methylation of Bdnf exon IV. Expression of DNA methyltransferases (Dnmt) 1 and 3a was increased in PNS rats in the amygdala and hippocampus. Our data suggest that PNS induces decreases in Bdnf expression that may at least in part be mediated by increased DNA methylation of Bdnf exon IV. PMID:24365909

  1. 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

  2. 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

  3. The BDNF gene Val66Met polymorphism as a modifier of psychiatric disorder susceptibility: progress and controversy.

    PubMed

    Notaras, M; Hill, R; van den Buuse, M

    2015-08-01

    Brain-derived neurotrophic factor (BDNF) has a primary role in neuronal development, differentiation and plasticity in both the developing and adult brain. A single-nucleotide polymorphism in the proregion of BDNF, termed the Val66Met polymorphism, results in deficient subcellular translocation and activity-dependent secretion of BDNF, and has been associated with impaired neurocognitive function in healthy adults and in the incidence and clinical features of several psychiatric disorders. Research investigating the Val66Met polymorphism has increased markedly in the past decade, and a gap in integration exists between and within academic subfields interested in the effects of this variant. Here we comprehensively review the role and relevance of the Val66Met polymorphism in psychiatric disorders, with emphasis on suicidal behavior and anxiety, eating, mood and psychotic disorders. The cognitive and molecular neuroscience of the Val66Met polymorphism is also concisely reviewed to illustrate the effects of this genetic variant in healthy controls, and is complemented by a commentary on the behavioral neuroscience of BDNF and the Val66Met polymorphism where relevant to specific disorders. Lastly, a number of controversies and unresolved issues, including small effect sizes, sampling of allele inheritance but not genotype and putative ethnicity-specific effects of the Val66Met polymorphism, are also discussed to direct future research. PMID:25824305

  4. 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…

  5. 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

  6. 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. PMID:23111884

  7. Targeted gene transfer to nigrostriatal neurons in the rat brain by helper virus-free HSV-1 vector particles that contain either a chimeric HSV-1 glycoprotein C-GDNF or a gC-BDNF protein

    PubMed Central

    Wang, Xiaodan; Kong, Lingxin; Zhang, Guo-rong; Sun, Mei; Geller, Alfred I.

    2006-01-01

    Direct gene transfer into neurons has potential for both studying neuronal physiology and for developing gene therapy treatments for specific neurological conditions. Due to the heterogeneous cellular composition of the brain, cell-type-specific recombinant gene expression is required for many potential applications of neuronal gene transfer. The two prevalent approaches for achieving cell-type-specific expression are to use a cell-type-specific promoter to control recombinant gene expression or to modify a virus vector particle to target gene transfer to a specific cell type. Targeted gene transfer to multiple peripheral cell types has been described, but targeted gene transfer to a specific type of neuron in the brain has yet to be reported. Targeted gene transfer approaches with Herpes Simplex Virus (HSV-1) vectors have focused on modifying glycoprotein C (gC) to remove the heparin binding domain and add a binding activity for a specific protein on the cell surface. This study was designed to develop HSV-1 vectors that target gene transfer to cells that contain receptors for either glial-cell-line-derived neurotrophic factor (GDNF) or brain-derived neurotrophic factor (BDNF), such as nigrostriatal neurons. We isolated chimeric gC-GDNF or chimeric gC-BDNF constructs, and the resulting proteins were incorporated into HSV-1 virus particles. We performed helper virus-free HSV-1 vector packaging in the presence of each chimeric protein. The resulting vector stocks supported 2.2- to 5.0-fold targeted gene transfer to nigrostriatal neurons in the rat brain, compared to vector particles that contained wild-type (wt) gC. Gene transfer to nigrostriatal neurons by vector particles that contained chimeric gC-BDNF was reduced by preincubation with an anti-BDNF antibody. Targeted gene transfer to neurons that contain specific neurotrophic factor receptors may benefit specific physiological and gene therapy studies. PMID:15993510

  8. 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. PMID:26844865

  9. 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

  10. 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. PMID:24824862

  11. 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

  12. 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. PMID:26557993

  13. [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. PMID:27239851

  14. 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…

  15. 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. PMID:27003443

  16. 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

  17. Functional Role of BDNF Production from Unique Promoters in Aggression and Serotonin Signaling.

    PubMed

    Maynard, Kristen R; Hill, Julia L; Calcaterra, Nicholas E; Palko, Mary E; Kardian, Alisha; Paredes, Daniel; Sukumar, Mahima; Adler, Benjamin D; Jimenez, Dennisse V; Schloesser, Robert J; Tessarollo, Lino; Lu, Bai; Martinowich, Keri

    2016-07-01

    Brain-derived neurotrophic factor (BDNF) regulates diverse biological functions ranging from neuronal survival and differentiation during development to synaptic plasticity and cognitive behavior in the adult. BDNF disruption in both rodents and humans is associated with neurobehavioral alterations and psychiatric disorders. A unique feature of Bdnf transcription is regulation by nine individual promoters, which drive expression of variants that encode an identical protein. It is hypothesized that this unique genomic structure may provide flexibility that allows different factors to regulate BDNF signaling in distinct cell types and circuits. This has led to the suggestion that isoforms may regulate specific BDNF-dependent functions; however, little scientific support for this idea exists. We generated four novel mutant mouse lines in which BDNF production from one of the four major promoters (I, II, IV, or VI) is selectively disrupted (Bdnf-e1, -e2, -e4, and -e6 mice) and used a comprehensive comparator approach to determine whether different Bdnf transcripts are associated with specific BDNF-dependent molecular, cellular, and behavioral phenotypes. Bdnf-e1 and -e2 mutant males displayed heightened aggression accompanied by convergent expression changes in specific genes associated with serotonin signaling. In contrast, BDNF-e4 and -e6 mutants were not aggressive but displayed impairments associated with GABAergic gene expression. Moreover, quantifications of BDNF protein in the hypothalamus, prefrontal cortex, and hippocampus revealed that individual Bdnf transcripts make differential, region-specific contributions to total BDNF levels. The results highlight the biological significance of alternative Bdnf transcripts and provide evidence that individual isoforms serve distinct molecular and behavioral functions. PMID:26585288

  18. BDNF Genotype Moderates the Relation Between Physical Activity and Depressive Symptoms

    PubMed Central

    Mata, Jutta; Thompson, Renee J.; Gotlib, Ian H.

    2010-01-01

    Objective To test whether the BDNF gene interacts with exercise to predict depressive symptoms. Physical activity is associated with a range of positive health outcomes, including fewer depressive symptoms. One plausible mechanism underlying these findings involves Brain-Derived Neurotrophic Factor (BDNF), a protein hypothesized to limit or repair the damage caused by stress. Physical activity increases expression of BDNF, which may enhance brain health. BDNF expression is controlled by the BDNF gene. Compared with individuals without a BDNF met allele, met-allele carriers have a lower expression of BDNF, which has been associated with Major Depressive Disorder. Design Eighty-two healthy adolescent girls were genotyped for the BDNF val66met polymorphism, and their depressive symptoms and physical activity were assessed using questionnaires. Main Outcome Measures BDNF genotype, Children's Depression Inventory, and the Physical Activity Questionnaire for Older Children and Adolescents. Results The BDNF polymorphism was found to moderate the relation between exercise and depressive symptoms: being physically active was protective for girls with a BDNF met allele (fewer depressive symptoms) but not for girls with the val/val polymorphism. Conclusion By integrating psychological and biological factors, the present study enhances our understanding of how physical activity contributes to resilience to psychopathology. PMID:20230085

  19. 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,…

  20. 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

  1. 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

  2. Localization of BDNF expression in the developing brain of zebrafish

    PubMed Central

    De Felice, E; Porreca, I; Alleva, E; De Girolamo, P; Ambrosino, C; Ciriaco, E; Germanà, A; Sordino, P

    2014-01-01

    The brain-derived neurotrophic factor (BDNF) gene is expressed in differentiating and post-mitotic neurons of the zebrafish embryo, where it has been implicated in Huntington's disease. Little is known, however, about the full complement of neuronal cell types that express BDNF in this important vertebrate model. Here, we further explored the transcriptional profiles during the first week of development using real-time quantitative polymerase chain reaction (RT-qPCR) and whole-mount in situ hybridization (WISH). RT-qPCR results revealed a high level of maternal contribution followed by a steady increase of zygotic transcription, consistent with the notion of a prominent role of BDNF in neuronal maturation and maintenance. Based on WISH, we demonstrate for the first time that BDNF expression in the developing brain of zebrafish is structure specific. Anatomical criteria and co-staining with genetic markers (shh, pax2a, emx1, krox20, lhx2b and lhx9) visualized major topological domains of BDNF-positive cells in the pallium, hypothalamus, posterior tuberculum and optic tectum. Moreover, the relative timing of BDNF transcription in the eye and tectum may illustrate a mechanism for coordinated development of the retinotectal system. Taken together, our results are compatible with a local delivery and early role of BDNF in the developing brain of zebrafish, adding basic knowledge to the study of neurotrophin functions in neural development and disease. PMID:24588510

  3. 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. PMID:24321557

  4. Combined cisplatin and aurora inhibitor treatment increase neuroblastoma cell death but surviving cells overproduce BDNF.

    PubMed

    Polacchini, Alessio; Albani, Clara; Baj, Gabriele; Colliva, Andrea; Carpinelli, Patrizia; Tongiorgi, Enrico

    2016-01-01

    Drug-resistance to chemotherapics in aggressive neuroblastoma (NB) is characterized by enhanced cell survival mediated by TrkB and its ligand, brain-derived neurotrophic factor (BDNF); thus reduction in BDNF levels represent a promising strategy to overcome drug-resistance, but how chemotherapics regulate BDNF is unknown. Here, cisplatin treatment in SK-N-BE neuroblastoma upregulated multiple BDNF transcripts, except exons 5 and 8 variants. Cisplatin increased BDNF mRNA and protein, and enhanced translation of a firefly reporter gene flanked by BDNF 5'UTR exons 1, 2c, 4 or 6 and 3'UTR-long. To block BDNF translation we focused on aurora kinases inhibitors which are proposed as new chemotherapeutics. NB cell survival after 24 h treatment was 43% with cisplatin, and 22% by cisplatin+aurora kinase inhibitor PHA-680632, while the aurora kinases inhibitor alone was less effective; however the combined treatment induced a paradoxical increase of BDNF in surviving cells with strong translational activation of exon6-3'UTR-long transcript, while translation of BDNF transcripts 1, 2C and 4 was suppressed. In conclusion, combined cisplatin and aurora kinase inhibitor treatment increases cell death, but induces BDNF overproduction in surviving cells through an aurora kinase-independent mechanism. PMID:27256407

  5. 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

  6. Combined cisplatin and aurora inhibitor treatment increase neuroblastoma cell death but surviving cells overproduce BDNF

    PubMed Central

    Polacchini, Alessio; Albani, Clara; Baj, Gabriele; Colliva, Andrea; Carpinelli, Patrizia

    2016-01-01

    ABSTRACT Drug-resistance to chemotherapics in aggressive neuroblastoma (NB) is characterized by enhanced cell survival mediated by TrkB and its ligand, brain-derived neurotrophic factor (BDNF); thus reduction in BDNF levels represent a promising strategy to overcome drug-resistance, but how chemotherapics regulate BDNF is unknown. Here, cisplatin treatment in SK-N-BE neuroblastoma upregulated multiple BDNF transcripts, except exons 5 and 8 variants. Cisplatin increased BDNF mRNA and protein, and enhanced translation of a firefly reporter gene flanked by BDNF 5′UTR exons 1, 2c, 4 or 6 and 3′UTR-long. To block BDNF translation we focused on aurora kinases inhibitors which are proposed as new chemotherapeutics. NB cell survival after 24 h treatment was 43% with cisplatin, and 22% by cisplatin+aurora kinase inhibitor PHA-680632, while the aurora kinases inhibitor alone was less effective; however the combined treatment induced a paradoxical increase of BDNF in surviving cells with strong translational activation of exon6-3′UTR-long transcript, while translation of BDNF transcripts 1, 2C and 4 was suppressed. In conclusion, combined cisplatin and aurora kinase inhibitor treatment increases cell death, but induces BDNF overproduction in surviving cells through an aurora kinase-independent mechanism. PMID:27256407

  7. Measurement of the levels of leptin, BDNF associated with polymorphisms LEP G2548A, LEPR Gln223Arg and BDNF Val66Met in Thai with metabolic syndrome

    PubMed Central

    2014-01-01

    Background Metabolic syndrome is a cluster of metabolic risk factors including dyslipidemia, impaired glucose tolerance, hypertension and central obesity. BDNF (Brain-derived neurotrophic factor) and leptin have been implied in the energy homeostasis. The purposes of this study were to examine concentrations of leptin, BDNF and biochemical parameters in metabolic-syndrome subjects and healthy controls, and also to search for associations of leptin gene (LEP) G2548A, leptin receptor gene (LEPR) Gln223Arg, and BDNF gene (BDNF) Val66Met polymorphisms with leptin levels, BDNF levels and metabolic syndrome among Thais. Methods The case-controlled design was performed using 322 Thai volunteers (160 metabolic-syndrome subjects; 162 controls) during the health screening program. Metabolic syndrome was assessed by using the modified National Cholesterol Education Program, Adult Treatment Panel III criteria. The levels of leptin, BDNF, insulin, glucose and lipids were measured in samples. Genotyping of LEP G2548A, LEPR Gln223Arg and BDNF Val66Met was carried out using polymerase chain reaction-restriction fragment length polymorphism technique. Results Serum leptin levels were significantly higher in the metabolic-syndrome group than the control group (p < 0.01), but the BDNF difference between them was not significant. Significant associations of LEPR Gln223Arg polymorphism were found with leptin and glucose levels (p < 0.05), after adjusting for potential covariates. This LEPR polymorphism in the metabolic-syndrome group was also significantly more frequent than in the control group (p < 0.05). However, other gene polymorphisms, LEP G2548A and BDNF Val66Met, showed no significant relationship with leptin levels, BDNF levels or metabolic syndrome. Conclusion These findings suggest leptin levels are linked with metabolic syndrome. LEPR Gln223Arg polymorphism impacted leptin concentrations, and this gene polymorphism may influence susceptibility to metabolic syndrome among

  8. 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

    2015-06-01

    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. PMID:26041908

  9. SORLA-mediated trafficking of TrkB enhances the response of neurons to BDNF.

    PubMed

    Rohe, Michael; Hartl, Daniela; Fjorback, Anja Nawarecki; Klose, Joachim; Willnow, Thomas E

    2013-01-01

    Stimulation of neurons with brain-derived neurotrophic factor (BDNF) results in robust induction of SORLA, an intracellular sorting receptor of the VPS10P domain receptor gene family. However, the relevance of SORLA for BDNF-induced neuronal responses has not previously been investigated. We now demonstrate that SORLA is a sorting factor for the tropomyosin-related kinase receptor B (TrkB) that facilitates trafficking of this BDNF receptor between synaptic plasma membranes, post-synaptic densities, and cell soma, a step critical for neuronal signal transduction. Loss of SORLA expression results in impaired neuritic transport of TrkB and in blunted response to BDNF in primary neurons; and it aggravates neuromotoric deficits caused by low BDNF activity in a mouse model of Huntington's disease. Thus, our studies revealed a key role for SORLA in mediating BDNF trophic signaling by regulating the intracellular location of TrkB. PMID:23977241

  10. Role of activity-dependent BDNF expression in hippocampal-prefrontal cortical regulation of behavioral perseverance.

    PubMed

    Sakata, Kazuko; Martinowich, Keri; Woo, Newton H; Schloesser, Robert J; Jimenez, Dennisse V; Ji, Yuanyuan; Shen, Liya; Lu, Bai

    2013-09-10

    Activity-dependent gene transcription, including that of the brain-derived neurotrophic factor (Bdnf) gene, has been implicated in various cognitive functions. We previously demonstrated that mutant mice with selective disruption of activity-dependent BDNF expression (BDNF-KIV mice) exhibit deficits in GABA-mediated inhibition in the prefrontal cortex (PFC). Here, we show that disruption of activity-dependent BDNF expression impairs BDNF-dependent late-phase long-term potentiation (L-LTP) in CA1, a site of hippocampal output to the PFC. Interestingly, early-phase LTP and conventional L-LTP induced by strong tetanic stimulation were completely normal in BDNF-KIV mice. In parallel, attenuation of activity-dependent BDNF expression significantly impairs spatial memory reversal and contextual memory extinction, two executive functions that require intact hippocampal-PFC circuitry. In contrast, spatial and contextual memory per se were not affected. Thus, activity-dependent BDNF expression in the hippocampus and PFC may contribute to cognitive and behavioral flexibility. These results suggest distinct roles for different forms of L-LTP and provide a link between activity-dependent BDNF expression and behavioral perseverance, a hallmark of several psychiatric disorders. PMID:23980178

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

    PubMed Central

    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

    2015-01-01

    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. PMID:25640280

  12. 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

    2015-01-01

    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. PMID:25640280

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  14. Genetics of serum BDNF: Meta-analysis of the Val66Met and genome-wide association study

    PubMed Central

    Terracciano, Antonio; Piras, Maria Grazia; Lobina, Monia; Mulas, Antonella; Meirelles, Osorio; Sutin, Angelina R.; Chan, Wayne; Sanna, Serena; Uda, Manuela; Crisponi, Laura; Schlessinger, David

    2011-01-01

    Objectives Lower levels of serum Brain Derived Neurotrophic Factor (BDNF) is one of the best known biomarkers of depression. To identify genetic variants associated with serum BDNF, we tested the Val66Met (rs6265) functional variant and conducted a genome-wide association scan (GWAS). Methods In a community-based sample (N = 2054; aged 19 to 101, M = 51, SD = 15) from Sardinia, Italy, we measured serum BDNF concentration and conducted a GWAS. Results We estimated the heritability of serum BDNF to be 0.48 from sib-pairs. There was no association between serum BDNF and Val66Met in the SardiNIA sample and in a meta-analysis of published studies (k = 13 studies, total n = 4727, p = 0.92). Although no genome-wide significant associations were identified, some evidence of association was found in the BDNF gene (rs11030102, P = .001) and at two loci (rs7170215, P = 4.8×10−5 and rs11073742 P = 1.2×10−5) near and within NTRK3 gene, a neurotrophic tyrosine kinase receptor. Conclusions Our study and meta-analysis of the literature indicate that the BDNF Val66Met variant is not associated with serum BDNF, but other variants in the BDNF and NTRK3 genes might regulate the level of serum BDNF. PMID:22047184

  15. 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

    2016-01-01

    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 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. PMID:27264956

  16. 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

  17. Prenatal stress and early-life exposure to fluoxetine have enduring effects on anxiety and hippocampal BDNF gene expression in adult male 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

    2016-05-01

    With the growing use of selective serotonin reuptake inhibitor medications (SSRIs) for the treatment of depression during the perinatal period, questions have been raised about the longterm impact of these medications on development. We aimed to investigate how developmental SSRI exposure may alter affect-related behaviors and associated molecular processes in offspring using a rodent model of maternal stress and depression. For this purpose, prenatally stressed or non-stressed male offspring were exposed to fluoxetine (5 mg/kg/day) or vehicle, via lactation, until weaning. Primary results show that postnatal fluoxetine exposure differentially altered anxiety-like behavior by increasing anxiety in non-stressed offspring and decreasing anxiety in prenatally stressed offspring. In the hippocampus, developmental fluoxetine exposure decreased BDNF IV and TrkB mRNA expression. Prenatal stress alone also decreased escape behaviors and decreased hippocampal BDNF IV mRNA expression. These data provide important evidence for the long-term programming effects of early-life exposure to SSRIs on brain and behavior. © 2015 Wiley Periodicals, Inc. Dev Psychobiol 58: 427-438, 2016. PMID:26608001

  18. Genetic Role of BDNF Val66Met and 5-HTTLPR Polymorphisms on Depressive Disorder

    PubMed Central

    Lee, Kyu Young; Jeong, Seong Hoon; Kim, Se Hyun; Ahn, Yong Min; Kim, Yong Sik; Jung, Hee Yeon; Bang, Yang Weon

    2014-01-01

    Objective We investigated possible association between depressive disorders and BDNF Val66Met and 5-HTTLPR. Brain derived neurotrophic factor (BDNF) gene and serotonin transporter (SLC6A4) gene are promising candidate genes for depressive disorders. It has been suggested that BDNF promotes the survival and differentiation of serotonergic neurons and that serotonergic transmission exerts powerful control over BDNF gene expression. Methods Final analyses were performed on 186 patients with depressive disorders and 1032 controls. Val66Met polymorphism of BDNF gene and 5-HTTLPR polymorphism of serotonin transporter gene were genotyped and allele and genotypic associations on the diagnosis of depression and age at onset of depression were analyzed. Results The 5-HTTLPR was positively associated with depressive affected status in the total sample and in females (p=0.038 for allelewise, p=0.015 for genotype-wise associations), but, not in males. The BDNF Val66Met showed no association with depression. BDNF Val66Met and 5-HTTLPR alone were not associated with age at onset of depression. Additional analysis on the interaction between BDNF Val66Met and 5-HTTLPR found a significant association with age at onset of depression in the entire patient group. This association was also found in the female but not in the male patient group. None of the positive results survived Bonferroni correction for multiple testing. Conclusion This result suggested that BDNF Val66Met and 5-HTTLPR may contribute to depressive disorders in a complex way and that the genetic effect could differ by gender. Further studies with large number of patients will be necessary. PMID:24843376

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

    PubMed Central

    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. PMID:26973456

  20. 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

    2015-02-01

    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. PMID:25653370

  1. The Role of Brain-Derived Neurotrophic Factor (BDNF) in the Development of Neurogenic Detrusor Overactivity (NDO)

    PubMed Central

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

    2015-01-01

    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. PMID:25653370

  2. 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

  3. Bdnf Overexpression in Hippocampal Neurons Prevents Dendritic Atrophy Caused by Rett-Associated MECP2 Mutations

    PubMed Central

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

    2008-01-01

    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. PMID:19217433

  4. 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

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

    PubMed

    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 for

  6. 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

  7. 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

    2016-01-01

    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. PMID:27253067

  8. 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

  9. 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. PMID:22240983

  10. BDNF is necessary and sufficient for spinal respiratory plasticity following intermittent hypoxia.

    PubMed

    Baker-Herman, Tracy L; Fuller, David D; Bavis, Ryan W; Zabka, Andrea G; Golder, Francis J; Doperalski, Nicholas J; Johnson, Rebecca A; Watters, Jyoti J; Mitchell, Gordon S

    2004-01-01

    Intermittent hypoxia causes a form of serotonin-dependent synaptic plasticity in the spinal cord known as phrenic long-term facilitation (pLTF). Here we show that increased synthesis of brain-derived neurotrophic factor (BDNF) in the spinal cord is necessary and sufficient for pLTF in adult rats. We found that intermittent hypoxia elicited serotonin-dependent increases in BDNF synthesis in ventral spinal segments containing the phrenic nucleus, and the magnitude of these BDNF increases correlated with pLTF magnitude. We used RNA interference (RNAi) to interfere with BDNF expression, and tyrosine kinase receptor inhibition to block BDNF signaling. These disruptions blocked pLTF, whereas intrathecal injection of BDNF elicited an effect similar to pLTF. Our findings demonstrate new roles and regulatory mechanisms for BDNF in the spinal cord and suggest new therapeutic strategies for treating breathing disorders such as respiratory insufficiency after spinal injury. These experiments also illustrate the potential use of RNAi to investigate functional consequences of gene expression in the mammalian nervous system in vivo. PMID:14699417

  11. Altered white matter architecture in BDNF met carriers.

    PubMed

    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

  12. 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. PMID:26758201

  13. Mutation screen of the brain derived neurotrophic factor gene (BDNF): identification of several genetic variants and association studies in patients with obesity, eating disorders, and attention-deficit/hyperactivity disorder.

    PubMed

    Friedel, S; Horro, F Fontenla; Wermter, A K; Geller, F; Dempfle, A; Reichwald, K; Smidt, J; Brönner, G; Konrad, K; Herpertz-Dahlmann, B; Warnke, A; Hemminger, U; Linder, M; Kiefl, H; Goldschmidt, H P; Siegfried, W; Remschmidt, H; Hinney, A; Hebebrand, J

    2005-01-01

    Several lines of evidence indicate an involvement of brain derived neurotrophic factor (BDNF) in body weight regulation and activity: heterozygous Bdnf knockout mice (Bdnf(+/-)) are hyperphagic, obese, and hyperactive; furthermore, central infusion of BDNF leads to severe, dose-dependent appetite suppression and weight loss in rats. We searched for the role of BDNF variants in obesity, eating disorders, and attention-deficit/hyperactivity disorder (ADHD). A mutation screen (SSCP and DHPLC) of the translated region of BDNF in 183 extremely obese children and adolescents and 187 underweight students was performed. Additionally, we genotyped two common polymorphisms (rs6265: p.V66M; c.-46C > T) in 118 patients with anorexia nervosa, 80 patients with bulimia nervosa, 88 patients with ADHD, and 96 normal weight controls. Three rare variants (c.5C > T: p.T2I; c.273G > A; c.*137A > G) and the known polymorphism (p.V66M) were identified. A role of the I2 allele in the etiology of obesity cannot be excluded. We found no association between p.V66M or the additionally genotyped variant c.-46C > T and obesity, ADHD or eating disorders. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148-7299:1/suppmat/index.html. PMID:15457498

  14. 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. PMID:22530815

  15. GABAA Receptor Blockade Enhances Memory Consolidation by Increasing Hippocampal BDNF Levels

    PubMed Central

    Kim, Dong Hyun; Kim, Jong Min; Park, Se Jin; Cai, Mudan; Liu, Xiaotong; Lee, Seungheon; Shin, Chan Young; Ryu, Jong Hoon

    2012-01-01

    Memory consolidation is the process by which acquired information is converted to something concrete to be retrieved later. Here we examined a potential role for brain-derived neurotrophic factor (BDNF) in mediating the enhanced memory consolidation induced by the GABAA receptor antagonist, bicuculline methiodide. With the administration of an acquisition trial in naïve mice using a passive avoidance task, mature BDNF (mBDNF) levels were temporally changed in the hippocampal CA1 region, and the lowest levels were observed 9 h after the acquisition trial. In the passive avoidance task, bicuculline methiodide administration within 1 h of training but not after 3 h significantly increased latency time in the retention trial 24 h after the acquisition trial. Concomitantly, 1 h post-training administration of bicuculline methiodide, which enhanced memory consolidation, significantly increased mBDNF levels 9 h after training compared to those of the vehicle-treated control group. In addition, exogenous human recombinant BDNF (hrBDNF) administration 9 h after training into the hippocampal CA1 region facilitated memory consolidation confirming that the increase in mBDNF at around 9 h after training plays a key role in the enhancement of memory consolidation. Moreover, the increases in latency time and immediate early gene expressions by bicuculline methiodide or hrBDNF were significantly blocked by anisomycin, a protein synthesis inhibitor, K252a, a tyrosine receptor kinase (Trk) inhibitor, or anti-TrkB IgG. These findings suggest that the increase in the level of mBDNF and its function during a restricted time window after training are required for the enhancement of memory consolidation by GABAA receptor blockade. PMID:21900885

  16. Alteration of the Centromedial Amygdala Glutamatergic Synapses by the BDNF Val66Met Polymorphism.

    PubMed

    Galvin, Christopher; Lee, Francis S; Ninan, Ipe

    2015-08-01

    Fear expression is mediated by an activation of the centromedial amygdala (CEm), the major output nucleus of the amygdaloid complex. Consistently, fear extinction is associated with an increased synaptic inhibition as well as a suppression of the excitability of the CEm neurons. However, little is known about the role of CEm glutamatergic synapses in fear regulation and anxiety-like behaviors. The BDNF Val66Met, a single-nucleotide polymorphism in the human BDNF gene, impairs fear extinction and leads to anxiety-like symptoms. To determine whether the BDNF Val66Met polymorphism affects the CEm excitatory synapses, we examined basal glutamatergic synaptic transmission and plasticity in the CEm neurons of BDNF Val66Met knock-in (BDNF(Met/Met)) mice. The BDNF Val66Met single-nucleotide polymorphism exerted an opposite effect on non-NMDA and NMDA receptor transmission with a potentiation of the former and a suppression of the latter. In addition, the decay time of NMDA currents was decreased in BDNF(Met/Met) mice, suggesting a modification of NMDA receptor subunit composition. Unlike the wild-type mice that exhibited a potentiation of non-NMDA receptor transmission following fear conditioning and a depotentiation upon fear extinction, BDNF(Met/Met) mice failed to show this experience-dependent synaptic plasticity in the CEm neurons. Our results suggest that the elevated non-NMDA receptor transmission, the suppression of NMDA receptor transmission, and an impairment of synaptic plasticity in the CEm neurons might contribute to the fear extinction deficit and increased anxiety-like symptoms in BDNF Val66Met carriers. PMID:25786582

  17. 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

  18. 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. PMID:25449839

  19. Neuroticism, depressive symptoms, and serum BDNF

    PubMed Central

    Terracciano, Antonio; Lobina, Monia; Piras, Maria Grazia; Mulas, Antonella; Cannas, Alessandra; Meirelles, Osorio; Sutin, Angelina R.; Zonderman, Alan B; Uda, Manuela; Crisponi, Laura; Schlessinger, David

    2011-01-01

    Objective Animal models and clinical studies suggest that brain-derived neurotrophic factor (BDNF) is involved in the pathophysiology of depression. We test whether serum and plasma levels of BDNF are associated with trait Neuroticism and its facets, and with state measure of depressive symptoms. Method In a community-based cohort (N = 2099) we measured serum and plasma BDNF concentration, administered the Revised NEO Personality Inventory (NEO-PI-R) and the Center for Epidemiologic Studies Depression Scale (CES-D). Covariates included age, sex, cigarette smoking, obesity, and antidepressant use. Results Serum BDNF concentrations were inversely related to Neuroticism (r = −0.074, P < 0.001), in particular the Depression facet (r = −0.08, P < 0.001). Lower BDNF concentrations were also associated with severe depressive symptoms (CES-D ≥ 28; OR = 0.906; 95%CI = 0.851–0.965). The association of serum BDNF with Neuroticism was independent of depressive symptoms, indicating that serum BDNF might represent a biological correlate of Neuroticism and not just of transient depressive states. Plasma BDNF was not associated with measures of depression. Conclusions Our study suggests that lower serum BDNF is associated with both a dispositional vulnerability to depression and acute depressive states in the general population. PMID:21949427

  20. Paradoxical Role of BDNF: BDNF+/− Retinas Are Protected against Light Damage–Mediated Stress

    PubMed Central

    Wilson, R. Brooks; Kunchithapautham, Kannan; Rohrer, Bärbel

    2007-01-01

    Purpose Photoreceptors can be prevented from undergoing apoptosis in response to constant light by the application of exogenous neuroprotective agents, including brain-derived neurotrophic factor (BDNF). BDNF, however, cannot exert its effect directly on photoreceptors because they do not express receptors for BDNF. It has been proposed that BDNF released from Müller cells provides a feed-forward loop, increasing ciliary neurotrophic factor (CNTF) and basic fibroblast growth factor (bFGF) production in Müller cells, which may enhance photoreceptor survival. The authors hypothesized that retinas with reduced BDNF levels in which the BDNF-mediated release of neuroprotective signals is dampened are more susceptible to light-induced photoreceptor degeneration. Methods Young adult BDNF+/+ and BDNF+/− littermates (B6.129-BDNFtm1-LT) were analyzed. Retinal neurotrophin and growth factor mRNA levels were determined by quantitative RT-PCR, photoreceptor function was assessed through electroretinography, and survival was documented in morphologic sections and in TUNEL assays. Oxidative stress was assayed by measuring glutathione peroxidase activity. Results baseline, BDNF+/− animals had significantly increased levels of glial-derived neurotrophic factor (GDNF) mRNA compared with their wild-type littermates. After light damage GDNF, CNTF, and BDNF mRNA levels dropped 14- to 16-fold in the BDNF+/+ mice but remained almost unchanged compared with baseline levels in the BDNF+/− mice. Preservation of neurotrophin levels in BDNF+/− mice correlated with photoreceptor cell survival, preservation of function, and reduced oxidative stress. Conclusions Contrary to the hypothesis, reducing BDNF levels resulted in photoreceptor protection against light damage. Survival was paralleled by a reduction in oxidative stress and the preservation of neurotrophin levels, suggesting that chronic reduction of BDNF in the retina provides a level of preconditioning against stress. PMID

  1. 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

  2. Hold the salt: vasopressor role for BDNF.

    PubMed

    Marosi, Krisztina; Mattson, Mark P

    2015-04-01

    In a recent publication in Neuron, Choe et al. (2015) demonstrate that brain-derived neurotrophic factor (BDNF) signaling mediates salt-induced blood pressure elevation by increasing the excitability of hypothalamic vasopressin-secreting neurons. These findings suggest complex roles for BDNF in adaptive cardiovascular responses to physiological challenges and in the pathogenesis of hypertension. PMID:25863241

  3. 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. PMID:26976342

  4. 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. PMID:25634725

  5. 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

  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. PMID:26901829

  7. Peripheral vascular reactivity and serum BDNF responses to aerobic training are impaired by the BDNF Val66Met polymorphism.

    PubMed

    Lemos, José R; Alves, Cleber R; de Souza, Sílvia B C; Marsiglia, Julia D C; Silva, Michelle S M; Pereira, Alexandre C; Teixeira, Antônio L; Vieira, Erica L M; Krieger, José E; Negrão, Carlos E; Alves, Guilherme B; de Oliveira, Edilamar M; Bolani, Wladimir; Dias, Rodrigo G; Trombetta, Ivani C

    2016-02-01

    Besides neuronal plasticity, the neurotrophin brain-derived neurotrophic factor (BDNF) is also important in vascular function. The BDNF has been associated with angiogenesis through its specific receptor tropomyosin-related kinase B (TrkB). Additionally, Val66Met polymorphism decreases activity-induced BDNF. Since BDNF and TrkB are expressed in vascular endothelial cells and aerobic exercise training can increase serum BDNF, this study aimed to test the hypotheses: 1) Serum BDNF levels modulate peripheral blood flow; 2) The Val66Met BDNF polymorphism impairs exercise training-induced vasodilation. We genotyped 304 healthy male volunteers (Val66Val, n = 221; Val66Met, n = 83) who underwent intense aerobic exercise training on a running track three times/wk for 4 mo. We evaluated pre- and post-exercise training serum BDNF and proBDNF concentration, heart rate (HR), mean blood pressure (MBP), forearm blood flow (FBF), and forearm vascular resistance (FVR). In the pre-exercise training, BDNF, proBDNF, BDNF/proBDNF ratio, FBF, and FVR were similar between genotypes. After exercise training, functional capacity (V̇o2 peak) increased and HR decreased similarly in both groups. Val66Val, but not Val66Met, increased BDNF (interaction, P = 0.04) and BDNF/proBDNF ratio (interaction, P < 0.001). Interestingly, FBF (interaction, P = 0.04) and the FVR (interaction, P = 0.01) responses during handgrip exercise (HG) improved in Val66Val compared with Val66Met, even with similar responses of HR and MBP. There were association between BDNF/proBDNF ratio and FBF (r = 0.64, P < 0.001) and FVR (r = -0.58, P < 0.001) during HG exercise. These results show that peripheral vascular reactivity and serum BDNF responses to exercise training are impaired by the BDNF Val66Met polymorphism and such responsiveness is associated with serum BDNF concentrations in healthy subjects. PMID:26603150

  8. 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…

  9. Comparison of the Adulthood Chronic Stress Effect on Hippocampal BDNF Signaling in Male and Female Rats.

    PubMed

    Niknazar, Somayeh; Nahavandi, Arezo; Peyvandi, Ali Asghar; Peyvandi, Hassan; Akhtari, Amin Shams; Karimi, Mohsen

    2016-08-01

    Studies show that gender plays an important role in stress-related disorders, and women are more vulnerable to its effect. The present study was undertaken to investigate differences in the change in expression of brain-derived neurotrophic factor (BDNF), and its tyrosine intracellular kinase-activating receptor (TrkB) genes in the male and female rats' hippocampus (HPC) under chronic mild repeated stress (CMRS) conditions. In this experiment, male and female Wistar rats were randomly divided into two groups: the CMRS and the control group. To induce stress, a repeated forced swimming paradigm was employed daily for adult male and female rats for 21 days. At the end of the stress phase, elevated plus maze (EPM) was used for measuring the stress behavioral effects. Serum corticosterone level was measured by ELISA. BDNF and TrkB gene methylation and protein expression in the HPC were detected using real-time PCR and Western blotting. Chronic stress in the adolescence had more effects on anxiety-like behavior and serum corticosterone concentration in female rats than males. Furthermore, stressed female rats had higher methylation levels and following reduced protein expression of BDNF but not TrkB compared to stressed male rats. These findings suggest that in exposure to a stressor, sex differences in BDNF methylation may be root cause of decreased BDNF levels in females and may underlie susceptibility to pathology development. PMID:26189832

  10. Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway

    PubMed Central

    Wrann, Christiane D.; White, James P.; Salogiannnis, John; Laznik-Bogoslavski, Dina; Wu, Jun; Ma, Di; Lin, Jiandie D.; Greenberg, Michael E.; Spiegelman, Bruce M.

    2014-01-01

    SUMMARY Exercise can improve cognitive function and has been linked to the increased expression of brain-derived neurotrophic factor (BDNF). However, the underlying molecular mechanisms driving the elevation of this neurotrophin remain unknown. Here we show that FNDC5, a previously identified muscle protein that is induced in exercise and is cleaved and secreted as irisin, is also elevated by endurance exercise in the hippocampus of mice. Neuronal Fndc5 gene expression is regulated by PGC-1α and Pgc1a−/− mice show reduced Fndc5 expression in the brain. Forced expression of FNDC5 in primary cortical neurons increases Bdnf expression, whereas RNAi-mediated knockdown of FNDC5 reduces Bdnf. Importantly, peripheral delivery of FNDC5 to the liver via adenoviral vectors, resulting in elevated blood irisin, induces expression of Bdnf and other neuroprotective genes in the hippocampus. Taken together, our findings link endurance exercise and the important metabolic mediators, PGC-1α and FNDC5, with BDNF expression in the brain. PMID:24120943

  11. Impaired spatial working memory and decreased frontal cortex BDNF protein level in dopamine transporter knock out mice

    PubMed Central

    Li, BingJin; Arime, Yosefu; Hall, F. Scott; Uhl, George R.; Sora, Ichiro

    2010-01-01

    Brain-derived neurotrophic factor (BDNF), one of the key brain neurotrophins, has been implicated in neuronal plasticity and memory. Recent studies document the importance of BDNF for normal long-term memory functions. However, there are few studies of the roles of BDNF in short term memory. Dopamine is likely to play important roles in BDNF gene expression in specific brain regions, including frontal cortical regions that are implicated in short term working memory processes that include spontaneous alternation. We have thus tested spatial working memory in dopamine transporter knockout (DAT KO) and wild-type mice. Spontaneous alternation in the Y-maze, an index of short-term spatial working memory in mice, was significantly decreased in DAT KO mice compared to wildtype mice. BDNF protein was significantly decreased in frontal cortex, though not in striatum or hippocampus, of the DAT KO mice. The data support the hypothesis that impaired spatial working memory in DAT KO mice may be related to decreased frontal cortical BDNF in these animals, and document apparent roles for BDNF in a short term memory process. PMID:19932884

  12. 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. PMID:25099302

  13. BDNF and Huntingtin protein modifications by Manganese: Implications for striatal medium spiny neuron pathology in manganese neurotoxicity

    PubMed Central

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

    2014-01-01

    High levels of manganese (Mn) exposure decreases 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 (S421). In Huntington's disease, pathogenic CAG-repeat expansions of HTT decrease synthesis and disrupt transport of cortical-striatal BDNF contributing 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 due to Mn 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. Further, 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 S421 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. PMID:25099302

  14. 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

  15. BDNF promoter methylation and genetic variation in late-life depression.

    PubMed

    Januar, V; Ancelin, M-L; Ritchie, K; Saffery, R; Ryan, J

    2015-01-01

    The regulation of the brain-derived neurotrophic factor (BDNF) is important for depression pathophysiology and epigenetic regulation of the BDNF gene may be involved. This study investigated whether BDNF methylation is a marker of depression. One thousand and twenty-four participants were recruited as part of a longitudinal study of psychiatric disorders in general population elderly (age ⩾ 65). Clinical levels of depression were assessed using the Mini International Neuropsychiatric Interview for the diagnosis of major depressive disorder according to the Diagnostic and Statistical Manual of Mental Disorder IV criteria, and the Centre for Epidemiologic Studies Depression Scale (CES-D) for assessment of moderate to severe depressive symptoms. Buccal DNA methylation at the two most widely studied BDNF promoters, I and IV, was investigated using the Sequenom MassARRAY platform that allows high-throughput investigation of methylation at individual CpG sites within defined genomic regions. In multivariate linear regression analyses adjusted for a range of participant characteristics including antidepressant use, depression at baseline, as well as chronic late-life depression over the 12-year follow-up, were associated with overall higher BDNF methylation levels, with two sites showing significant associations (promoter I, Δ mean = 0.4%, P = 0.0002; promoter IV, Δ mean = 5.4%, P = 0.021). Three single-nucleotide polymorphisms (rs6265, rs7103411 and rs908867) were also found to modify the association between depression and promoter I methylation. As one of the largest epigenetic studies of depression, and the first investigating BDNF methylation in buccal tissue, our findings highlight the potential for buccal BDNF methylation to be a biomarker of depression. PMID:26285129

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

    PubMed

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

    2016-01-01

    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

  17. 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

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

    PubMed Central

    Bałkowiec-Iskra, Ewa; Vermehren-Schmaedick, Anke; Balkowiec, Agnieszka

    2011-01-01

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

  19. 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

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

    PubMed

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

    2015-06-01

    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

  1. 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. PMID:25792232

  2. Methylation of BDNF in women with bulimic eating syndromes: associations with childhood abuse and borderline personality disorder.

    PubMed

    Thaler, Lea; Gauvin, Lise; Joober, Ridha; Groleau, Patricia; de Guzman, Rosherrie; Ambalavanan, Amirthagowri; Israel, Mimi; Wilson, Samantha; Steiger, Howard

    2014-10-01

    DNA methylation allows for the environmental regulation of gene expression and is believed to link environmental stressors to such mental-illness phenotypes as eating disorders. Numerous studies have shown an association between bulimia nervosa (BN) and variations in brain-derived neurotrophic factor (BDNF). BDNF has also been linked to borderline personality disorder (BPD) and to such traits as reward dependence. We examined the extent to which BDNF methylation corresponded to bulimic or normal-eater status, and also to the presence of comorbid borderline personality disorder (BPD) and childhood abuse. Our sample consisted of 64 women with BN and 32 normal-eater (NE) control women. Participants were assessed for eating-disorder symptoms, comorbid psychopathology, and childhood trauma, and then they were required to provide blood samples for methylation analyses. We observed a significant site×group (BN vs. NE) interaction indicating that women with BN showed increases in methylation at specific regions of the BDNF promoter. Furthermore, examining effects of childhood abuse and BPD, we observed significant site×group interactions such that groups composed of individuals with childhood abuse or BPD had particularly high levels of methylation at selected CpG sites. Our findings suggest that BN, especially when co-occurring with childhood abuse or BPD, is associated with a propensity towards elevated methylation at specific BDNF promoter region sites. These findings imply that hypermethylation of the BDNF gene may be related to eating disorder status, developmental stress exposure, and comorbid psychopathology. PMID:24801751

  3. 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

  4. 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. PMID:26783111

  5. Increased cerebellar volume and BDNF level following quadrato motor training.

    PubMed

    Ben-Soussan, Tal Dotan; Piervincenzi, Claudia; Venditti, Sabrina; Verdone, Loredana; Caserta, Micaela; Carducci, Filippo

    2015-01-01

    Using whole-brain structural measures coupled to analysis of salivary brain-derived neurotrophic factor (BDNF), we demonstrate sensory motor training-induced plasticity, including cerebellar gray matter volume increment and increased BDNF level. The increase of cerebellar volume was positively correlated with the increase of BDNF level. PMID:25311848

  6. Decoding BDNF-LTP coupling in cocaine addiction

    PubMed Central

    Mao, Li-Min; Fibuch, Eugene E; Wang, John Q.

    2010-01-01

    BDNF is a neurotrophic peptide that regulates synaptic plasticity. New work by Lu and coworkers in this issue of Neuron now identifies BDNF as a gatekeeper of synaptic and behavioral plasticity in cocaine sensitization. In the medial prefrontal cortex, upregulated BDNF facilitates LTP and contributes to neurobehavioral adaptations to psychostimulants. PMID:20890399

  7. Prenatal Cocaine Exposure Upregulates BDNF-TrkB Signaling.

    PubMed

    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

  8. Identification of a new splice variant of BDNF in chicken

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Brain-derived neurotrophic factor (BDNF) appears to be involved in the central regulation of energy homeostasis. BDNF splicing variants were discovered in vertebrates. Results from human, mouse and rat suggest that alternative BDNF splicing variants potentially play a role in fat deposition. Using t...

  9. 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

  10. Sex-dependent alterations in BDNF-TrkB signaling in the hippocampus of reelin heterozygous mice: a role for sex steroid hormones.

    PubMed

    Hill, Rachel A; Wu, Yee-Wen Candace; Gogos, Andrea; van den Buuse, Maarten

    2013-08-01

    Neurodevelopmental psychiatric disorders such as schizophrenia may be caused by a combination of gene × environment, gene × gene, and/or gene × sex interactions. Reduced expression of both Reelin and Brain-Derived Neurotrophic factor (BDNF) has been associated with schizophrenia in human post-mortem studies. However, it remains unclear how Reelin and BDNF interact (gene × gene) and whether this is sex-specific (gene × sex). This study investigated BDNF-TrkB signaling in the hippocampus of male and female Reelin heterozygous (Rln(+/-) ) mice. We found significantly increased levels of BDNF in the ventral hippocampus (VHP) of female, but not male Rln(+/-) compared to wild-type (WT) controls. While levels of TrkB were not significantly altered, phosphorylated TrkB (pTrkB) levels were significantly lower, again only in female Rln(+/-) compared to WT. This translated to downstream effects with a significant decrease in phosphorylated ERK1 (pERK1). No changes in BDNF, TrkB, pTrkB or pERK1/2 were observed in the dorsal hippocampus of Rln(+/-) mice. Ovariectomy (OVX) had no effect in WT controls, but caused a significant decrease in BDNF expression in the VHP of Rln(+/-) mice to the levels of intact WT controls. The high expression of BDNF was restored in OVX Rln(+/-) mice by 17β-estradiol treatment, suggesting that Rln(+/-) mice respond differently to an altered estradiol state than WT controls. In addition, while OVX had no significant effect on TrkB or ERK expression/phosphorylation, OVX + estradiol treatment markedly increased TrkB and ERK1 phosphorylation in Rln(+/-) and, to a lesser extent in WT controls, compared to intact genotype-matched controls. These data may provide a better understanding of the interaction of Reelin and BDNF in the hippocampus, which may be involved in schizophrenia. PMID:23414458

  11. 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

  12. No association between BDNF Val66Met polymorphism and treatment response in obsessive-compulsive disorder in the Japanese population

    PubMed Central

    Umehara, Hidehiro; Numata, Shusuke; Kinoshita, Makoto; Watanabe, Shinya; Nakaaki, Shutaro; Sumitani, Satsuki; Ohmori, Tetsuro

    2016-01-01

    Aim Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family, and it promotes the development and function of dopaminergic and serotonergic neurons. The Met allele of the BDNF Val66Met polymorphism is associated with a decrease in activity-dependent secretion of BDNF compared with the Val allele, and a number of studies have provided evidence for the association between this polymorphism and obsessive-compulsive disorder (OCD). The purpose of this study was to investigate whether this functional variant of the BDNF gene is associated with OCD and treatment response in patients with OCD in the Japanese population. Methods We first performed a case–control association study between the BDNF Val66Met polymorphism and OCD (175 cases and 2,027 controls). Then, we examined an association between this polymorphism and treatment response in 96 patients with OCD. Results We found no significant association between the Met allele and OCD risk or between the Met allele and treatment responses to selective serotonin reuptake inhibitors or serotonin reuptake inhibitor with an atypical antipsychotic (P>0.05). Conclusion Our results suggest that the BDNF Val66Met polymorphism may not be associated as a risk factor for developing OCD or with therapeutic response in patients with OCD in the Japanese population. PMID:27042072

  13. No Association of the BDNF Val66met Polymorphism with Implicit Associative Vocabulary and Motor Learning

    PubMed Central

    Freundlieb, Nils; Philipp, Stephan; Schneider, Susanne A.; Brüggemann, Norbert; Klein, Christine; Gerloff, Christian; Hummel, Friedhelm C.

    2012-01-01

    Brain-derived neurotrophic factor (BDNF) has been suggested to play a major role in plasticity, neurogenesis and learning in the adult brain. The BDNF gene contains a common val66met polymorphism associated with decreased activity-dependent excretion of BDNF and a potential influence on behaviour, more specifically, on motor learning. The objective of this study was to determine the influence of the BDNF val66met polymorphism on short-term implicit associative learning and whether its influence is cognitive domain-specific (motor vs. language). A sample of 38 young healthy participants was genotyped, screened for background and neuropsychological differences, and tested with two associative implicit learning paradigms in two different cognitive domains, i.e., motor and vocabulary learning. Subjects performed the serial reaction time task (SRTT) to determine implicit motor learning and a recently established associative vocabulary learning task (AVL) for implicit learning of action and object words. To determine the influence of the BDNF polymorphism on domain-specific implicit learning, behavioural improvements in the two tasks were compared between val/val (n = 22) and met carriers (val/met: n = 15 and met/met: n = 1). There was no evidence for an impact of the BDNF val66met polymorphism on the behavioural outcome in implicit short-term learning paradigms in young healthy subjects. Whether this polymorphism plays a relevant role in long-term training paradigms or in subjects with impaired neuronal plasticity or reduced learning capacity, such as aged individuals, demented patients or patients with brain lesions, has to be determined in future studies. PMID:23152767

  14. 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

  15. BDNF G196A (Val66Met) polymorphism associated with cognitive impairment in Parkinson's disease.

    PubMed

    Białecka, Monika; Kurzawski, Mateusz; Roszmann, Anna; Robowski, Piotr; Sitek, Emilia J; Honczarenko, Krystyna; Mak, Monika; Deptuła-Jarosz, Monika; Gołąb-Janowska, Monika; Droździk, Marek; Sławek, Jarosław

    2014-02-21

    Brain-derived neurotrophic factor (BDNF) is a neurotrophin widely expressed in the mammalian brain, regulating neuronal survival and known to influence dopaminergic neurons and cognitive processes. The present study investigated the BDNF Val66Met polymorphism associations with PD risk, and cognitive impairment in PD. A total of 486 study subjects (244 PD and 242 age and sex matched controls) were included in the study. UPDRS score, Hoehn-Yahr staging and the Schwab-England scale were used to assess motor abilities and activity during daily life. The patients were classified into groups with dementia (PDD, n=69) and without it (nPDD, n=166) on the basis of neuropsychological assessment. The most common functional polymorphism in BDNF Val66Met (rs6265, G196A) gene was determined using TaqMan real-time PCR assay. Frequencies of evaluated BDNF alleles and genotypes were similar in PD and the controls. The mean age of disease onset among BDNF Met/Met carriers was later (65.00±6.13) in comparison to Val/Val (57.45±10.68) and Val/Met (56.33±10.91) subjects (p=0.077). The studied BDNF polymorphism was not associated with cognitive status in PD patients. However, patients with Met/Met alleles demonstrated better delayed recall of information than patients with Val/Val alleles. The results of multivariate logistic regression analysis revealed age (p=0.0003) and the disease stage (p=0.002) as independent risk factors predisposing to PD dementia. PMID:24394906

  16. Nuclear Factor-kappaB-Dependent Sestrin2 Induction Mediates the Antioxidant Effects of BDNF Against Mitochondrial Inhibition in Rat Cortical Neurons.

    PubMed

    Wu, Chia-Lin; Chen, Shang-Der; Yin, Jiu-Haw; Hwang, Chi-Shin; Yang, Ding-I

    2016-08-01

    Brain-derived neurotrophic factor (BDNF), in addition to its neurotrophic action, also possesses antioxidant activities. However, the underlying mechanisms remain to be fully defined. Sestrin2 is a stress-responsive gene implicated in the cellular defense against oxidative stress. Currently, the potential functions of sestrin2 in nervous system, in particular its correlation with neurotrophic factors, have not been well established. In this study, we hypothesized that BDNF may enhance sestrin2 expression to confer neuronal resistance against oxidative stress induced by 3-nitropropionic acid (3-NP), an irreversible mitochondrial complex II inhibitor, and characterized the molecular mechanisms underlying BDNF induction of sestrin2 in primary rat cortical cultures. We found that BDNF-mediated sestrin2 expression in cortical neurons required formation of nitric oxide (NO) with subsequent production of 3',5'-cyclic guanosine monophosphate (cGMP) and activation of cGMP-dependent protein kinase (PKG). BDNF induced localization of nuclear factor-kappaB (NF-κB) subunits p65 and p50 into neuronal nuclei that required PKG activities. Interestingly, BDNF exposure led to formation of a protein complex containing at least PKG-1 and p65/p50, which bound to sestrin2 promoter with resultant upregulation of its protein products. Finally, BDNF preconditioning mitigated production of reactive oxygen species (ROS) as a result of 3-NP exposure; this antioxidative effect of BDNF was dependent upon PKG activity, NF-κB, and sestrin2. Taken together, our results indicated that BDNF enhances sestrin2 expression to confer neuronal resistance against oxidative stress induced by 3-NP through attenuation of ROS formation; furthermore, BDNF induction of sestrin2 requires activation of a pathway involving NO/PKG/NF-κB. PMID:26208700

  17. 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

  18. PKA-CREB-BDNF signaling regulated long lasting antidepressant activities of Yueju but not ketamine.

    PubMed

    Xue, Wenda; Wang, Wei; Gong, Tong; Zhang, Hailou; Tao, Weiwei; Xue, Lihong; Sun, Yan; Wang, Fushun; Chen, Gang

    2016-01-01

    Yueju confers antidepressant effects in a rapid and long-lasting manner, similar to ketamine. CREB (cAMP-response element binding protein) signaling is implicated in depression pathology and antidepressant responses. However, the role of CREB and associated brain derived neurotrophic factor (BDNF) signaling in rapid and long-lasting antidepressant effects remains unclear. Here, we demonstrated that ICR and Kunming strain mice conferred antidepressant responses lasting for 1 and 5 days, respectively, following a single dose of Yueju. One day post Yueju in Kunming but not ICR strain mice, expression of total and phosphorylated CREB, as well as the CREB signaling activator, PKA (protein kinase A) was up-regulated in the hippocampus. Although BDNF gene expression increased at 3 hours in both strains, it remained up-regulated at 1 day only in Kunming mice. Ketamine showed similar strain-dependent behavioral effects. However, blockade of PKA/CREB signaling blunted the antidepressant effects and reversed the up-regulation of BDNF gene expression by Yueju, but not ketamine. Conversely, blockade of mammalian target of rapamycin signaling led to opposite effects. Taken altogether, prolonged transcriptional up-regulation of hippocampal BDNF may account for the stain-dependent enduring antidepressant responses to Yueju and ketamine, but it was mediated via PKA/CREB pathway only for Yueju. PMID:27197752

  19. PKA-CREB-BDNF signaling regulated long lasting antidepressant activities of Yueju but not ketamine

    PubMed Central

    Xue, Wenda; Wang, Wei; Gong, Tong; Zhang, Hailou; Tao, Weiwei; Xue, Lihong; Sun, Yan; Wang, Fushun; Chen, Gang

    2016-01-01

    Yueju confers antidepressant effects in a rapid and long-lasting manner, similar to ketamine. CREB (cAMP-response element binding protein) signaling is implicated in depression pathology and antidepressant responses. However, the role of CREB and associated brain derived neurotrophic factor (BDNF) signaling in rapid and long-lasting antidepressant effects remains unclear. Here, we demonstrated that ICR and Kunming strain mice conferred antidepressant responses lasting for 1 and 5 days, respectively, following a single dose of Yueju. One day post Yueju in Kunming but not ICR strain mice, expression of total and phosphorylated CREB, as well as the CREB signaling activator, PKA (protein kinase A) was up-regulated in the hippocampus. Although BDNF gene expression increased at 3 hours in both strains, it remained up-regulated at 1 day only in Kunming mice. Ketamine showed similar strain-dependent behavioral effects. However, blockade of PKA/CREB signaling blunted the antidepressant effects and reversed the up-regulation of BDNF gene expression by Yueju, but not ketamine. Conversely, blockade of mammalian target of rapamycin signaling led to opposite effects. Taken altogether, prolonged transcriptional up-regulation of hippocampal BDNF may account for the stain-dependent enduring antidepressant responses to Yueju and ketamine, but it was mediated via PKA/CREB pathway only for Yueju. PMID:27197752

  20. 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. PMID:26286685

  1. Propofol alleviates electroconvulsive shock-induced memory impairment by modulating proBDNF/mBDNF ratio in depressive rats.

    PubMed

    Zhang, Fan; Luo, Jie; Min, Su; Ren, Li; Qin, Peipei

    2016-07-01

    This study investigated the effects of propofol and electroconvulsive shock (ECS), the analogue of electroconvulsive therapy (ECT) in animals, on tissue plasminogen activator (tPA) and its inhibitor (PAI-1) as well as the precursor of brain-derived neurotrophic factor (proBDNF)/mature BDNF (mBDNF) ratio in depressive rats. ECT is an effective treatment for depression, but can cause cognitive deficit. Some studies have indicated that propofol can ameliorate cognitive decline induced by ECT, but the underlying molecular mechanism is still unclear. Recent evidence has found that mBDNF and its precursor proBDNF are related to depression and cognitive function; they elicit opposite effects on cellular functions. Chronic unpredicted mild stress is widely used to induce depressive behaviors in rodents. This study found that the depression resulted in an increased expression of PAI-1 and upregulation of the proBDNF/mBDNF ratio, together with a decreased level of tPA, long-term potentiation (LTP) impairment, and cognitive decline. The proBDNF/mBDNF ratio was further upregulated after the ECS treatment in depressive rats, resulting in the deterioration of cognitive function and hippocampal LTP. Propofol alone did not reverse the changes in depressive rats, but when co-administered with ECS, it improved the cognitive function, alleviated the impairment of LTP, downregulated the proBDNF/mBDNF ratio, and increased the tPA expression. The results of this study suggest that propofol ameliorates cognitive decline induced by ECT, which was partly by modulating the proBDNF/mBDNF ratio and reversing the excessive changes in hippocampal synaptic plasticity, providing a new evidence for involving the proBDNF/mBDNF system in the progression and treatment of depression. PMID:27017958

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

    PubMed

    Foltran, Rocío Beatriz; Diaz, Silvina Laura

    2016-07-01

    The brain-derived neurotrophic factor, BDNF, was discovered more than 30 years ago and, like other members of the neurotrophin family, this neuropeptide is synthetized as a proneurotrophin, the pro-BDNF, which is further cleaved to yield mature BDNF. The myriad of actions of these two BDNF isoforms in the central nervous system is constantly increasing and requires the development of sophisticated tools and animal models to refine our understanding. This review is focused on BDNF isoforms, their participation in the process of neurogenesis taking place in the hippocampus of adult mammals, and the modulation of their expression by serotonergic agents. Interestingly, around this triumvirate of BDNF, serotonin, and neurogenesis, a series of recent research has emerged with apparently counterintuitive results. This calls for an exhaustive analysis of the data published so far and encourages thorough work in the quest for new hypotheses in the field. BDNF is synthetized as a pre-proneurotrophin. After removal of the pre-region, proBDNF can be cleaved by intracellular or extracellular proteases. Mature BDNF can bind TrkB receptors, promoting their homodimerization and intracellular phosphorylation. Phosphorylated-TrkB can activate three different signaling pathways. Whereas G-protein-coupled receptors can transactivate TrkB receptors, truncated forms can inhibit mBDNF signaling. Pro-BDNF binds p75(NTR) by its mature domain, whereas the pro-region binds co-receptors. PMID:27167299

  3. Exercise influences hippocampal plasticity by modulating BDNF processing

    PubMed Central

    Ding, Qinxue; Ying, Zhe; Gómez-Pinilla, Fernando

    2011-01-01

    Exercise has been shown to impact brain plasticity and function by involving the action of BDNF; however, mechanisms involved are poorly understood. Two types of BDNF coexist in the brain, the precursor (proBDNF) and its mature product (mBDNF), which preferentially bind specific receptors and exert distinct functions. It is crucial to understand how exercise affects crucial steps in the BDNF processing and signaling to evaluate therapeutic applications. We found that 7 days of voluntary exercise increased both pro and mature BDNF in the rat hippocampus. Exercise also increased the activity of tissue-type plasminogen activator (tPA), a serine proteinase shown to facilitate proBDNF cleavage into mBDNF. The blockade of tPA activity reduced the exercise effects on proBDNF and mBDNF. The tPA blocking also inhibited the activation of TrkB receptor, and the TrkB signaling downstream effectors phospho-ERK, phospho-Akt, and phospho-CaMKII. The blocking of tPA also counteracted the effects of exercise on the plasticity markers phospho-synapsin I and GAP-43. These results indicate that the effects of exercise on hippocampal plasticity are dependent on BDNF processing and subsequent TrkB signaling, with important implications for neuronal function. PMID:21756980

  4. 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. PMID:24451568

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

    PubMed Central

    Scharfman, Helen E.; MacLusky, Neil J.

    2007-01-01

    In the CNS, there are widespread and diverse interactions between growth factors and estrogen. Here we examine the interactions of estrogen and brain-derived neurotrophic factor (BDNF), two molecules that have historically been studied separately, despite the fact that they seem to share common targets, effects, and mechanisms of action. The demonstration of an estrogen-sensitive response element on the BDNF gene provided an impetus to explore a direct relationship between estrogen and BDNF, 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. PMID:17055560

  6. Slitrk5 Mediates BDNF-Dependent TrkB Receptor Trafficking and Signaling.

    PubMed

    Song, Minseok; Giza, Joanna; Proenca, Catia C; Jing, Deqiang; Elliott, Mark; Dincheva, Iva; Shmelkov, Sergey V; Kim, Jihye; Schreiner, Ryan; Huang, Shu-Hong; Castrén, Eero; Prekeris, Rytis; Hempstead, Barbara L; Chao, Moses V; Dictenberg, Jason B; Rafii, Shahin; Chen, Zhe-Yu; Rodriguez-Boulan, Enrique; Lee, Francis S

    2015-06-22

    Recent studies in humans and in genetic mouse models have identified Slit- and NTRK-like family (Slitrks) as candidate genes for neuropsychiatric disorders. All Slitrk isotypes are highly expressed in the CNS, where they mediate neurite outgrowth, synaptogenesis, and neuronal survival. However, the molecular mechanisms underlying these functions are not known. Here, we report that Slitrk5 modulates brain-derived neurotrophic factor (BDNF)-dependent biological responses through direct interaction with TrkB receptors. Under basal conditions, Slitrk5 interacts primarily with a transsynaptic binding partner, protein tyrosine phosphatase δ (PTPδ); however, upon BDNF stimulation, Slitrk5 shifts to cis-interactions with TrkB. In the absence of Slitrk5, TrkB has a reduced rate of ligand-dependent recycling and altered responsiveness to BDNF treatment. Structured illumination microscopy revealed that Slitrk5 mediates optimal targeting of TrkB receptors to Rab11-positive recycling endosomes through recruitment of a Rab11 effector protein, Rab11-FIP3. Thus, Slitrk5 acts as a TrkB co-receptor that mediates its BDNF-dependent trafficking and signaling. PMID:26004511

  7. 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

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

    PubMed

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

    2015-10-01

    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

  9. 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. PMID:24760847

  10. 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

  11. Impaired Eye-Blink Conditioning in waggler, a Mutant Mouse With Cerebellar BDNF Deficiency

    PubMed Central

    Bao, Shaowen; Chen, Lu; Qiao, Xiaoxi; Knusel, Beat; Thompson, Richard F.

    1998-01-01

    In addition to their trophic functions, neurotrophins are also implicated in synaptic modulation and learning and memory. Although gene knockout techniques have been used widely in studying the roles of neurotrophins at molecular and cellular levels, behavioral studies using neurotrophin knockouts are limited by the early-onset lethality and various sensory deficits associated with the gene knockout mice. In the present study, we found that in a spontaneous mutant mouse, waggler, the expression of brain-derived neurotrophic factor (BDNF) was selectively absent in the cerebellar granule cells. The cytoarchitecture of the waggler cerebellum appeared to be normal at the light microscope level. The mutant mice exhibited no sensory deficits to auditory stimuli or heat-induced pain. However, they were massively impaired in classic eye-blink conditioning. These results suggest that BDNF may have a role in normal cerebellar neuronal function, which, in turn, is essential for classic eye-blink conditioning. PMID:10454360

  12. BDNF mediates adaptive brain and body responses to energetic challenges.

    PubMed

    Marosi, Krisztina; Mattson, Mark P

    2014-02-01

    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 the beneficial effects of energetic challenges such as vigorous exercise and fasting on cognition, mood, cardiovascular function, and on 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, and this may contribute to the pathogenesis of metabolic syndrome. Novel BDNF-focused interventions are being developed for obesity, diabetes, and neurological disorders. PMID:24361004

  13. The Interplay of Stress and Sleep Impacts BDNF Level

    PubMed Central

    Brand, Serge; Calabrese, Pasquale; Holsboer-Trachsler, Edith; Eckert, Anne

    2013-01-01

    Background Sleep plays a pivotal role in normal biological functions. Sleep loss results in higher stress vulnerability and is often found in mental disorders. There is evidence that brain-derived neurotrophic factor (BDNF) could be a central player in this relationship. Recently, we could demonstrate that subjects suffering from current symptoms of insomnia exhibited significantly decreased serum BDNF levels compared with sleep-healthy controls. In accordance with the paradigm indicating a link between sleep and BDNF, we aimed to investigate if the stress system influences the association between sleep and BDNF. Methodology/Principal Findings Participants with current symptoms of insomnia plus a former diagnosis of Restless Legs Syndrome (RLS) and/or Periodic Limb Movement (PLM) and sleep healthy controls were included in the study. They completed questionnaires on sleep (ISI, Insomnia Severity Index) and stress (PSS, Perceived Stress Scale) and provided a blood sample for determination of serum BDNF. We found a significant interaction between stress and insomnia with an impact on serum BDNF levels. Moreover, insomnia severity groups and score on the PSS each revealed a significant main effect on serum BDNF levels. Insomnia severity was associated with increased stress experience affecting serum BDNF levels. Of note, the association between stress and BDNF was only observed in subjects without insomnia. Using a mediation model, sleep was revealed as a mediator of the association between stress experience and serum BDNF levels. Conclusions This is the first study to show that the interplay between stress and sleep impacts BDNF levels, suggesting an important role of this relationship in the pathogenesis of stress-associated mental disorders. Hence, we suggest sleep as a key mediator at the connection between stress and BDNF. Whether sleep is maintained or disturbed might explain why some individuals are able to handle a certain stress load while others develop a

  14. 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

  15. Proteolytic cleavage of proBDNF into mature BDNF in the basolateral amygdala is necessary for defeat-induced social avoidance.

    PubMed

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

    2016-04-01

    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 the BLA/central amygdala. We also showed that blocking plasmin in the BLA with microinjection of α2-antiplasmin immediately following social defeat decreases social avoidance 24 h later. These data suggest the proteolytic cleavage of BDNF in the BLA is necessary for defeat-induced social avoidance. PMID:26980783

  16. 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

  17. 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. PMID:27551971

  18. 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. PMID:27288826

  19. Functional interactions between steroid hormones and neurotrophin BDNF.

    PubMed

    Numakawa, Tadahiro; Yokomaku, Daisaku; Richards, Misty; Hori, Hiroaki; Adachi, Naoki; Kunugi, Hiroshi

    2010-05-26

    Brain-derived neurotrophic factor (BDNF), a critical neurotrophin, regulates many neuronal aspects including cell differentiation, cell survival, neurotransmission, and synaptic plasticity in the central nervous system (CNS). Though BDNF has two types of receptors, high affinity tropomyosin-related kinase (Trk)B and low affinity p75 receptors, BDNF positively exerts its biological effects on neurons via activation of TrkB and of resultant intracellular signaling cascades including mitogen-activated protein kinase/extracellular signal-regulated protein kinase, phospholipase Cγ, and phosphoinositide 3-kinase pathways. Notably, it is possible that alteration in the expression and/or function of BDNF in the CNS is involved in the pathophysiology of various brain diseases such as stroke, Parkinson's disease, Alzheimer's disease, and mental disorders. On the other hand, glucocorticoids, stress-induced steroid hormones, also putatively contribute to the pathophysiology of depression. Interestingly, in addition to the reduction in BDNF levels due to increased glucocorticoid exposure, current reports demonstrate possible interactions between glucocorticoids and BDNF-mediated neuronal functions. Other steroid hormones, such as estrogen, are involved in not only sexual differentiation in the brain, but also numerous neuronal events including cell survival and synaptic plasticity. Furthermore, it is well known that estrogen plays a role in the pathophysiology of Parkinson's disease, Alzheimer's disease, and mental illness, while serving to regulate BDNF expression and/or function. Here, we present a broad overview of the current knowledge concerning the association between BDNF expression/function and steroid hormones (glucocorticoids and estrogen). PMID:21540998

  20. BDNF plasma levels variations in major depressed patients receiving duloxetine.

    PubMed

    Fornaro, Michele; Escelsior, Andrea; Rocchi, Giulio; Conio, Benedetta; Magioncalda, Paola; Marozzi, Valentina; Presta, Andrea; Sterlini, Bruno; Contini, Paola; Amore, Mario; Fornaro, Pantaleo; Martino, Matteo

    2015-05-01

    It has been frequently reported that brain-derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of major depressive disorder (MDD). Objective of the study was to investigate BDNF levels variations in MDD patients during antidepressant treatment with duloxetine. 30 MDD patients and 32 healthy controls were assessed using Hamilton Depression Scale (HAM-D) and monitored for BDNF plasma levels at baseline, week 6 and week 12 of duloxetine treatment (60 mg/day) and at baseline, respectively. According to early clinical response to duloxetine (defined at week 6 by reduction >50 % of baseline HAM-D score), MDD patients were distinguished in early responders (ER) and early non-responders (ENR), who reached clinical response at week 12. Laboratory analysis showed significant lower baseline BDNF levels among patients compared to controls. During duloxetine treatment, in ENR BDNF levels increased, reaching values not significantly different compared to controls, while in ER BDNF levels remained nearly unchanged. Lower baseline BDNF levels observed in patients possibly confirm an impairment of the NEI stress-adaptation system and neuroplasticity in depression, while BDNF increase and normalization observed only in ENR might suggest differential neurobiological backgrounds in ER vs. ENR within the depressive syndrome. PMID:25501804

  1. Association study between BDNF C-281A polymorphism and paranoid schizophrenia in Polish population.

    PubMed

    Suchanek, Renata; Owczarek, Aleksander; Kowalski, Jan

    2012-01-01

    Brain-derived neurotrophic factor (BDNF) is one of the candidate genes for schizophrenia. Polymorphism C-281A (rs28383487) in BDNF gene leads to the reduction of promoter activity in the hippocampal neurons in vitro. To our knowledge, this is the first study to examine the influence of alleles and genotypes of BDNF C-281A polymorphism on development, as well as the clinical course (age of onset, suicidal behaviour and psychopathology) of paranoid schizophrenia. The psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) as subscale scores and also single-item scores. We have also performed the haplotype analysis with val66met BDNF polymorphism, which is known to be involved in the pathogenesis of schizophrenia. We have not found significant differences in the distribution of genotypes and alleles between schizophrenic patients and controls in both the overall analysis, as well as sex stratified. Also, we have not shown statistically significant differences between genotype groups and PANSS scale. However, an association between C-281A polymorphism and time of the first episode of paranoid schizophrenia was revealed. Genotype C/A had been connected with later age of onset of paranoid schizophrenia in men but not in women (p < 0.01). The C-281A and val66met polymorphisms have been in a strong linkage disequilibrium (D' = 0.9875; p < 0.05). The haplotype analysis has shown a tendency to a significantly lower frequency of the Met-C haplotype in the schizophrenia group compared to the controls. PMID:21710362

  2. BDNF genetic variability modulates psychopathological symptoms in patients with eating disorders.

    PubMed

    Gamero-Villarroel, Carmen; Gordillo, Inmaculada; Carrillo, Juan Antonio; García-Herráiz, Angustias; Flores, Isalud; Jiménez, Mercedes; Monge, Melchora; Rodríguez-López, Raquel; Gervasini, Guillermo

    2014-08-01

    The brain-derived neurotrophic factor (BDNF) gene may influence eating behavior, body weight and cognitive impairments. We aimed to investigate whether BDNF genetic variability may affect anthropometric and psychological parameters in patients with anorexia or bulimia nervosa (AN, BN) and/or modulate the risk for the disorder. A total of 169 unrelated female patients and 312 healthy controls were genotyped for two common BDNF single-nucleotide polymorphisms (SNPs), Val66Met and C-270T, and several selected tag-SNPs. Associated personality characteristics and psychopathological symptoms were assessed by the EDI-2 and SCL-90R inventories, respectively. No single SNP or haplotype played a relevant role in the risk for AN or BN. The rs16917237 TT genotype was significantly associated with increased weight (74.63 ± 16.58 vs. 57.93 ± 13.02) and body mass index (28.94 ± 6.22 vs. 22.23 ± 4.77) in the BN group after correcting for multiple testing. Haplotype analyses using a sliding window approach with three adjacent SNPs produced four loci of interest. Locus 3 (rs10835210/rs16917237/C-270T) showed a broad impact on the measured psychopathological symptoms. Haplotypes CGC and CGT in this locus correlated with scores in all three scales of the SCL-90R inventory, both in AN and BN patients. In contrast, the results of the EDI-2 inventory were largely unaffected. These preliminary results suggest that variability in the BDNF gene locus may contribute to anthropometric characteristics and also psychopathological symptoms that are common but not exclusive of ED patients. PMID:24292283

  3. Conjunctivally Applied BDNF Protects Photoreceptors from Light-Induced Damage

    PubMed Central

    Cerri, Elisa; Origlia, Nicola; Falsini, Benedetto; Barloscio, Davide; Fabiani, Carlotta; Sansò, Marco; Ottino, Sara; Giovannini, Luca; Domenici, Luciano

    2015-01-01

    Purpose To test whether the topical eye treatment with BDNF prevents the effects of continuous light exposure (LE) in the albino rat retina. Methods Two groups of albino rats were used. The first group of rats received an intraocular injection of BDNF (2 μL, 1 μg/μL) before LE, while the second group was treated with one single drop of BDNF (10 μL, 12 μg/μL) dissolved in different types of solutions (physiological solution, the polysaccharide fraction of Tamarind gum, TSP, and sodium carboxy methyl cellulose), at the level of conjunctival fornix before LE. The level of BDNF in the retina and optic nerve was determined by enzyme-linked immunosorbent assay. We recorded the flash electroretinogram (fERG) in dark adapted rats 1 week after LE. At the end of the recording session, the retinas were removed and labeled so that the number of photoreceptors nuclear rows and thickness of the outer nuclear layer was analyzed. Results Intravitreal injection of BDNF before LE prevented fERG impairment. Different ophthalmic preparations were used for topical eye application; the TSP resulted the most suitable vehicle to increase BDNF level in the retina and optic nerve. Topical eye application with BDNF/TSP before LE partially preserved both fERG response and photoreceptors. Conclusions Topical eye treatment with BDNF represents a suitable, noninvasive tool to increase the retinal content of BDNF up to a level capable of exerting neuroprotection toward photoreceptors injured by prolonged LE. Translational Relevance A collyrium containing BDNF may serve as an effective, clinically translational treatment against retinal degeneration. PMID:27190697

  4. 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…

  5. 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. PMID:25681161

  6. 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

  7. 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.

  8. Recovery of low plasma BDNF over the course of treatment among patients with bulimia nervosa.

    PubMed

    Yamada, Hisashi; Yoshimura, Chiho; Nakajima, Takenori; Nagata, Toshihiko

    2012-08-15

    Recent studies have suggested that brain-derived neurotrophic factor (BDNF) is associated with energy balance, eating behaviors, and psychological states such as depression. Although decreased BDNF levels in patients with bulimia nervosa (BN) have been reported, the mechanism is still unclear. Few studies have investigated longitudinal changes of BDNF in BN patients. We investigated changes in the levels of plasma BDNF before and after inpatient treatment. Subjects were 16 female patients with BN and 10 control females. The levels of plasma BDNF were measured. In seven patients who completed a 4-week inpatient treatment program based on cognitive behavior therapy, levels of plasma BDNF were measured twice, before and after inpatient treatment. Plasma BDNF levels were significantly lower in BN subjects than in controls. BDNF levels were significantly higher following inpatient treatment. Increased plasma BDNF after inpatient treatment suggests that lower plasma BDNF levels in BN patients are associated with abnormal eating behaviors, especially binge eating. PMID:22425474

  9. Mechanisms of BDNF regulation in asthmatic airway smooth muscle.

    PubMed

    Aravamudan, Bharathi; Thompson, Michael A; Pabelick, Christina M; Prakash, Y S

    2016-08-01

    Brain-derived neurotrophic factor (BDNF), a neurotrophin produced by airway smooth muscle (ASM), enhances inflammation effects on airway contractility, supporting the idea that locally produced growth factors influence airway diseases such as asthma. We endeavored to dissect intrinsic mechanisms regulating endogenous, as well as inflammation (TNF-α)-induced BDNF secretion in ASM of nonasthmatic vs. asthmatic humans. We focused on specific Ca(2+) regulation- and inflammation-related signaling cascades and quantified BDNF secretion. We find that TNF-α enhances BDNF release by ASM cells, via several mechanisms relevant to asthma, including transient receptor potential channels TRPC3 and TRPC6 (but not TRPC1), ERK 1/2, PI3K, PLC, and PKC cascades, Rho kinase, and transcription factors cAMP response element binding protein and nuclear factor of activated T cells. Basal BDNF expression and secretion are elevated in asthmatic ASM and increase further with TNF-α exposure, involving many of these regulatory mechanisms. We conclude that airway BDNF secretion is regulated at multiple levels, providing a basis for autocrine effects of BDNF under conditions of inflammation and disease, with potential downstream influences on contractility and remodeling. PMID:27317689

  10. Decreased Bdnf expression and reduced social behavior in periadolescent rats following prenatal stress.

    PubMed

    Berry, Alessandra; Panetta, Pamela; Luoni, Alessia; Bellisario, Veronica; Capoccia, Sara; Riva, Marco Andrea; Cirulli, Francesca

    2015-04-01

    Prenatal stress (PNS) is a risk factor for the development of neuropsychiatric disorders. This study was aimed at assessing, in a rodent model, changes in gene expression profiles and behavioral output as a result of PNS, during periadolescence, a critical developmental period for the onset of psychopathology. Social behavior was studied in a standardized social interaction paradigm and the expression of Brain-Derived Neurotrophic Factor (Bdnf), a marker of neuronal plasticity, and of inhibitory and excitatory mechanisms (Na(+)-K(+)-2Cl(-) and K(+)-Cl(-) cotransporters ratio, NKCC1/KCC2) was analyzed. Results indicate that PNS reduced Bdnf transcripts while increasing the NKCC1/KCC2 ratio, primarily in the hippocampus. In the prefrontal cortex, changes in Bdnf were found to be gender-dependent. These effects were accompanied by reduced levels of affiliative and investigative social behaviors. Interestingly, interaction with non-stressed subjects was able to improve sociality in PNS rats suggesting that the social environment could be exploited for therapeutic intervention. PMID:25783782

  11. Cognitive Impairment in Schizophrenia: Interplay of BDNF and Childhood Trauma? A Review of Literature.

    PubMed

    Sahu, Geetanjali; Malavade, Kishor; Jacob, Theresa

    2016-09-01

    Cognitive impairment is a core feature of schizophrenia. These deficits can also serve as an endophenotype for the illness in genetic studies. There is evidence that suggests that cognition can be considered a reasonable target for intervention in both schizophrenia and bipolar disorder. One of the most studied genetic phenotypes for psychosis is brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms. BDNF has an established role in neuronal development and cell survival in response to stress and is abnormally expressed in schizophrenia. Studies have shown that childhood trauma is associated with poor prognosis of schizophrenic patients. BDNF-Val66Met polymorphism has been shown to moderate the impact of childhood adversity on later expression of affective symptoms, suggesting the possibility of gene environment interactions. Considering the recent advances of neuroscience an up to date review of relevant literature is warranted in this field. This article reviews the current literature available regarding associations between the Val66Met polymorphism, childhood trauma and cognitive dysfunction in schizophrenia. PMID:26603624

  12. 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

  13. BDNF polymorphism-dependent OFC and DLPFC plasticity differentially moderates implicit and explicit bias.

    PubMed

    Forbes, Chad E; Poore, Joshua C; Barbey, Aron K; Krueger, Frank; Solomon, Jeffrey; Lipsky, Robert H; Hodgkinson, Colin A; Goldman, David; Grafman, Jordan

    2012-11-01

    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

  14. Aging Triggers a Repressive Chromatin State at Bdnf Promoters in Hippocampal Neurons.

    PubMed

    Palomer, Ernest; Martín-Segura, Adrián; Baliyan, Shishir; Ahmed, Tariq; Balschun, Detlef; Venero, Cesar; Martin, Mauricio G; Dotti, Carlos G

    2016-09-13

    Cognitive capacities decline with age, an event accompanied by the altered transcription of synaptic plasticity genes. Here, we show that the transcriptional induction of Bdnf by a mnemonic stimulus is impaired in aged hippocampal neurons. Mechanistically, this defect is due to reduced NMDA receptor (NMDAR)-mediated activation of CaMKII. Decreased NMDAR signaling prevents changes associated with activation at specific Bdnf promoters, including displacement of histone deacetylase 4, recruitment of the histone acetyltransferase CBP, increased H3K27 acetylation, and reduced H3K27 trimethylation. The decrease in NMDA-CaMKII signaling arises from constitutive reduction of synaptic cholesterol that occurs with normal aging. Increasing the levels of neuronal cholesterol in aged neurons in vitro, ex vivo, and in vivo restored NMDA-induced Bdnf expression and chromatin remodeling. Furthermore, pharmacological prevention of age-associated cholesterol reduction rescued signaling and cognitive deficits of aged mice. Thus, reducing hippocampal cholesterol loss may represent a therapeutic approach to reverse cognitive decline during aging. PMID:27626660

  15. ENDOGENOUS BDNF IN THE DORSOLATERAL STRIATUM GATES ALCOHOL DRINKING

    PubMed Central

    Jeanblanc, Jerome; He, Dao-Yao; Carnicella, Sebastien; Kharazia, Viktor; Janak, Patricia H.; Ron, Dorit

    2010-01-01

    We previously found that brain-derived neurotrophic factor (BDNF) haplodeficient mice exhibit greater ethanol-induced place preference and psychomotor sensitization, and greater ethanol consumption after deprivation. We further observed that, in mice, voluntary ethanol intake increases BDNF expression in the dorsal striatum (DS). Here, we determined whether BDNF within the DS regulates ethanol self-administration in Long Evans rats trained to self-administer a 10% ethanol solution. We observed a greater increase in BDNF expression after ethanol self-administration in the dorsolateral striatum (DLS) than in the dorsomedial striatum (DMS). We further found that downregulation of endogenous BDNF using viral-mediated siRNA in the DLS, but not in the DMS, significantly increased ethanol self-administration. Infusion of exogenous BDNF (0.25 μg/μl/side into the DMS; 0.25 and 0.75 μg/μl/side into the DLS) attenuated responding for ethanol when infused 3 hrs prior to the beginning of the self-administration session. Although the decrease in ethanol intake was similar in the DLS and DMS, BDNF infused in the DLS but not in the DMS induced an early termination of the drinking episode. Furthermore, the action of BDNF in the DLS was specific for ethanol, as infusion of the neurotrophic factor in the DMS but not DLS resulted in a reduction of sucrose intake. Together, these findings demonstrate that the BDNF pathway within the DLS controls the level of ethanol self-administration. Importantly, our results suggest that an endogenous signaling pathway within the same brain region that mediates drug-taking behavior also plays a critical role in gating the level of ethanol intake. PMID:19864562

  16. 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. PMID:26088421

  17. 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

  18. MicroRNA-15a-5p suppresses cancer proliferation and division in human hepatocellular carcinoma by targeting BDNF.

    PubMed

    Long, Jianting; Jiang, Chunlin; Liu, Baoxian; Fang, Shi; Kuang, Ming

    2016-05-01

    We examined the expression pattern and functional roles of microRNA 15a-5p (miR-15a-5p) in human hepatocellular carcinoma (HCC). Possible miR-15a-5p aberrant expression in HCC cell lines or clinical HCC specimens was examined by quantitative real-time PCR (qRT-PCR). In HCC HepG2 and SNU-182 cells, miR-15a-5p was ectopically overexpressed by lentiviral transduction. Its effect on HCC proliferation, cancer division, and in vivo tumor growth were examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, cell cycle assay, and tumorigenicity assay, respectively. The targeting of miR-15a-5p on its downstream gene, brain-derived neurotrophic factor (BDNF), was examined by dual-luciferase assay, qRT-PCR, and Western blot, respectively. BDNF was then overexpressed in HepG2 and SNU-182 cells to evaluate its selective effect on miR-15a-5p in HCC modulation. MiR-15a-5p is aberrantly downregulated in in vitro HCC cell lines and in vivo HCC clinical specimens. Ectopic overexpression of miR-15a-5p suppressed cancer proliferation, induced cell cycle arrest in HepG2 or SNU-182 cells in vitro, and inhibited HCC tumor growth in vivo. MiR-15a-5p selectively and negatively regulated BDNF at both gene and protein levels in HCC cells. Forced overexpression of BDNF effectively reversed the tumor suppressive functions of miR-15a-5p on HCC proliferation and cell division in vitro. Our study demonstrated that miR-15a-5p is a tumor suppressor in HCC and its regulation is through BDNF in HCC. PMID:26581909

  19. Activation of the cAMP Pathway Induces RACK1-Dependent Binding of β-Actin to BDNF Promoter

    PubMed Central

    Neasta, Jeremie; Fiorenza, Anna; He, Dao-Yao; Phamluong, Khanhky; Kiely, Patrick A.; Ron, Dorit

    2016-01-01

    RACK1 is a scaffolding protein that contributes to the specificity and propagation of several signaling cascades including the cAMP pathway. As such, RACK1 participates in numerous cellular functions ranging from cell migration and morphology to gene transcription. To obtain further insights on the mechanisms whereby RACK1 regulates cAMP-dependent processes, we set out to identify new binding partners of RACK1 during activation of the cAMP signaling using a proteomics strategy. We identified β-actin as a direct RACK1 binding partner and found that the association between β-actin and RACK1 is increased in response to the activation of the cAMP pathway. Furthermore, we show that cAMP-dependent increase in BDNF expression requires filamentous actin. We further report that β-actin associates with the BDNF promoter IV upon the activation of the cAMP pathway and present data to suggest that the association of β-actin with BDNF promoter IV is RACK1-dependent. Taken together, our data suggest that β-actin is a new RACK1 binding partner and that the RACK1 and β-actin association participate in the cAMP-dependent regulation of BDNF transcription. PMID:27505161

  20. Reversal of deficits in dendritic spines, BDNF and Arc expression in the amygdala during alcohol dependence by HDAC inhibitor treatment.

    PubMed

    You, Chang; Zhang, Huaibo; Sakharkar, Amul J; Teppen, Tara; Pandey, Subhash C

    2014-02-01

    Development of anxiety-like behaviours during ethanol withdrawal has been correlated with increased histone deacetylase (HDAC) activity and decreased brain-derived neurotrophic factor (BDNF) and activity-regulated cytoskeleton-associated protein (Arc) gene expression in the amygdala. Furthermore, HDAC-mediated histone modifications play a role in synaptic plasticity. In this study we used the HDAC inhibitor trichostatin A (TSA) to determine whether HDAC inhibition could prevent ethanol withdrawal-induced deficits in dendritic spine density (DSD), BDNF or Arc expression in the amygdala of rats. It was found that decreased BDNF and Arc expression in the central (CeA) and medial nucleus of amygdala (MeA), observed during withdrawal after chronic ethanol exposure, were normalized following acute TSA treatment. TSA treatment was also able to attenuate anxiety-like behaviours during ethanol withdrawal and correct the observed decrease in DSD in the CeA and MeA of ethanol-withdrawn rats. Taken together, these findings demonstrate that correcting the deficits in histone acetylation through TSA treatment also amends downstream synaptic plasticity-related deficits such as BDNF and Arc expression, and DSD in the CeA and MeA as well as attenuates anxiety-like behaviours in rats during withdrawal after chronic ethanol exposure. PMID:24103311

  1. BDNF mechanisms in late LTP formation: A synthesis and breakdown.

    PubMed

    Panja, Debabrata; Bramham, Clive R

    2014-01-01

    Unraveling the molecular mechanisms governing long-term synaptic plasticity is a key to understanding how the brain stores information in neural circuits and adapts to a changing environment. Brain-derived neurotrophic factor (BDNF) has emerged as a regulator of stable, late phase long-term potentiation (L-LTP) at excitatory glutamatergic synapses in the adult brain. However, the mechanisms by which BDNF triggers L-LTP are controversial. Here, we distill and discuss the latest advances along three main lines: 1) TrkB receptor-coupled translational control underlying dendritic protein synthesis and L-LTP, 2) Mechanisms for BDNF-induced rescue of L-LTP when protein synthesis is blocked, and 3) BDNF-TrkB regulation of actin cytoskeletal dynamics in dendritic spines. Finally, we explore the inter-relationships between BDNF-regulated mechanisms, how these mechanisms contribute to different forms of L-LTP in the hippocampus and dentate gyrus, and outline outstanding issues for future research. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'. PMID:23831365

  2. A Simple Role for BDNF in Learning and Memory?

    PubMed Central

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

    2009-01-01

    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. PMID:20162032

  3. Spike-timing-dependent BDNF secretion and synaptic plasticity.

    PubMed

    Lu, Hui; Park, Hyungju; Poo, Mu-Ming

    2014-01-01

    In acute hippocampal slices, we found that the presence of extracellular brain-derived neurotrophic factor (BDNF) is essential for the induction of spike-timing-dependent long-term potentiation (tLTP). To determine whether BDNF could be secreted from postsynaptic dendrites in a spike-timing-dependent manner, we used a reduced system of dissociated hippocampal neurons in culture. Repetitive pairing of iontophoretically applied glutamate pulses at the dendrite with neuronal spikes could induce persistent alterations of glutamate-induced responses at the same dendritic site in a manner that mimics spike-timing-dependent plasticity (STDP)-the glutamate-induced responses were potentiated and depressed when the glutamate pulses were applied 20 ms before and after neuronal spiking, respectively. By monitoring changes in the green fluorescent protein (GFP) fluorescence at the dendrite of hippocampal neurons expressing GFP-tagged BDNF, we found that pairing of iontophoretic glutamate pulses with neuronal spiking resulted in BDNF secretion from the dendrite at the iontophoretic site only when the glutamate pulses were applied within a time window of approximately 40 ms prior to neuronal spiking, consistent with the timing requirement of synaptic potentiation via STDP. Thus, BDNF is required for tLTP and BDNF secretion could be triggered in a spike-timing-dependent manner from the postsynaptic dendrite. PMID:24298135

  4. Dysregulation of BDNF-TrkB signaling in developing hippocampal neurons by Pb(2+): implications for an environmental basis of neurodevelopmental disorders.

    PubMed

    Stansfield, Kirstie H; Pilsner, J Richard; Lu, Quan; Wright, Robert O; Guilarte, Tomás R

    2012-05-01

    Dysregulation of synaptic development and function has been implicated in the pathophysiology of neurodegenerative disorders and mental disease. A neurotrophin that has an important function in neuronal and synaptic development is brain-derived neurotrophic factor (BDNF). In this communication, we examined the effects of lead (Pb(2+)) exposure on BDNF-tropomyosin-related kinase B (TrkB) signaling during the period of synaptogenesis in cultured neurons derived from embryonic rat hippocampi. We show that Pb(2+) exposure decreases BDNF gene and protein expression, and it may also alter the transport of BDNF vesicles to sites of release by altering Huntingtin phosphorylation and protein levels. Combined, these effects of Pb(2+) resulted in decreased concentrations of extracellular mature BDNF. The effect of Pb(2+) on BDNF gene expression was associated with a specific decrease in calcium-sensitive exon IV transcript levels and reduced phosphorylation and protein expression of the transcriptional repressor methyl-CpG-binding protein (MeCP2). TrkB protein levels and autophosphorylation at tyrosine 816 were significantly decreased by Pb(2+) exposure with a concomitant increase in p75 neurotrophin receptor (p75(NTR)) levels and altered TrkB-p75(NTR) colocalization. Finally, phosphorylation of Synapsin I, a presynaptic target of BDNF-TrkB signaling, was significantly decreased by Pb(2+) exposure with no effect on total Synapsin I protein levels. This effect of Pb(2+) exposure on Synapsin I phosphorylation may help explain the impairment in vesicular release documented by us previously (Neal, A. P., Stansfield, K. H., Worley, P. F., Thompson, R. E., and Guilarte, T. R. (2010). Lead exposure during synaptogenesis alters vesicular proteins and impairs vesicular release: Potential role of N-Methyl-D-aspartate receptor (NMDAR) dependent BDNF signaling. Toxicol. Sci. 116, 249-263) because it controls vesicle movement from the reserve pool to the readily releasable pool. In

  5. Neuroprotective effects of 3,6'-disinapoyl sucrose through increased BDNF levels and CREB phosphorylation via the CaMKII and ERK1/2 pathway.

    PubMed

    Hu, Yuan; Liu, Ming-Yue; Liu, Ping; Dong, XianZhe; Boran, Aislyn D W

    2014-08-01

    3,6'-Disinapoyl sucrose (DISS) is an oligosaccharide ester natural product originating from the root of wild Polygala tenuifolia. Our previous reports suggested that DISS can have neuroprotective effects and antidepressive activity in rats, at least in part, by increased expression of cyclic AMP response element (CRE)-binding protein (CREB) and its downstream target protein, brain-derived neurotrophic factor (BDNF). The aim of the present study was to explore the mechanism of DISS-modulated BDNF and CREB expression. In this study, we confirmed its neuroprotective effect by showing that DISS, at concentrations above 30 μM, could promote the neuron cell viability and protected the glutamate and H2O2-induced toxicity in the human neuroblastoma (SH-SY5Y) cell line. DISS treatment also increased acute (from 15 to 30 min) BDNF expression and CREB phosphorylation in a dose-dependent manner. Pharmacological inhibition of mitogen-activated protein kinase 1 (ERK1/2), CaMKII, and Trk (with U0126, KN93, or K252a, respectively) partially attenuated the stimulatory effect of DISS on phospho-CREB and BDNF expression; however, it was not inhibited by pharmacological inhibition of PKA or PI3K (with H89 and LY294002, respectively). The results are consistent with the effects of DISS on CRE-directed gene transcription, as U0126 and KN-93 treatment also blocked the DISS-induced expression of the CRE-luciferase reporter gene. The results from the present study suggest that DISS-mediated regulation of BDNF gene expression is associated with CREB-mediated transcription of BDNF and upstream activation of ERK1/2 and CaMKII. Finally, DISS may exert neuroprotective and antidepressant effects through these signaling pathways in neuronal cells. PMID:24488601

  6. 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

  7. 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

  8. 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. PMID:26923413

  9. Activity-dependent BDNF release via endocytic pathways is regulated by synaptotagmin-6 and complexin

    PubMed Central

    Wong, Yu-Hui; Lee, Chia-Ming; Xie, Wenjun; Cui, Bianxiao; Poo, Mu-ming

    2015-01-01

    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. PMID:26216953

  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. PMID:26216953

  11. BDNF signaling in the rat cerebello-vestibular pathway during vestibular compensation: BDNF signaling in vestibular compensation.

    PubMed

    Zhou, Liuqing; Zhou, Wen; Zhang, Sulin; Liu, Bo; Liang, Pei; Zhou, Yan; Zhou, Tao; Zhang, Kun; Leng, Yangming; Kong, Weijia

    2015-09-01

    Vestibular compensation, which is the behavioral recovery from lesions to the peripheral vestibular system, is attributed to plasticity of the central vestibular system. It has been reported that brain-derived neurotrophic factor (BDNF) is expressed and released in an activity-dependent manner. Upon binding to the tyrosine receptor kinase B (TrkB), BDNF can acutely modulate synaptic transmission and plasticity in the central nervous system. To assess the possible contribution of BDNF to this recovery process, we studied the expression of BDNF, TrkB.FL, TrkB.T1 and KCC2 (K(+) -Cl(-) cotransporter isoform 2) in the bilateral medial vestibular nucleus (MVN) and the flocculus of rats at 4 h, 8 h, 1, 3 and 7 days following unilateral labyrinthectomy (UL) using immunohistochemistry, quantitative real-time PCR and western blotting. Our results have shown that, compared with the sham controls and the contra-lesional side, (a) the expression of BDNF and TrkB.FL increased at 4 h in the ipsi-lesional flocculus after UL; (b) the expression of TrkB.T1 decreased at 4 h and KCC2 decreased at 8 h and 1 day in the ipsi-lesional flocculus after UL; and (c) BDNF and TrkB.FL expression was enhanced and KCC2 expression was reduced in the ipsi-lesional MVN at 8 h after UL. Our data supported the hypothesis that BDNF upregulation may reduce the inhibitory effects of the flocculus and commissural inhibition system by regulating inhibitory GABAergic synaptic transmission in floccular Purkinje cells and Purkinje cell terminals in the MVN. Additionally, KCC2 may be a switch in this process. PMID:26111610

  12. Exploring the Association between Serum BDNF and Attempted Suicide

    PubMed Central

    Eisen, Rebecca B.; Perera, Stefan; Bawor, Monica; Dennis, Brittany B.; El-Sheikh, Wala; DeJesus, Jane; Rangarajan, Sumathy; Vair, Judith; Sholer, Heather; Hutchinson, Nicole; Iordan, Elizabeth; Mackie, Pam; Islam, Shofiqul; Dehghan, Mahshid; Brasch, Jennifer; Anglin, Rebecca; Minuzzi, Luciano; Thabane, Lehana; Samaan, Zainab

    2016-01-01

    Suicide is a leading cause of death and a significant public health concern. Brain-derived neurotrophic factor (BDNF), a protein important to nervous system function, has been implicated in psychiatric disorders and suicidal behaviour. We investigated the association between serum levels of BDNF and attempted suicide in a sample of 281 participants using a case-control study design. Participants were recruited from clinical and community settings between March 2011 and November 2014. Cases (individuals who had attempted suicide) (n = 84) were matched on sex and age (within five years) to both psychiatric controls (n = 104) and community controls (n = 93) with no history of suicide attempts. We collected fasting blood samples, socio-demographic information, physical measurements, and detailed descriptions of suicide attempts. We used linear regression analysis to determine the association between BDNF level (dependent variable) and attempted suicide (key exposure variable), adjusting for age, sex, body mass index, current smoking status, and antidepressant use. 250 participants were included in this analysis. In the linear regression model, attempted suicide was not significantly associated with BDNF level (β = 0.28, SE = 1.20, P = 0.82). Our findings suggest that no significant association exists between attempted suicide and BDNF level. However, the findings need to be replicated in a larger cohort study. PMID:27121496

  13. Higher reward value of starvation imagery in anorexia nervosa and association with the Val66Met BDNF polymorphism.

    PubMed

    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

  14. BDNF and the maturation of posttranscriptional regulatory networks in human SH-SY5Y neuroblast differentiation

    PubMed Central

    Goldie, Belinda J.; Barnett, Michelle M.; Cairns, Murray J.

    2014-01-01

    The SH-SY5Y culture system is a convenient neuronal model with the potential to elaborate human/primate-specific transcription networks and pathways related to human cognitive disorders. While this system allows for the exploration of specialized features in the human genome, there is still significant debate about how this model should be implemented, and its appropriateness for answering complex functional questions related to human neural architecture. In view of these questions we sought to characterize the posttranscriptional regulatory structure of the two-stage ATRA differentiation, BDNF maturation protocol proposed by Encinas et al. (2000) using integrative whole-genome gene and microRNA (miRNA) expression analysis. We report that ATRA-BDNF induced significant increases in expression of key synaptic genes, brain-specific miRNA and miRNA biogenesis machinery, and in AChE activity, compared with ATRA alone. Functional annotation clustering associated BDNF more significantly with neuronal terms, and with synaptic terms not found in ATRA-only clusters. While our results support use of SH-SY5Y as a neuronal model, we advocate considered selection of the differentiation agent/s relative to the system being modeled. PMID:25360083

  15. Lactoferrin Promotes Early Neurodevelopment and Cognition in Postnatal Piglets by Upregulating the BDNF Signaling Pathway and Polysialylation.

    PubMed

    Chen, Yue; Zheng, Zhiqiang; Zhu, Xi; Shi, Yujie; Tian, Dandan; Zhao, Fengjuan; Liu, Ni; Hüppi, Petra S; Troy, Frederic A; Wang, Bing

    2015-08-01

    Lactoferrin (Lf) is a sialic acid (Sia)-rich, iron-binding milk glycoprotein that has multifunctional health benefits. Its potential role in neurodevelopment and cognition remains unknown. To test the hypothesis that Lf may function to improve neurodevelopment and cognition, the diet of postnatal piglets was supplemented with Lf from days 3 to 38. Expression levels of selected genes and their cognate protein profiles were quantitatively determined. The importance of our new findings is that Lf (1) upregulated several canonical signaling pathways associated with neurodevelopment and cognition; (2) influenced ~10 genes involved in the brain-derived neurotrophin factor (BDNF) signaling pathway in the hippocampus and upregulated the expression of polysialic acid, a marker of neuroplasticity, cell migration and differentiation of progenitor cells, and the growth and targeting of axons; (3) upregulated transcriptional and translational levels of BDNF and increased phosphorylation of the cyclic adenosine monophosphate (cAMP) response element-binding protein, CREB, a downstream target of the BDNF signaling pathway, and a protein of crucial importance in neurodevelopment and cognition; and (4) enhanced the cognitive function and learning of piglets when tested in an eight-arm radial maze. The finding that Lf can improve neural development and cognition in postnatal piglets has not been previously described. PMID:25146846

  16. 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

  17. Motoneuron Programmed Cell Death in Response to proBDNF

    PubMed Central

    Taylor, AR; Gifondorwa, DJ; Robinson, MB; Strupe, JL; Prevette, D; Johnson, JE; Hempstead, BL; Oppenheim, RW; Milligan, CE

    2011-01-01

    Motoneurons (MN) as well as most neuronal populations undergo a temporally and spatially specific period of programmed cell death (PCD). Several factors have been considered to regulate the survival of MNs during this period, including availability of muscle-derived trophic support and activity. The possibility that target-derived factors may also negatively regulate MN survival has been considered, but not pursued. Neurotrophin precursors, through their interaction with p75NTR and sortilin receptors have been shown to induce cell death during development and following injury in the CNS. In this study, we find that muscle cells produce and secrete proBDNF. ProBDNF through its interaction with p75NTR and sortilin, promotes a caspase-dependent death of MNs in culture. We also provide data to suggest that proBDNF regulates MN PCD during development in vivo. PMID:21834083

  18. Effects of phenytoin and lamotrigine treatment on serum BDNF levels in offsprings of epileptic rats.

    PubMed

    Soysal, Handan; Doğan, Zümrüt; Kamışlı, Özden

    2016-04-01

    The role of brain-derived neurotrophic factor (BDNF) is to promote and modulate neuronal responses across neurotransmitter systems in the brain. Therefore, abnormal BDNF signaling may be associated with the pathophysiology of schizophrenia. Low BDNF levels have been reported in brains and serums of patients with psychotic disorders. In the present study, we investigated the effects of antiepileptic drugs on BDNF in developing rats. Pregnant rats were treated with phenytoin (PHT), lamotrigine (LTG) and folic acid for long-term, all through their gestational periods. Experimental epilepsy (EE) model was applied in pregnant rats. Epileptic seizures were determined with electroencephalography. After birth, serum BDNF levels were measured in 136 newborn rats on postnatal day (PND) 21 and postnatal day 38. In postnatal day 21, serum BDNF levels of experimental epilepsy group were significantly lower compared with PHT group. This decrease is statistically significant. Serum BDNF levels increased in the group LTG. This increase compared with LTG+EE group was statistically significant. In the folic acid (FA) group, levels of serum BDNF decreased statistically significantly compared to the PHT group. On postnatal day 38, no significant differences were found among the groups for serum BDNF levels. We concluded that, the passed seizures during pregnancy adversely affect fetal brain development, lowering of serum BDNF levels. PHT use during pregnancy prevents seizure-induced injury by increasing the levels of BDNF. About the increase level of BDNF, LTG is much less effective than PHT, the positive effect of folic acid on serum BDNF levels was not observed. LTG increase in BDNF is much less effective than PHT, folic acid did not show a positive effect on serum BDNF levels. Epilepsy affects fetal brain development during gestation in pregnant rats, therefore anti-epileptic therapy should be continued during pregnancy. PMID:26706181

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

    PubMed Central

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

    2011-01-01

    The adolescent brain is particularly vulnerable to the effects of alcohol, with intoxications at this developmental age often producing long-lasting effects. The present study addresses the effects of a single acute ethanol exposure on GAP-43 and BDNF gene expression in neurons in the cerebellum and hippocampus of adolescent rats. Male postnatal day 23 (P23) Sprague-Dawley rats were exposed to ethanol vapors for two hours and after a recovery period of two hours, the cerebellum and hippocampus were harvested and samples were taken for blood alcohol concentration (BAC) determinations. We found that this exposure resulted in a mean BAC of 174 mg/dl, which resembles levels in human adolescents after binge drinking. Analyses of total RNA and protein by qRT-PCR and western blotting, respectively, revealed that this single ethanol exposure significantly decreased the levels of GAP-43 mRNA and protein in the cerebellum but increased the levels of mRNA and protein in the hippocampus. BDNF mRNA and protein levels were also increased in the hippocampus but not in the cerebellum of these animals. In situ hybridizations revealed that GAP-43 and BDNF mRNA levels were primarily increased by alcohol exposure in hippocampal dentate granule cells and CA3 neurons. Overall, the reported alterations in the expression of the plasticity-associated genes GAP-43 and BDNF in juvenile rats are consistent with the known deleterious effects of binge drinking on motor coordination and cognitive function. PMID:21367572

  20. 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. PMID:26241953

  1. Local Administration of AAV-BDNF to Subventricular Zone Induces Functional Recovery in Stroke Rats

    PubMed Central

    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. PMID:24312581

  2. 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

  3. CREB-BDNF Pathway Influences Alcohol Cue-Elicited Hyperactivation in Drinkers

    PubMed Central

    Chen, Jiayu; Hutchison, Kent E.; Calhoun, Vince D.; Claus, Eric; Turner, Jessica A.; Sui, Jing; Liu, Jingyu

    2016-01-01

    Alcohol dependence (AD) is suggested to have polygenic risk factors and also exhibits neurological complications, strongly encouraging a translational study to explore the associations between aggregates of genetic variants and brain function alterations related to alcohol use. In this study, we used a semiblind multivariate approach, parallel independent component analysis with multiple references (pICA-MR) to investigate relationships of genome-wide single nucleotide polymorphisms (SNPs) with alcohol cue elicited brain activations in 326 healthy drinkers. The genetic component derived from the CREB-BDNF pathway reference was significantly associated (r = −0.36, p = 2.98×10−11) with an imaging component reflecting hyperactivation in precuneus, superior parietal lobule, and posterior cingulate for drinkers with more severe AD scores. The highlighted brain regions participate in many cognitive processes and have been robustly implicated in craving-related studies. The genetic factor highlighted the CREB and BDNF references, as well as other genes including GRM5, GRM7, GRID1, GRIN2A, PRKCA and PRKCB. Ingenuity Pathway Analysis indicated that the genetic component was enriched in synaptic plasticity, GABA and protein kinase A signaling. In summary, our findings suggest genetic variations in various neural plasticity and signaling pathways partially explain the variance of precuneus reactivity to alcohol cue which appears to be associated with AD severity. PMID:25939814

  4. The neuroprotective roles of BDNF in hypoxic ischemic brain injury.

    PubMed

    Chen, Ai; Xiong, Li-Jing; Tong, Yu; Mao, Meng

    2013-03-01

    Hypoxia-ischemia (H/I) brain injury results in various degrees of damage to the body, and the immature brain is particularly fragile to oxygen deprivation. Hypothermia and erythropoietin (EPO) have long been known to be neuroprotective in ischemic brain injury. Brain-derived neurotrophic factor (BDNF) has recently been recognized as a potent modulator capable of regulating a wide repertoire of neuronal functions. This review was based on studies concerning the involvement of BDNF in the protection of H/I brain injury following a search in PubMed between 1995 and December, 2011. We initially examined the background of BDNF, and then focused on its neuroprotective mechanisms against ischemic brain injury, including its involvement in promoting neural regeneration/cognition/memory rehabilitation, angiogenesis within ischemic penumbra and the inhibition of the inflammatory process, neurotoxicity, epilepsy and apoptosis. We also provided a literature overview of experimental studies, discussing the safety and the potential clinical application of BDNF as a neuroprotective agent in the ischemic brain injury. PMID:24648914

  5. Differential Effects of AAV.BDNF and AAV.Ntf3 in the Deafened Adult Guinea Pig Ear

    PubMed Central

    Budenz, Cameron L.; Wong, Hiu Tung; Swiderski, Donald L.; Shibata, Seiji B.; Pfingst, Bryan E.; Raphael, Yehoash

    2015-01-01

    Cochlear hair cell loss results in secondary regression of peripheral auditory fibers (PAFs) and loss of spiral ganglion neurons (SGNs). The performance of cochlear implants (CI) in rehabilitating hearing depends on survival of SGNs. Here we compare the effects of adeno-associated virus vectors with neurotrophin gene inserts, AAV.BDNF and AAV.Ntf3, on guinea pig ears deafened systemically (kanamycin and furosemide) or locally (neomycin). AAV.BDNF or AAV.Ntf3 was delivered to the guinea pig cochlea one week following deafening and ears were assessed morphologically 3 months later. At that time, neurotrophins levels were not significantly elevated in the cochlear fluids, even though in vitro and shorter term in vivo experiments demonstrate robust elevation of neurotrophins with these viral vectors. Nevertheless, animals receiving these vectors exhibited considerable re-growth of PAFs in the basilar membrane area. In systemically deafened animals there was a negative correlation between the presence of differentiated supporting cells and PAFs, suggesting that supporting cells influence the outcome of neurotrophin over-expression aimed at enhancing the cochlear neural substrate. Counts of SGN in Rosenthal's canal indicate that BDNF was more effective than NT-3 in preserving SGNs. The results demonstrate that a transient elevation in neurotrophin levels can sustain the cochlear neural substrate in the long term. PMID:25726967

  6. Up-regulating BDNF with an ampakine rescues synaptic plasticity and memory in Huntington's disease knockin mice

    PubMed Central

    Simmons, Danielle A.; Rex, Christopher S.; Palmer, Linda; Pandyarajan, Vijay; Fedulov, Vadim; Gall, Christine M.; Lynch, Gary

    2009-01-01

    Cognitive problems occur in asymptomatic gene carriers of Huntington's disease (HD), and mouse models of the disease exhibit impaired learning and substantial deficits in the cytoskeletal changes that stabilize long-term potentiation (LTP). The latter effects may be related to the decreased production of brain-derived neurotrophic factor (BDNF) associated with the HD mutation. This study asked whether up-regulating endogenous BDNF levels with an ampakine, a positive modulator of AMPA-type glutamate receptors, rescues plasticity and reduces learning problems in HD (CAG140) mice. Twice-daily injections of a short half-life ampakine normalized BDNF levels, activity-driven actin polymerization in dendritic spines, and LTP stabilization in 8-week-old mutants. Comparable results were obtained in 16-week-old HD mice with more severe LTP deficits. Ampakine treatments had no measurable effect on the decreased locomotor activity observed in the mutants but offset their impairments in long-term memory. Given that ampakines are well tolerated in clinical trials and were effective in this study after brief exposures, these results suggest a novel strategy for chronic treatment of the cognitive difficulties that occur in the early stages of HD. PMID:19264961

  7. Environmental and Genetic Activation of Hypothalamic BDNF Modulates T-cell Immunity to Exert an Anticancer Phenotype.

    PubMed

    Xiao, Run; Bergin, Stephen M; Huang, Wei; Slater, Andrew M; Liu, Xianglan; Judd, Ryan T; Lin, En-Ju D; Widstrom, Kyle J; Scoville, Steven D; Yu, Jianhua; Caligiuri, Michael A; Cao, Lei

    2016-06-01

    Macroenvironmental factors, including a patient's physical and social environment, play a role in cancer risk and progression. Our previous studies show that living in an enriched environment (EE) providing complex stimuli confers an anticancer phenotype in mice mediated, in part by a specific neuroendocrine axis, with brain-derived neurotrophic factor (BDNF) as the key brain mediator. Here, we investigated how an EE modulated T-cell immunity and its role in the EE-induced anticancer effects. Our data demonstrated that CD8 T cells were required to mediate the anticancer effects of an EE in an orthotropic model of melanoma. In secondary lymphoid tissue (SLT), an EE induced early changes in the phenotype of T-cell populations, characterized by a decrease in the ratio of CD4 T helper to CD8 cytotoxic T lymphocytes (CTL). Overexpression of hypothalamic BDNF reproduced EE-induced T-cell phenotypes in SLT, whereas knockdown of hypothalamic BDNF inhibited EE-induced immune modulation in SLT. Both propranolol and mifepristone blocked the EE-associated modulation of CTLs in SLT, suggesting that both the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis were involved. Our results demonstrated that enhanced anticancer effect of an EE was mediated at least in part through modulation of T-cell immunity and provided support to the emerging concept of manipulating a single gene in the brain to improve cancer immunotherapy. Cancer Immunol Res; 4(6); 488-97. ©2016 AACR. PMID:27045020

  8. BDNF Val66Met and reward-related brain function in adolescents: role for early alcohol consumption.

    PubMed

    Nees, F; Witt, S H; Dinu-Biringer, R; Lourdusamy, A; Tzschoppe, J; Vollstädt-Klein, S; Millenet, S; Bach, C; Poustka, L; Banaschewski, T; Barker, G J; Bokde, A L W; Bromberg, U; Büchel, C; Conrod, P J; Frank, J; Frouin, V; Gallinat, J; Garavan, H; Gowland, P; Heinz, A; Ittermann, B; Mann, K; Martinot, J-L; Paus, T; Pausova, Z; Robbins, T W; Smolka, M N; Rietschel, M; Schumann, G; Flor, H

    2015-03-01

    Changes in reward processing have been identified as one important pathogenetic mechanism in alcohol addiction. The nonsynonymous single nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene (rs6265/Val66Met) modulates the central nervous system activity of neurotransmitters involved in reward processing such as serotonin, dopamine, and glutamate. It was identified as crucial for alcohol consumption in healthy adults and, in rats, specifically related to the function in the striatum, a region that is commonly involved in reward processing. However, studies in humans on the association of BDNF Val66Met and reward-related brain functions and its role for alcohol consumption, a significant predictor of later alcohol addiction, are missing. Based on an intermediate phenotype approach, we assessed the early orientation toward alcohol and alcohol consumption in 530 healthy adolescents that underwent a monetary incentive delay task during functional magnetic resonance imaging. We found a significantly lower response in the putamen to reward anticipation in adolescent Met carriers with high versus low levels of alcohol consumption. During reward feedback, Met carriers with low putamen reactivity were significantly more likely to orient toward alcohol and to drink alcohol 2 years later. This study indicates a possible effect of BDNF Val66Met on alcohol addiction-related phenotypes in adolescence. PMID:25650137

  9. Conditional BDNF release under pathological conditions improves Huntington's disease pathology by delaying neuronal dysfunction

    PubMed Central

    2011-01-01

    Background Brain-Derived Neurotrophic Factor (BDNF) is the main candidate for neuroprotective therapy for Huntington's disease (HD), but its conditional administration is one of its most challenging problems. Results Here we used transgenic mice that over-express BDNF under the control of the Glial Fibrillary Acidic Protein (GFAP) promoter (pGFAP-BDNF mice) to test whether up-regulation and release of BDNF, dependent on astrogliosis, could be protective in HD. Thus, we cross-mated pGFAP-BDNF mice with R6/2 mice to generate a double-mutant mouse with mutant huntingtin protein and with a conditional over-expression of BDNF, only under pathological conditions. In these R6/2:pGFAP-BDNF animals, the decrease in striatal BDNF levels induced by mutant huntingtin was prevented in comparison to R6/2 animals at 12 weeks of age. The recovery of the neurotrophin levels in R6/2:pGFAP-BDNF mice correlated with an improvement in several motor coordination tasks and with a significant delay in anxiety and clasping alterations. Therefore, we next examined a possible improvement in cortico-striatal connectivity in R62:pGFAP-BDNF mice. Interestingly, we found that the over-expression of BDNF prevented the decrease of cortico-striatal presynaptic (VGLUT1) and postsynaptic (PSD-95) markers in the R6/2:pGFAP-BDNF striatum. Electrophysiological studies also showed that basal synaptic transmission and synaptic fatigue both improved in R6/2:pGAP-BDNF mice. Conclusions These results indicate that the conditional administration of BDNF under the GFAP promoter could become a therapeutic strategy for HD due to its positive effects on synaptic plasticity. PMID:21985529

  10. 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. PMID:25903950

  11. Exercise as Gene Therapy: BDNF and DNA Damage Repair.

    PubMed

    Schmidt, Robin H; Nickerson, John M; Boatright, Jeffrey H

    2016-01-01

    DNA damage is a common feature of neurodegenerative illnesses, and the ability to repair DNA strand breaks and lesions is crucial for neuronal survival, reported by Jeppesen et al (Prog Neurobiol. 2011;94:166-200) and Shiwaku et al (Curr Mol Med. 2015;15:119-128). Interventions aimed at repairing these lesions, therefore, could be useful for preventing or delaying the progression of disease. One potential strategy for promoting DNA damage repair (DDR) is exercise. Although the role of exercise in DDR is not understood, there is increasing evidence that simple physical activity may impact clinical outcomes for neurodegeneration. Here, we discuss what is currently known about the molecular mechanisms of brain-derived neurotrophic factor and how these mechanisms might influence the DDR process. PMID:27488073

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

    PubMed Central

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

    2012-01-01

    After peripheral nerve injury, neurotrophins play a key role in the regeneration of damaged axons which can be augmented by exercise, although the distinct roles played by neurons and Schwann cells are unclear. In this study, we evaluated the requirement for the neurotrophin, brain derived neurotrophic factor (BDNF), in neurons and Schwann cells, for the regeneration of peripheral axons after injury. Common fibular or tibial nerves in thy-1-YFP-H mice were cut bilaterally and repaired using a graft of the same nerve from transgenic mice lacking BDNF in Schwann cells (BDNF-/-) or wild-type mice (WT). Two weeks post-repair, axonal regeneration into BDNF-/- grafts were markedly less than WT grafts, emphasizing the importance of Schwann cell BDNF. Nerve regeneration was enhanced by treadmill training post-transection, regardless of the BDNF content of the nerve graft. We further tested the hypothesis that training-induced increases in BDNF in neurons allow regenerating axons to overcome a lack of BDNF expression in cells in the pathway through which they regenerate. Nerves in mice lacking BDNF in YFP+ neurons (SLICK) were cut and repaired with BDNF-/- and WT nerves. SLICK axons lacking BDNF did not regenerate into grafts lacking Schwann cell BDNF. Treadmill training could not rescue the regeneration into BDNF-/- grafts if the neurons also lacked BDNF. Both Schwann cell- and neuron-derived BDNF are thus important for axon regeneration in cut peripheral nerves. PMID:22492055

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

    PubMed

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

    2014-04-01

    Tyrosinemia type II, which is also known as Richner-Hanhart syndrome, is an inborn error of metabolism that is due to a block in the transamination reaction that converts tyrosine to p-hydroxyphenylpyruvate. Because the mechanisms of neurological dysfunction in hypertyrosinemic patients are poorly known and the symptoms of these patients are related to the central nervous system, the present study evaluated brain-derived neurotrophic factor (BDNF) levels and bdnf mRNA expression in young rats and during growth. In our acute protocol, Wistar rats (10 and 30 days old) were killed 1 h after a single intraperitoneal L-tyrosine injection (500 mg/kg) or saline. Chronic administration consisted of L-tyrosine (500 mg/kg) or saline injections 12 h apart for 24 days in Wistar rats (7 days old), and the rats were killed 12 h after the last injection. The brains were rapidly removed, and we evaluated the BDNF levels and bdnf mRNA expression. The present results showed that the acute administration of L-tyrosine decreased both BDNF and bdnf mRNA levels in the striatum of 10-day-old rats. In the 30-day-old rats, we observed decreased BDNF levels without modifications in bdnf transcript level in the hippocampus and striatum. Chronic administration of L-tyrosine increased the BDNF levels in the striatum of rats during their growth, whereas bdnf mRNA expression was not altered. We hypothesize that oxidative stress can interact with the BDNF system to modulate synaptic plasticity and cognitive function. The present results enhance our knowledge of the pathophysiology of hypertyrosinemia. PMID:24091827

  14. BDNF Val66Met polymorphism and bipolar disorder in European populations: A risk association in case-control, family-based and GWAS studies.

    PubMed

    Li, Ming; Chang, Hong; Xiao, Xiao

    2016-09-01

    Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that has antidepressant-like effects in animal models and may be implicated in the etiology of mood-related phenotypes. A functional polymorphism (Val66Met) in the BDNF gene was demonstrated to influence BDNF's secretion and function, as well as mood and cognitive related phenotypes. However, previous genetic association studies of Val66Met polymorphism in the clinical risk of mood disorders have been complicated, possibly due to phenotypic diversity, underpowered statistical association or ancestry-specific effects. Here, we collected mood phenotypic and genetic data in over 90,000 individuals from diverse ethnic groups and conducted a systematic meta-analysis. The results showed that the Val66Met polymorphism was significantly associated with BPD in Europeans (Pmeta=0.0029, OR=1.136), but not in Asians (Pmeta=0.443). Also, it appears that the risk for MDD conferred by BDNF is waning, as the Val66Met variant was not associated with MDD in either European or Asian samples (Pmeta>0.5). PMID:27236043

  15. Human NR5A1/SF-1 Mutations Show Decreased Activity on BDNF (Brain-Derived Neurotrophic Factor), an Important Regulator of Energy Balance: Testing Impact of Novel SF-1 Mutations Beyond Steroidogenesis

    PubMed Central

    Malikova, Jana; Camats, Núria; Fernández-Cancio, Mónica; Heath, Karen; González, Isabel; Caimarí, María; del Campo, Miguel; Albisu, Marian; Kolouskova, Stanislava; Audí, Laura; Flück, Christa E.

    2014-01-01

    Context Human NR5A1/SF-1 mutations cause 46,XY disorder of sex development (DSD) with broad phenotypic variability, and rarely cause adrenal insufficiency although SF-1 is an important transcription factor for many genes involved in steroidogenesis. In addition, the Sf-1 knockout mouse develops obesity with age. Obesity might be mediated through Sf-1 regulating activity of brain-derived neurotrophic factor (BDNF), an important regulator of energy balance in the ventromedial hypothalamus. Objective To characterize novel SF-1 gene variants in 4 families, clinical, genetic and functional studies were performed with respect to steroidogenesis and energy balance. Patients 5 patients with 46,XY DSD were found to harbor NR5A1/SF-1 mutations including 2 novel variations. One patient harboring a novel mutation also suffered from adrenal insufficiency. Methods SF-1 mutations were studied in cell systems (HEK293, JEG3) for impact on transcription of genes involved in steroidogenesis (CYP11A1, CYP17A1, HSD3B2) and in energy balance (BDNF). BDNF regulation by SF-1 was studied by promoter assays (JEG3). Results Two novel NR5A1/SF-1 mutations (Glu7Stop, His408Profs*159) were confirmed. Glu7Stop is the 4th reported SF-1 mutation causing DSD and adrenal insufficiency. In vitro studies revealed that transcription of the BDNF gene is regulated by SF-1, and that mutant SF-1 decreased BDNF promoter activation (similar to steroid enzyme promoters). However, clinical data from 16 subjects carrying SF-1 mutations showed normal birth weight and BMI. Conclusions Glu7Stop and His408Profs*159 are novel SF-1 mutations identified in patients with 46,XY DSD and adrenal insufficiency (Glu7Stop). In vitro, SF-1 mutations affect not only steroidogenesis but also transcription of BDNF which is involved in energy balance. However, in contrast to mice, consequences on weight were not found in humans with SF-1 mutations. PMID:25122490

  16. [Blood levels of brain-derived neurotrophic factor (BDNF) in major depressive disorder].

    PubMed

    Yoshimura, Reiji; Ikenouchi-Sugita, Atsuko; Hori, Hikaru; Umene-Nakano, Wakako; Hayashi, Kenji; Katsuki, Asuka; Ueda, Nobuhisa; Nakamura, Jun

    2010-01-01

    Brain-derived neurotrophic factor (BDNF) is a neurotrophin that has been linked to the viability of neurons in brain circuits that regulate emotion, memory, learning, sleep, and appetite. BDNF has been most extensively studied in relation to depression. Depressed patients show reduced levels of hippocampal and cortical BDNF in postmortem studies. Recently, to the best of our knowledge, there are at least three meta-analyses regarding blood BDNF levels in depressed patients, suggesting that blood BDNF levels are decreased in depressive state, and those are recovered after treatment with biological treatments such as antidepressants, ECT, and rTMS. From these findings into account, it is possible that blood (plasma and serum) BDNF level is a biological marker for depressive state. We have recently demonstrated that a significantly negative correlation was observed between the HAMD scores and serum BDNF levels. In addition, responders to fluvoxamine, paroxetine, milnacipran, and sertraline all increased serum BDNF levels. Blood BDNF levels did not distinguish between responders and remitters to the treatment. In conclusion, blood BDNF levels partially reflect those in the brain, and there is also strong and consistent evidence indicating that these levels normalize following the biological intervention for depression. PMID:21179660

  17. Real-time Imaging of Axonal Transport of Quantum Dot-labeled BDNF in Primary Neurons

    PubMed Central

    Zhao, Xiaobei; Zhou, Yue; Weissmiller, April M.; Pearn, Matthew L.; Mobley, William C.; Wu, Chengbiao

    2014-01-01

    BDNF plays an important role in several facets of neuronal survival, differentiation, and function. Structural and functional deficits in axons are increasingly viewed as an early feature of neurodegenerative diseases, including Alzheimer’s disease (AD) and Huntington’s disease (HD). As yet unclear is the mechanism(s) by which axonal injury is induced. We reported the development of a novel technique to produce biologically active, monobiotinylated BDNF (mBtBDNF) that can be used to trace axonal transport of BDNF. Quantum dot-labeled BDNF (QD-BDNF) was produced by conjugating quantum dot 655 to mBtBDNF. A microfluidic device was used to isolate axons from neuron cell bodies. Addition of QD-BDNF to the axonal compartment allowed live imaging of BDNF transport in axons. We demonstrated that QD-BDNF moved essentially exclusively retrogradely, with very few pauses, at a moving velocity of around 1.06 μm/sec. This system can be used to investigate mechanisms of disrupted axonal function in AD or HD, as well as other degenerative disorders. PMID:25286194

  18. Cellular mechanisms of activity-dependent BDNF expression in primary sensory neurons.

    PubMed

    Vermehren-Schmaedick, A; Khanjian, R A; Balkowiec, A

    2015-12-01

    Brain-derived neurotrophic factor (BDNF) is abundantly expressed by both developing and adult rat visceral sensory neurons from the nodose ganglion (NG) in vivo and in vitro. We have previously shown that BDNF is released from neonatal NG neurons by activity and regulates dendritic development in their postsynaptic targets in the brainstem. The current study was carried out to examine the cellular and molecular mechanisms of activity-dependent BDNF expression in neonatal rat NG neurons, using our established in vitro model of neuronal activation by electrical field stimulation with patterns that mimic neuronal activity in vivo. We show that BDNF mRNA (transcript 4) increases over threefold in response to a 4-h tonic or bursting pattern delivered at the frequency of 6 Hz, which corresponds to the normal heart rate of a newborn rat. No significant increase in BDNF expression was observed following stimulation at 1 Hz. The latter effect suggests a frequency-dependent mechanism of regulated BDNF expression. In addition to BDNF transcript 4, which is known to be regulated by activity, transcript 1 also showed significant upregulation. The increases in BDNF mRNA were followed by BDNF protein upregulation of a similar magnitude after 24h of stimulation at 6 Hz. Electrical stimulation-evoked BDNF expression was inhibited by pretreating neurons with the blocker of voltage-gated sodium channels tetrodotoxin and by removing extracellular calcium. Moreover, our data show that repetitive stimulation-evoked BDNF expression requires calcium influx through N-, but not L-type, channels. Together, our study reveals novel mechanisms through which electrical activity stimulates de novo synthesis of BDNF in sensory neurons, and points to the role of N-type calcium channels in regulating BDNF expression in sensory neurons in response to repetitive stimulation. PMID:26459016

  19. Rapid Increases in proBDNF after Pilocarpine-Induced Status Epilepticus in Mice Are Associated with Reduced proBDNF Cleavage Machinery123

    PubMed Central

    Cruz Del Angel, Yasmin; Gonzalez, Marco I.; Carrel, Andrew J.; Carlsen, Jessica; Lam, Philip M.; Hempstead, Barbara L.; Russek, Shelley. J.

    2016-01-01

    Abstract Brain-derived neurotrophic factor (BDNF) levels are elevated after status epilepticus (SE), leading to activation of multiple signaling pathways, including the janus kinase/signal transducer and activator of transcription pathway that mediates a decrease in GABAA receptor α1 subunits in the hippocampus (Lund et al., 2008). While BDNF can signal via its pro or mature form, the relative contribution of these forms to signaling after SE is not fully known. In the current study, we investigate changes in proBDNF levels acutely after SE in C57BL/6J mice. In contrast to previous reports (Unsain et al., 2008; Volosin et al., 2008; VonDran et al., 2014), our studies found that levels of proBDNF in the hippocampus are markedly elevated as early as 3 h after SE onset and remain elevated for 7 d. Immunohistochemistry studies indicate that seizure-induced BDNF localizes to all hippocampal subfields, predominantly in principal neurons and also in astrocytes. Analysis of the proteolytic machinery that cleaves proBDNF to produce mature BDNF demonstrates that acutely after SE there is a decrease in tissue plasminogen activator and an increase in plasminogen activator inhibitor-1 (PAI-1), an inhibitor of extracellular and intracellular cleavage, which normalizes over the first week after SE. In vitro treatment of hippocampal slices from animals 24 h after SE with a PAI-1 inhibitor reduces proBDNF levels. These findings suggest that rapid proBDNF increases following SE are due in part to reduced cleavage, and that proBDNF may be part of the initial neurotrophin response driving intracellular signaling during the acute phase of epileptogenesis. PMID:27057559

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

    PubMed

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

    2016-04-01

    The interplay between BDNF signaling and the serotonergic system remains incompletely understood. Using a highly sensitive enzyme-linked immunosorbent assay, we studied BDNF concentrations in hippocampus and cortex of two mouse models of altered serotonin signaling: tryptophan hydroxylase (Tph)2-deficient (Tph2 (-/-)) mice lacking brain serotonin and serotonin transporter (SERT)-deficient (SERT(-/-)) mice lacking serotonin re-uptake. Surprisingly, hippocampal BDNF was significantly elevated in Tph2 (-/-) mice, whereas no significant changes were observed in SERT(-/-) mice. Furthermore, BDNF levels were increased in the prefrontal cortex of Tph2 (-/-) but not of SERT(-/-) mice. Our results emphasize the interaction between serotonin signaling and BDNF. Complete lack of brain serotonin induces BDNF expression. PMID:26100147

  1. Prefrontal cortical BDNF: A regulatory key in cocaine- and food-reinforced behaviors.

    PubMed

    Pitts, Elizabeth G; Taylor, Jane R; Gourley, Shannon L

    2016-07-01

    Brain-derived neurotrophic factor (BDNF) affects synaptic plasticity and neural structure and plays key roles in learning and memory processes. Recent evidence also points to important, yet complex, roles for BDNF in rodent models of cocaine abuse and addiction. Here we examine the role of prefrontal cortical (PFC) BDNF in reward-related decision making and behavioral sensitivity to, and responding for, cocaine. We focus on BDNF within the medial and orbital PFC, its regulation by cocaine during early postnatal development and in adulthood, and how BDNF in turn influences responding for drug reinforcement, including in reinstatement models. When relevant, we draw comparisons and contrasts with experiments using natural (food) reinforcers. We also summarize findings supporting, or refuting, the possibility that BDNF in the medial and orbital PFC regulate the development and maintenance of stimulus-response habits. Further investigation could assist in the development of novel treatment approaches for cocaine use disorders. PMID:26923993

  2. Effects of sleep deprivation on behaviors and abnormal hippocampal BDNF/miR-10B expression in rats with chronic stress depression.

    PubMed

    Jiang, Yuxue; Zhu, Jinfu

    2015-01-01

    Being sleep-deprived can relieve the depressed emotions in rats, but the underlying mechanisms remain unknown. In this study, male rats were divided into 3 groups: normal control (NC), chronicunpredictable stress (CUPS) and sleep-deprived (SD). All of the groups were examined using the sucrose consumption test and the open field test. The sucrose consumption test and the open field test were performed for all three groups. The BDNF and miR-10B expressions were examined using real-time PCR and the level of BNDF was discovered by western blotting. In the sucrose consumption test and the open field test, the CUPS rats consumed less sucrose and got fewer score than the NC rats, however the SD rats consumed significantly more sucrose and received higher scores than the CUPS rats. Both the expression of BNDF and the protein levels in the CUPS group was significantly lower than in the NC group. Also, the CUPS group also showed a higher miR-10B expression than the NC group. However, the SD group demonstrated higher BDNF expression and lower miR-10B expression when compared with the CUPS group. Further investigation demonstrated that the BDNF is the direct target gene of miR-10B and BDNF expression, which is negatively correlated with the expression of miR-10B. In the sucrose consumption test, BNDF expression is positively correlated with the sucrose preference rate whereas miR-10B has an opposing correlation. Moreover, the open field test demonstrated that BNDF expression is positively correlated with the scores and the miR-10B expression is negatively correlated. These results indicate that sleep deprivation is closely linked with the downregulation of miR-10B and possibly the upregulation of BDNF in the hippocampus in the CUPS rats. PMID:25755749

  3. Brain ischaemia induces shedding of a BDNF-scavenger ectodomain from TrkB receptors by excitotoxicity activation of metalloproteinases and γ-secretases.

    PubMed

    Tejeda, Gonzalo S; Ayuso-Dolado, Sara; Arbeteta, Raquel; Esteban-Ortega, Gema M; Vidaurre, Oscar G; Díaz-Guerra, Margarita

    2016-04-01

    Stroke remains a leading cause of death and disability in the world with limited therapies available to restrict brain damage or improve functional recovery after cerebral ischaemia. A promising strategy currently under investigation is the promotion of brain-derived neurotrophic factor (BDNF) signalling through tropomyosin-related kinase B (TrkB) receptors, a pathway essential for neuronal survival and function. However, TrkB and BDNF-signalling are impaired by excitotoxicity, a primary pathological process in stroke also associated with neurodegenerative diseases. Pathological imbalance of TrkB isoforms is critical in neurodegeneration and is caused by calpain processing of BDNF high affinity full-length receptor (TrkB-FL) and an inversion of the transcriptional pattern of the Ntrk2 gene, to favour expression of the truncated isoform TrkB-T1 over TrkB-FL. We report here that both TrkB-FL and neuronal TrkB-T1 also undergo ectodomain shedding by metalloproteinases activated after ischaemic injury or excitotoxic damage of cortical neurons. Subsequently, the remaining membrane-bound C-terminal fragments (CTFs) are cleaved by γ-secretases within the transmembrane region, releasing their intracellular domains (ICDs) into the cytosol. Therefore, we identify TrkB-FL and TrkB-T1 as new substrates of regulated intramembrane proteolysis (RIP), a mechanism that highly contributes to TrkB-T1 regulation in ischaemia but is minor for TrkB-FL which is mainly processed by calpain. However, since the secreted TrkB ectodomain acts as a BDNF scavenger and significantly alters BDNF/TrkB signalling, the mechanism of RIP could contribute to neuronal death in excitotoxicity. These results are highly relevant since they reveal new targets for the rational design of therapies to treat stroke and other pathologies with an excitotoxic component. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:26712630

  4. Effects of sleep deprivation on behaviors and abnormal hippocampal BDNF/miR-10B expression in rats with chronic stress depression

    PubMed Central

    Jiang, Yuxue; Zhu, Jinfu

    2015-01-01

    Being sleep-deprived can relieve the depressed emotions in rats, but the underlying mechanisms remain unknown. In this study, male rats were divided into 3 groups: normal control (NC), chronicunpredictable stress (CUPS) and sleep-deprived (SD). All of the groups were examined using the sucrose consumption test and the open field test. The sucrose consumption test and the open field test were performed for all three groups. The BDNF and miR-10B expressions were examined using real-time PCR and the level of BNDF was discovered by western blotting. In the sucrose consumption test and the open field test, the CUPS rats consumed less sucrose and got fewer score than the NC rats, however the SD rats consumed significantly more sucrose and received higher scores than the CUPS rats. Both the expression of BNDF and the protein levels in the CUPS group was significantly lower than in the NC group. Also, the CUPS group also showed a higher miR-10B expression than the NC group. However, the SD group demonstrated higher BDNF expression and lower miR-10B expression when compared with the CUPS group. Further investigation demonstrated that the BDNF is the direct target gene of miR-10B and BDNF expression, which is negatively correlated with the expression of miR-10B. In the sucrose consumption test, BNDF expression is positively correlated with the sucrose preference rate whereas miR-10B has an opposing correlation. Moreover, the open field test demonstrated that BNDF expression is positively correlated with the scores and the miR-10B expression is negatively correlated. These results indicate that sleep deprivation is closely linked with the downregulation of miR-10B and possibly the upregulation of BDNF in the hippocampus in the CUPS rats. PMID:25755749

  5. A BDNF loop-domain mimetic acutely reverses spontaneous apneas and respiratory abnormalities during behavioral arousal in a mouse model of Rett syndrome

    PubMed Central

    Kron, Miriam; Lang, Min; Adams, Ian T.; Sceniak, Michael; Longo, Frank; Katz, David M.

    2014-01-01

    Reduced levels of brain-derived neurotrophic factor (BDNF) are thought to contribute to the pathophysiology of Rett syndrome (RTT), a severe neurodevelopmental disorder caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). In Mecp2 mutant mice, BDNF deficits have been associated with breathing abnormalities, a core feature of RTT, as well as with synaptic hyperexcitability within the brainstem respiratory network. Application of BDNF can reverse hyperexcitability in acute brainstem slices from Mecp2-null mice, suggesting that therapies targeting BDNF or its receptor, TrkB, could be effective at acute reversal of respiratory abnormalities in RTT. Therefore, we examined the ability of LM22A-4, a small-molecule BDNF loop-domain mimetic and TrkB partial agonist, to modulate synaptic excitability within respiratory cell groups in the brainstem nucleus tractus solitarius (nTS) and to acutely reverse abnormalities in breathing at rest and during behavioral arousal in Mecp2 mutants. Patch-clamp recordings in Mecp2-null brainstem slices demonstrated that LM22A-4 decreases excitability at primary afferent synapses in the nTS by reducing the amplitude of evoked excitatory postsynaptic currents and the frequency of spontaneous and miniature excitatory postsynaptic currents. In vivo, acute treatment of Mecp2-null and -heterozygous mutants with LM22A-4 completely eliminated spontaneous apneas in resting animals, without sedation. Moreover, we demonstrate that respiratory dysregulation during behavioral arousal, a feature of human RTT, is also reversed in Mecp2 mutants by acute treatment with LM22A-4. Together, these data support the hypothesis that reduced BDNF signaling and respiratory dysfunction in RTT are linked, and establish the proof-of-concept that treatment with a small-molecule structural mimetic of a BDNF loop domain and a TrkB partial agonist can acutely reverse abnormal breathing at rest and in response to behavioral arousal

  6. Multimarker analysis suggests the involvement of BDNF signaling and microRNA biosynthesis in suicidal behavior.

    PubMed

    Pulay, Attila J; Réthelyi, János M

    2016-09-01

    Despite moderate heritability estimates the genetics of suicidal behavior remains unclear, genome-wide association and candidate gene studies focusing on single nucleotide associations reported inconsistent findings. Our study explored biologically informed, multimarker candidate gene associations with suicidal behavior in mood disorders. We analyzed the GAIN Whole Genome Association Study of Bipolar Disorder version 3 (n = 999, suicidal n = 358) and the GAIN Major Depression: Stage 1 Genomewide Association in Population-Based Samples (n = 1,753, suicidal n = 245) datasets. Suicidal behavior was defined as severe suicidal ideation or attempt. Candidate genes were selected based on literature search (Geneset1, n = 35), gene expression data of microRNA genes, (Geneset2, n = 68) and their target genes (Geneset3, n = 11,259). Quality control, dosage analyses were carried out with PLINK. Gene-based associations of Geneset1 were analyzed with KGG. Polygenic profile scores of suicidal behavior were computed in the major depression dataset both with PRSice and LDpred and validated in the bipolar disorder data. Several nominally significant gene-based associations were detected, but only DICER1 associated with suicidal behavior in both samples, while only the associations of NTRK2 in the depression sample reached family wise and experiment wise significance. Polygenic profile scores negatively predicted suicidal behavior in the bipolar sample for only Geneset2, with the strongest prediction by PRSice at Pt  < 0.03 (Nagelkerke R(2)  = 0.01, P < 0.007). Gene-based association results confirmed the potential involvement of the BDNF-NTRK2-CREB pathway in the pathogenesis of suicide and the cross-disorder association of DICER1. Polygenic risk prediction of the selected miRNA genes indicates that the miRNA system may play a mediating role, but with considerable pleiotropy. © 2016 Wiley Periodicals, Inc. PMID:26921221

  7. A possible role of BDNF in prostate cancer detection.

    PubMed

    Bronzetti, E; Artico, M; Forte, F; Pagliarella, G; Felici, L M; D'Ambrosio, A; Vespasiani, G; Bronzetti, B

    2008-04-01

    Many studies have demonstrated that both normal and malignant prostate cells respond to a variety of growth factors, while several significant differences were found between normal and tumoural cells. The aim of this study was to focus on the localization and distribution of the immuno-reactivity for neurotrophins (NTs) and neurotrophin receptors (NTRs) in normal, hyperplastic and prostate cancer cells, obtained from 40 subjects. We studied samples obtained from 16 prostate cancer (PC, retropubic radical prostatectomy), 20 benign prostatic hyperplasia (BPH, supra-pubic prostatectomy) and normal peripheral prostate tissue from four fresh male cadavers. Samples were examined via immunohistochemical techniques in order to detect the expression of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) and their own receptors TrkA, p75, TrkB and TrkC. We observed a high expression of BDNF and TrkB in PC and BPH, though no immuno-reactivity was found for p75. Low expression was reported by other NTs and NTRs in the normal peripheral prostate zone, BPH and PC. These data suggest a possible predictive role for NTs and NTRs, especially for BDNF and TrkB, in the diagnosis and/or management of prostate cancer. The absence of p75 expression confirms its supposed role in apoptotic phenomenon. PMID:18357383

  8. BDNF restricted knockout mice as an animal model for aggression

    PubMed Central

    Ito, Wataru; Chehab, Mahmoud; Thakur, Siddarth; Li, Jiayang; Morozov, Alexei

    2011-01-01

    Mice with global deletion of one BDNF allele, or with forebrain-restricted deletion of both alleles show elevated aggression, but this phenotype is accompanied by other behavioral changes, including increases in anxiety and deficits in cognition. Here, we performed behavioral characterization of conditional BDNF knockout mice generated using a Cre recombinase driver line, KA1-Cre, which expresses Cre in few areas of brain: highly at hippocampal area CA3, moderately in dentate gyrus, cerebellum and facial nerve nucleus. The mutant animals exhibited elevated conspecific aggression and social dominance, but did not show changes in anxiety-like behaviors assessed using the elevated plus maze and open field test. There were no changes in depression like behaviors tested in the forced swim test, but small increase in immobility in the tail suspension test. In cognitive tasks, mutants showed normal social recognition and normal spatial and fear memory, but exhibited a deficit in object recognition. Thus, this knockout can serve as a robust model of BDNF-dependent aggression and object recognition deficiency. PMID:21255268

  9. Microglia Control Neuronal Network Excitability via BDNF Signalling

    PubMed Central

    2013-01-01

    Microglia-neuron interactions play a crucial role in several neurological disorders characterized by altered neural network excitability, such as epilepsy and neuropathic pain. While a series of potential messengers have been postulated as substrates of the communication between microglia and neurons, including cytokines, purines, prostaglandins, and nitric oxide, the specific links between messengers, microglia, neuronal networks, and diseases have remained elusive. Brain-derived neurotrophic factor (BDNF) released by microglia emerges as an exception in this riddle. Here, we review the current knowledge on the role played by microglial BDNF in controlling neuronal excitability by causing disinhibition. The efforts made by different laboratories during the last decade have collectively provided a robust mechanistic paradigm which elucidates the mechanisms involved in the synthesis and release of BDNF from microglia, the downstream TrkB-mediated signals in neurons, and the biophysical mechanism by which disinhibition occurs, via the downregulation of the K+-Cl− cotransporter KCC2, dysrupting Cl−homeostasis, and hence the strength of GABAA- and glycine receptor-mediated inhibition. The resulting altered network activity appears to explain several features of the associated pathologies. Targeting the molecular players involved in this canonical signaling pathway may lead to novel therapeutic approach for ameliorating a wide array of neural dysfunctions. PMID:24089642

  10. BDNF heightens the sensitivity of motor neurons to excitotoxic insults through activation of TrkB

    NASA Technical Reports Server (NTRS)

    Hu, Peter; Kalb, Robert G.; Walton, K. D. (Principal Investigator)

    2003-01-01

    The survival promoting and neuroprotective actions of brain-derived neurotrophic factor (BDNF) are well known but under certain circumstances this growth factor can also exacerbate excitotoxic insults to neurons. Prior exploration of the receptor through which BDNF exerts this action on motor neurons deflects attention away from p75. Here we investigated the possibility that BDNF acts through the receptor tyrosine kinase, TrkB, to confer on motor neurons sensitivity to excitotoxic challenge. We blocked BDNF activation of TrkB using a dominant negative TrkB mutant or a TrkB function blocking antibody, and found that this protected motor neurons against excitotoxic insult in cultures of mixed spinal cord neurons. Addition of a function blocking antibody to BDNF to mixed spinal cord neuron cultures is also neuroprotective indicating that endogenously produced BDNF participates in vulnerability to excitotoxicity. We next examined the intracellular signaling cascades that are engaged upon TrkB activation. Previously we found that inhibition of the phosphatidylinositide-3'-kinase (PI3'K) pathway blocks BDNF-induced excitotoxic sensitivity. Here we show that expression of a constitutively active catalytic subunit of PI3'K, p110, confers excitotoxic sensitivity (ES) upon motor neurons not incubated with BDNF. Parallel studies with purified motor neurons confirm that these events are likely to be occuring specifically within motor neurons. The abrogation of BDNF's capacity to accentuate excitotoxic insults may make it a more attractive neuroprotective agent.

  11. BDNF/TrkB signaling protects HT-29 human colon cancer cells from EGFR inhibition

    SciTech Connect

    Brunetto de Farias, Caroline; Heinen, Tiago Elias; Pereira dos Santos, Rafael; Abujamra, Ana Lucia; Schwartsmann, Gilberto; and others

    2012-08-24

    Highlights: Black-Right-Pointing-Pointer BDNF protected HT-29 colorectal cancer cells from the antitumor effect of cetuximab. Black-Right-Pointing-Pointer TrkB inhibition potentiated the antitumor effect of cetuximab. Black-Right-Pointing-Pointer BDNF/TrkB signaling might be involved in resistance to anti-EGFR therapy. -- Abstract: The clinical success of targeted treatment of colorectal cancer (CRC) is often limited by resistance to anti-epidermal growth factor receptor (EGFR) therapy. The neurotrophin brain-derived neurotrophic factor (BDNF) and its receptor TrkB have recently emerged as anticancer targets, and we have previously shown increased BDNF levels in CRC tumor samples. Here we report the findings from in vitro experiments suggesting that BDNF/TrkB signaling can protect CRC cells from the antitumor effects of EGFR blockade. The anti-EGFR monoclonal antibody cetuximab reduced both cell proliferation and the mRNA expression of BDNF and TrkB in human HT-29 CRC cells. The inhibitory effect of cetuximab on cell proliferation and survival was counteracted by the addition of human recombinant BDNF. Finally, the Trk inhibitor K252a synergistically enhanced the effect of cetuximab on cell proliferation, and this effect was blocked by BDNF. These results provide the first evidence that increased BDNF/TrkB signaling might play a role in resistance to EGFR blockade. Moreover, it is possible that targeting TrkB could potentiate the anticancer effects of anti-EGFR therapy.

  12. APATHY AND APOE4 ARE ASSOCIATED WITH REDUCED BDNF LEVELS IN ALZHEIMER’S DISEASE

    PubMed Central

    Álvarez, Antón; Aleixandre, Manuel; Linares, Carlos; Masliah, Eliezer; Moessler, Herbert

    2016-01-01

    Reduced brain-derived neurotrophic factor (BDNF) signaling is considered as a pathogenic event in early Alzheimer’s disease (AD), but the influence of apathy and apolipoprotein E epsilon-4 allele (APOE4) on serum BDNF values was not previously investigated in AD. We evaluated serum BDNF levels in AD, amnestic mild cognitive impairment (MCI) and control subjects. Baseline BDNF levels were similar in AD, MCI and controls. AD patients having apathy showed lower BDNF values than patients without apathy (p<0.05). After correction for the influence of apathy, APOE4 carriers showed lower BDNF levels (p<0.01) and MMSE scores (p<0.01) than non-APOE4 carriers in the subgroup of AD females, but not in males. Significant (p<0.05) positive correlations between BDNF values and MMSE scores were only observed in subgroups of AD males and of AD patients without apathy. These results are showing the association of apathy and APOE4 with reduced serum BDNF levels in AD, and are suggesting that BDNF reductions might contribute to the worse cognitive performance exhibited by AD apathetic patients and female APOE4 carriers. PMID:25024337

  13. Glutamatergic axon-derived BDNF controls GABAergic synaptic differentiation in the cerebellum

    PubMed Central

    Chen, Albert I.; Zang, Keling; Masliah, Eliezer; Reichardt, Louis F.

    2016-01-01

    To study mechanisms that regulate the construction of inhibitory circuits, we examined the role of brain-derived neurotrophic factor (BDNF) in the assembly of GABAergic inhibitory synapses in the mouse cerebellar cortex. We show that within the cerebellum, BDNF-expressing cells are restricted to the internal granular layer (IGL), but that the BDNF protein is present within mossy fibers which originate from cells located outside of the cerebellum. In contrast to deletion of TrkB, the cognate receptor for BDNF, deletion of Bdnf from cerebellar cell bodies alone did not perturb the localization of pre- or postsynaptic constituents at the GABAergic synapses formed by Golgi cell axons on granule cell dendrites within the IGL. Instead, we found that BDNF derived from excitatory mossy fiber endings controls their differentiation. Our findings thus indicate that cerebellar BDNF is derived primarily from excitatory neurons—precerebellar nuclei/spinal cord neurons that give rise to mossy fibers—and promotes GABAergic synapse formation as a result of release from axons. Thus, within the cerebellum the preferential localization of BDNF to axons enhances the specificity through which BDNF promotes GABAergic synaptic differentiation. PMID:26830657

  14. BDNF contributes to IBS-like colonic hypersensitivity via activating the enteroglia-nerve unit

    PubMed Central

    Wang, Peng; Du, Chao; Chen, Fei-Xue; Li, Chang-Qing; Yu, Yan-Bo; Han, Ting; Akhtar, Suhail; Zuo, Xiu-Li; Tan, Xiao-Di; Li, Yan-Qing

    2016-01-01

    The over-expressed colonic brain-derived neurotrophic factor (BDNF) has been reported to be associated with abdominal pain in patients with irritable bowel syndrome (IBS). However, the neuropathological mechanism is unclear. We here investigated the involvement of enteroglial cells (EGCs) and enteric nerves in IBS-like visceral hypersensitivity. We showed that glial fibrillary acidic protein (GFAP), tyrosine receptor kinase B (TrkB) and substance P (SP) were significantly increased in the colonic mucosa of IBS patients. The upregulation of those proteins was also observed in the colon of mice with visceral hypersensitivity, but not in the colon of BDNF+/− mice. Functionally, TrkB or EGC inhibitors, or BDNF knockdown significantly suppressed visceral hypersensitivity in mice. Using the EGC cell line, we found that recombinant human BDNF (r-HuBDNF) could directly activate EGCs via the TrkB-phospholipase Cγ1 pathway, thereby inducing a significant upregulation of SP. Moreover, supernatants from r-HuBDNF-activated EGC culture medium, rather than r-HuBDNF alone, triggered markedly augmented discharges in isolated intestinal mesenteric afferent nerves. r-HuBDNF alone could cause mesenteric afferent mechanical hypersensitivity independently, and this effect was synergistically enhanced by activated EGCs. We conclude that EGC-enteric nerve unit may be involved in IBS-like visceral hypersensitivity, and this process is likely initiated by BDNF-TrkB pathway activation. PMID:26837784

  15. Neuronal activity controls Bdnf expression via Polycomb de-repression and CREB/CBP/JMJD3 activation in mature neurons

    PubMed Central

    Palomer, Ernest; Carretero, Javier; Benvegnù, Stefano; Dotti, Carlos G.; Martin, Mauricio G.

    2016-01-01

    It has been recently described that in embryonic stem cells, the expression of some important developmentally regulated genes is repressed, but poised for fast activation under the appropriate stimuli. In this work we show that Bdnf promoters are repressed by Polycomb Complex 2 in mature hippocampal neurons, and basal expression is guaranteed by the coexistence with activating histone marks. Neuronal stimulation triggered by N-methyl-D-aspartate application induces the transcription of these promoters by H3K27Me3 demethylation and H3K27Me3 phosphorylation at Serine 28 leading to displacement of EZH2, the catalytic subunit of Polycomb Repressor Complex 2. Our data show that the fast transient expression of Bdnf promoters II and VI after neuronal stimulation is dependent on acetylation of histone H3K27 by CREB-p/CBP. Thus, regulatory mechanisms established during development seem to remain after differentiation controlling genes induced by different stimuli, as would be the case of early memory genes in mature neurons. PMID:27010597

  16. The brain-derived neurotrophic factor (BDNF) val66met polymorphism differentially affects performance on subscales of the Wechsler Memory Scale – Third Edition (WMS-III)

    PubMed Central

    Lamb, Yvette N.; Thompson, Christopher S.; McKay, Nicole S.; Waldie, Karen E.; Kirk, Ian J.

    2015-01-01

    Single nucleotide polymorphisms in the brain-derived neurotrophic factor (BDNF) gene and the catechol-O-methyltransferase (COMT) gene influence brain structure and function, as well as cognitive abilities. They are most influential in the hippocampus and prefrontal cortex (PFC), respectively. Recall and recognition are forms of memory proposed to have different neural substrates, with recall having a greater dependence on the PFC and hippocampus. This study aimed to determine whether the BDNF val66met or COMT val158met polymorphisms differentially affect recall and recognition, and whether these polymorphisms interact. A sample of 100 healthy adults was assessed on recall and familiarity-based recognition using the Faces and Family Pictures subscales of the Wechsler Memory Scale – Third Edition (WMS-III). COMT genotype did not affect performance on either task. The BDNF polymorphism (i.e., met carriers relative to val homozygotes) was associated with poorer recall ability, while not influencing recognition. Combining subscale scores in memory tests such as the WMS might obscure gene effects. Our results demonstrate the importance of distinguishing between recall and familiarity-based recognition in neurogenetics research. PMID:26347681

  17. 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. PMID:24582626

  18. Control of spine maturation and pruning through proBDNF synthesized and released in dendrites.

    PubMed

    Orefice, Lauren L; Shih, Chien-Cheng; Xu, Haifei; Waterhouse, Emily G; Xu, Baoji

    2016-03-01

    Excess synapses formed during early postnatal development are pruned over an extended period, while the remaining synapses mature. Synapse pruning is critical for activity-dependent refinement of neuronal connections and its dysregulation has been found in neurodevelopmental disorders such as autism spectrum disorders; however, the mechanism underlying synapse pruning remains largely unknown. As dendritic spines are the postsynaptic sites for the vast majority of excitatory synapses, spine maturation and pruning are indicators for maturation and elimination of these synapses. Our previous studies have found that dendritically localized mRNA for brain-derived neurotrophic factor (BDNF) regulates spine maturation and pruning. Here we investigated the mechanism by which dendritic Bdnf mRNA, but not somatically restricted Bdnf mRNA, promotes spine maturation and pruning. We found that neuronal activity stimulates both translation of dendritic Bdnf mRNA and secretion of its translation product mainly as proBDNF. The secreted proBDNF promotes spine maturation and pruning, and its effect on spine pruning is in part mediated by the p75(NTR) receptor via RhoA activation. Furthermore, some proBDNF is extracellularly converted to mature BDNF and then promotes maturation of stimulated spines by activating Rac1 through the TrkB receptor. In contrast, translation of somatic Bdnf mRNA and the release of its translation product mainly as mature BDNF are independent of action potentials. These results not only reveal a biochemical pathway regulating synapse pruning, but also suggest that BDNF synthesized in the soma and dendrites is released through distinct secretory pathways. PMID:26705735

  19. BDNF Expression in Larval and Adult Zebrafish Brain: Distribution and Cell Identification

    PubMed Central

    Cacialli, Pietro; Gueguen, Marie-Madeleine; Coumailleau, Pascal; D’Angelo, Livia; Kah, Olivier; Lucini, Carla; Pellegrini, Elisabeth

    2016-01-01

    Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, has emerged as an active mediator in many essential functions in the central nervous system of mammals. BDNF plays significant roles in neurogenesis, neuronal maturation and/or synaptic plasticity and is involved in cognitive functions such as learning and memory. Despite the vast literature present in mammals, studies devoted to BDNF in the brain of other animal models are scarse. Zebrafish is a teleost fish widely known for developmental genetic studies and is emerging as model for translational neuroscience research. In addition, its brain shows many sites of adult neurogenesis allowing higher regenerative properties after traumatic injuries. To add further knowledge on neurotrophic factors in vertebrate brain models, we decided to determine the distribution of bdnf mRNAs in the larval and adult zebrafish brain and to characterize the phenotype of cells expressing bdnf mRNAs by means of double staining studies. Our results showed that bdnf mRNAs were widely expressed in the brain of 7 days old larvae and throughout the whole brain of mature female and male zebrafish. In adults, bdnf mRNAs were mainly observed in the dorsal telencephalon, preoptic area, dorsal thalamus, posterior tuberculum, hypothalamus, synencephalon, optic tectum and medulla oblongata. By combining immunohistochemistry with in situ hybridization, we showed that bdnf mRNAs were never expressed by radial glial cells or proliferating cells. By contrast, bdnf transcripts were expressed in cells with neuronal phenotype in all brain regions investigated. Our results provide the first demonstration that the brain of zebrafish expresses bdnf mRNAs in neurons and open new fields of research on the role of the BDNF factor in brain mechanisms in normal and brain repairs situations. PMID:27336917

  20. Impact of partial dopamine depletion on cognitive flexibility in BDNF heterozygous mice

    PubMed Central

    Parikh, Vinay; Naughton, Sean X.; Yegla, Brittney; Guzman, Dawn M.

    2016-01-01

    Rationale Cognitive flexibility is a key component of executive function and is disrupted in major psychiatric disorders. Brain-derived neurotrophic factor (BDNF) exerts neuromodulatory effects on synaptic transmission and cognitive/affective behaviors. However the causal mechanisms linking BDNF hypofunction with executive deficits are not well understood. Objectives Here, we assessed the consequences of BDNF hemizygosity on cognitive flexibility in mice performing an operant conditioning task. As dopaminergic-glutamatergic interaction in the striatum is important for cognitive processing, and BDNF heterozygous (BDNF+/−) mice display a higher dopamine tone in the dorsal striatum, we also assessed the effects of partial striatal dopamine depletion on task performance and glutamate release. Results BDNF+/− mice acquired discrimination learning as well as new rule learning during set-shifting as efficiently as wild-type mice. However, partial removal of striatal dopaminergic inputs with 6-hydroxydopamine (6-OHDA) impaired these cognitive processes by impeding the maintenance of a new learning strategy in both genotypes. BDNF mutants exhibited performance impairments during reversal learning and these deficits were associated with increased perseveration to the previously acquired strategy. Partial dopamine depletion of the striatum reversed these cognitive impairments. Additionally, reduction in depolarization-evoked glutamate release noted in the dorsal striatum of BDNF+/− mice was not observed in 6-OHDA-infused BDNF mutants indicating normalization of glutamatergic transmission in these animals. Conclusions Our data illustrate that BDNF signaling regulates cognitive control processes presumably by maintaining striatal dopamine-glutamate balance. Moreover, aberrations in BDNF signaling may act as a common neurobiological substrate that accounts for executive dysfunction observed in multiple psychiatric conditions. PMID:26861892

  1. The requirement of BDNF for hippocampal synaptic plasticity is experience-dependent.

    PubMed

    Aarse, Janna; Herlitze, Stefan; Manahan-Vaughan, Denise

    2016-06-01

    Brain-derived neurotrophic factor (BDNF) supports neuronal survival, growth, and differentiation and has been implicated in forms of hippocampus-dependent learning. In vitro, a specific role in hippocampal synaptic plasticity has been described, although not all experience-dependent forms of synaptic plasticity critically depend on BDNF. Synaptic plasticity is likely to enable long-term synaptic information storage and memory, and the induction of persistent (>24 h) forms, such as long-term potentiation (LTP) and long-term depression (LTD) is tightly associated with learning specific aspects of a spatial representation. Whether BDNF is required for persistent (>24 h) forms of LTP and LTD, and how it contributes to synaptic plasticity in the freely behaving rodent has never been explored. We examined LTP, LTD, and related forms of learning in the CA1 region of freely dependent mice that have a partial knockdown of BDNF (BDNF(+/-) ). We show that whereas early-LTD (<90min) requires BDNF, short-term depression (<45 min) does not. Furthermore, BDNF is required for LTP that is induced by mild, but not strong short afferent stimulation protocols. Object-place learning triggers LTD in the CA1 region of mice. We observed that object-place memory was impaired and the object-place exploration failed to induce LTD in BDNF(+/-) mice. Furthermore, spatial reference memory, that is believed to be enabled by LTP, was also impaired. Taken together, these data indicate that BDNF is required for specific, but not all, forms of hippocampal-dependent information storage and memory. Thus, very robust forms of synaptic plasticity may circumvent the need for BDNF, rather it may play a specific role in the optimization of weaker forms of plasticity. The finding that both learning-facilitated LTD and spatial reference memory are both impaired in BDNF(+/-) mice, suggests moreover, that it is critically required for the physiological encoding of hippocampus-dependent memory. © 2015 The

  2. Elevation of Ser9 phosphorylation of GSK3β is required for HERV-W env-mediated BDNF signaling in human U251 cells.

    PubMed

    Qin, Chengchen; Li, Shan; Yan, Qiujin; Wang, Xiuling; Chen, Yatang; Zhou, Ping; Lu, Mengxin; Zhu, Fan

    2016-08-01

    Human endogenous retrovirus W family (HERV-W) envelope (env) is known to be associated with neurological and psychiatric disorders, such as multiple sclerosis and schizophrenia. Previous studies showed that overexpression of HERV-W env could induce brain-derived neurotrophic factor (BDNF) gene expression. In human and rat cells, BDNF-mediated signal transduction might be modulated by glycogen synthase kinase 3β (GSK3β). Both BDNF and GSK3β are schizophrenia-related genes. In this paper, we investigated whether GSK3β was involved in the HERV-W env-induced expression of BDNF. We found that HERV-W env increased phosphorylation of GSK3β at Ser9 (p-GSK3β (Ser9)) and the ratio of p-GSK3β (Ser9) to total GSK3β (p<0.05) in U251 cells. Overexpression of HERV-W env led to a 36.2% reduction in GSK3β activity compared to control (p<0.05). The levels of β-catenin, cyclin D1 and TSC2 mRNAs were upregulated (p<0.05). These data suggested that overexpression of HERV-W env might activate the GSK3β signaling pathway in U251 cells. Further, knockdown of GSK3β reduced the expression of total GSK3β, p-GSK3β (Ser9), and the ratio of p-GSK3β (Ser9) to total GSK3β by 28.6%, 50.4%, and 30.2%, respectively (p<0.05). Levels of β-catenin, cyclin D1 and TSC2 mRNAs were also reduced (p<0.05). Interestingly, GSK3β activity increased (p<0.05). Knockdown of GSK3β also decreased mRNA and protein expression of BDNF by 49.9% and 48.5% respectively (p<0.05). These results indicated that phosphorylation of GSK3β at Ser9 might be involved in HERV-W env-induced BDNF expression, and will hopefully improve our understanding of the role of HERV-W env in neurological and psychiatric diseases (schizophrenia, etc). PMID:27235578

  3. BDNF val66met affects hippocampal volume and emotion-related hippocampal memory activity.

    PubMed

    Molendijk, M L; van Tol, M-J; Penninx, B W J H; van der Wee, N J A; Aleman, A; Veltman, D J; Spinhoven, P; Elzinga, B M

    2012-01-01

    The val(66)met polymorphism on the BDNF gene has been reported to explain individual differences in hippocampal volume and memory-related activity. These findings, however, have not been replicated consistently and no studies to date controlled for the potentially confounding impact of early life stress, such as childhood abuse, and psychiatric status. Using structural and functional MRI, we therefore investigated in 126 depressed and/or anxious patients and 31 healthy control subjects the effects of val(66)met on hippocampal volume and encoding activity of neutral, positive and negative words, while taking into account childhood abuse and psychiatric status. Our results show slightly lower hippocampal volumes in carriers of a met allele (n=54) relative to val/val homozygotes (n=103) (P=0.02, effect size (Cohen's d)=0.37), which appeared to be independent of childhood abuse and psychiatric status. For hippocampal encoding activity, we found a val(66)met-word valence interaction (P=0.02) such that carriers of a met allele showed increased levels of activation in response to negative words relative to activation in the neutral word condition and relative to val/val homozygotes. This, however, was only evident in the absence of childhood abuse, as abused val/val homozygotes showed hippocampal encoding activity for negative words that was comparable to that of carriers of a met allele. Neither psychiatric status nor memory accuracy did account for these associations. In conclusion, BDNF val(66)met has a significant impact on hippocampal volume independently of childhood abuse and psychiatric status. Furthermore, early adverse experiences such as childhood abuse account for individual differences in hippocampal encoding activity of negative stimuli but this effect manifests differently as a function of val(66)met. PMID:22832736

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

    PubMed

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

    2013-11-27

    Brain-derived neurotrophic factor (BDNF) regulates the survival and growth of neurons, and influences synaptic efficiency and plasticity. Peripheral BDNF levels in patients with schizophrenia have been widely reported in the literature. However, it is still controversial whether peripheral levels of BDNF are altered in patients with schizophrenia. The peripheral BDNF levels previously reported in patients with schizophrenia were total BDNF (proBDNF and mature BDNF) as it was unable to specifically measure mature BDNF due to limited BDNF antibody specificity. In this study, we examined whether peripheral levels of mature BDNF were altered in patients with treatment-resistant schizophrenia. Matrix metalloproteinase-9 (MMP-9) levels were also measured, as MMP-9 plays a role in the conversion of proBDNF to mature BDNF. Twenty-two patients with treatment-resistant schizophrenia treated with clozapine and 22 age- and sex-matched healthy controls were enrolled. The plasma levels of mature BDNF and MMP-9 were measured using ELISA kits. No significant difference was observed for mature BDNF however, MMP-9 was significantly increased in patients with schizophrenia. The significant correlation was observed between mature BDNF and MMP-9 plasma levels. Neither mature BDNF nor MMP-9 plasma levels were associated clinical variables. Our results do not support the view that peripheral BDNF levels are associated with schizophrenia. MMP-9 may play a role in the pathophysiology of schizophrenia and serve as a biomarker for schizophrenia. PMID:24141084

  5. Institutionalization and indiscriminate social behavior: Differential-susceptibility versus diathesis-stress models for the 5-HTTLPR and BDNF genotypes.

    PubMed

    Mesquita, A R; Belsky, J; Li, Z; Baptista, J; Carvalho-Correia, E; Maciel, P; Soares, I

    2015-12-01

    Institutionalization adversely impacts children's emotional functioning, proving related to attachment disorders, perhaps most notably that involving indiscriminate behavior, the subject of this report. In seeking to extend work in this area, this research on gene X environment (GXE) interplay investigated whether the serotonin transporter (5-HTTLPR) and val66met Brain-Derived Neurotrophic Factor (BDNF) polymorphisms moderated the effect of institutional care on indiscriminate behavior in preschoolers. Eighty-five institutionalized and 135 home-reared Portuguese children were assessed using Disturbances of Attachment Interview (DAI). GXE results indicated that s/s homozygotes of the 5-HTTLPR gene displayed significantly higher levels of indiscriminate behavior than all other children if institutionalized, something not true of such children when family reared. These findings proved consistent with the diathesis-stress rather than differential-susceptibility model of person×environment interaction. BDNF proved unrelated to indiscriminate behavior. Results are discussed in relation to previous work on this subject of indiscriminate behavior, institutionalization and GXE interaction. PMID:26386404

  6. On the genetics of loss aversion: An interaction effect of BDNF Val66Met and DRD2/ANKK1 Taq1a.

    PubMed

    Voigt, Gesine; Montag, Christian; Markett, Sebastian; Reuter, Martin

    2015-12-01

    Loss aversion is the tendency to overweight losses compared with gains in decision situations. Several studies have investigated the neurobiological background of this phenomenon and it was found that activation in the mesolimbic-mesocortical dopamine system during a gambling decision correlates with loss aversion. In a behavioral experiment with N = 143 subjects, the present study investigates the influence of 2 functional single-nucleotide polymorphisms on the BDNF gene (BDNF Val66Met polymorphism) and ANKK1 gene (DRD2 Taq1a/ANKK1 polymorphism), that are known to affect the dopamine system, on loss aversion. Additionally, associations of alexithymia, a personality construct describing the disability to consciously experience emotions in the self, with loss aversion and with the mentioned polymorphisms were assessed using the TAS-20 questionnaire, to replicate associations that have been reported before. Results revealed a significant interaction effect of the 2 polymorphisms on loss aversion. Carriers of the genetic constellation 66Met+/A1+ had the lowest loss aversion scores, compared with all other allelic groups. According to the literature this allelic configuration is characterized by a relatively low D2/3 receptor binding in the striatum and an impaired activity-dependent secretion of BDNF. This is the first study showing that loss aversion is related to naturally occurring differences in dopamine function. PMID:26501178

  7. proBDNF negatively regulates neuronal remodeling, synaptic transmission, and synaptic plasticity in hippocampus.

    PubMed

    Yang, Jianmin; Harte-Hargrove, Lauren C; Siao, Chia-Jen; Marinic, Tina; Clarke, Roshelle; Ma, Qian; Jing, Deqiang; Lafrancois, John J; Bath, Kevin G; Mark, Willie; Ballon, Douglas; Lee, Francis S; Scharfman, Helen E; Hempstead, Barbara L

    2014-05-01

    Experience-dependent plasticity shapes postnatal development of neural circuits, but the mechanisms that refine dendritic arbors, remodel spines, and impair synaptic activity are poorly understood. Mature brain-derived neurotrophic factor (BDNF) modulates neuronal morphology and synaptic plasticity, including long-term potentiation (LTP) via TrkB activation. BDNF is initially translated as proBDNF, which binds p75(NTR). In vitro, recombinant proBDNF modulates neuronal structure and alters hippocampal long-term plasticity, but the actions of endogenously expressed proBDNF are unclear. Therefore, we generated a cleavage-resistant probdnf knockin mouse. Our results demonstrate that proBDNF negatively regulates hippocampal dendritic complexity and spine density through p75(NTR). Hippocampal slices from probdnf mice exhibit depressed synaptic transmission, impaired LTP, and enhanced long-term depression (LTD) in area CA1. These results suggest that proBDNF acts in vivo as a biologically active factor that regulates hippocampal structure, synaptic transmission, and plasticity, effects that are distinct from those of mature BDNF. PMID:24746813

  8. A Longitudinal Study of BDNF Promoter Methylation and Depression in Breast Cancer

    PubMed Central

    Kang, Hee-Ju; Kim, Seon-Young; Kim, Sung-Wan; Shin, Il-Seon; Kim, Hye-Ran; Park, Min-Ho; Shin, Myung-Geun; Yoon, Jung-Han; Yoon, Jin-Sang

    2015-01-01

    Objective Brain-derived neurotrophic factor (BDNF) is investigated in depression related to medical disorders and its secretion is influenced by epigenetic factors. We investigated the association between BDNF promoter methylation and depression following mastectomy for breast cancer. Methods In total, 309 patients with breast cancer were evaluated 1 week after mastectomy, and 244 (79%) were followed up 1 year later. Depression was diagnosed (major or minor depressive disorder) according to DSM-IV criteria and depression severity was estimated by Montgomery-Asberg Depression Rating Scale (MADRS). We assessed BDNF promoter methylation using leukocyte DNA. The effects of BDNF methylation on depression diagnosis and severity were investigated using multivariate logistic and linear regression models, respectively. The two-way interaction between BDNF methylation and the val66met polymorphism on depression was also evaluated using multivariate logistic regression models. Results Higher BDNF methylation was independently associated with depression diagnosis and with more severe symptoms at both 1 week and 1 year after mastectomy. No significant methylation-genotype interactions were found. Conclusion A role for BDNF in depression related to breast cancer was supported. Indeed, the association between depression and BDNF methylation may be useful for identifying patients who are at high risk for depression and for suggesting directions for promising drug research. PMID:26508964

  9. Alternative Splicing Variants and DNA Methylation Status of BDNF in Inbred Chicken Lines

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Brain derived neurotrophic factor (BDNF) plays essential roles in neuronal survival and differentiation, synaptic plasticity, central regulation of energy homeostasis, and neuronal development of the central and peripheral nerve system. Here, we report two new splicing variants of the chicken BDNF g...

  10. Age-Dependent Deficits in Fear Learning in Heterozygous BDNF Knock-Out Mice

    ERIC Educational Resources Information Center

    Endres, Thomas; Lessmann, Volkmar

    2012-01-01

    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…