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Sample records for activity-dependent bdnf secretion

  1. 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

  2. BDNF-secreting capsule exerts neuroprotective effects on epilepsy model of rats.

    PubMed

    Kuramoto, Satoshi; Yasuhara, Takao; Agari, Takashi; Kondo, Akihiko; Jing, Meng; Kikuchi, Yoichiro; Shinko, Aiko; Wakamori, Takaaki; Kameda, Masahiro; Wang, Feifei; Kin, Kyohei; Edahiro, Satoru; Miyoshi, Yasuyuki; Date, Isao

    2011-01-12

    Brain-derived neurotrophic factor (BDNF) is a well neurotrophic factor with neuroprotective potentials for various diseases in the central nervous system. However several previous studies demonstrated that BDNF might deteriorate symptoms for epilepsy model of animals by progression of abnormal neurogenesis. We hypothesized that continuous administration of BDNF at low dose might be more effective for epilepsy model of animals because high dose of BDNF was used in many studies. BDNF-secreting cells were genetically made and encapsulated for transplantation. Rats receiving BDNF capsule showed significant amelioration of seizure stage and reduction of the number of abnormal spikes at 7 days after kainic acid administration, compared to those of control group. The number of BrdU and BrdU/doublecortin positive cells in the hippocampus of BDNF group significantly increased, compared to that of control group. NeuN positive cells in the CA1 and CA3 of BDNF group were significantly preserved, compared to control group. In conclusion, low dose administration using encapsulated BDNF-secreting cells exerted neuroprotective effects with enhanced neurogenesis on epilepsy model of rats. These results might suggest the importance of the dose and administrative way of this neurotrophic factor to the epilepsy model of animals.

  3. BDNF-induced nitric oxide signals in cultured rat hippocampal neurons: time course, mechanism of generation, and effect on neurotrophin secretion

    PubMed Central

    Kolarow, Richard; Kuhlmann, Christoph R. W.; Munsch, Thomas; Zehendner, Christoph; Brigadski, Tanja; Luhmann, Heiko J.; Lessmann, Volkmar

    2014-01-01

    BDNF and nitric oxide signaling both contribute to plasticity at glutamatergic synapses. However, the role of combined signaling of both pathways at the same synapse is largely unknown. Using NO imaging with diaminofluoresceine in cultured hippocampal neurons we analyzed the time course of neurotrophin-induced NO signals. Application of exogenous BDNF, NT-4, and NT-3 (but not NGF) induced NO signals in the soma and in proximal dendrites of hippocampal neurons that were sensitive to NO synthase activity, TrkB signaling, and intracellular calcium elevation. The effect of NO signaling on neurotrophin secretion was analyzed in BDNF-GFP, and NT-3-GFP transfected hippocampal neurons. Exogenous application of the NO donor sodium-nitroprusside markedly inhibited neurotrophin secretion. However, endogenously generated NO in response to depolarization and neurotrophin stimulation, both did not result in a negative feedback on neurotrophin secretion. These results suggest that a negative feedback of NO signaling on synaptic secretion of neurotrophins operates only at high intracellular levels of nitric oxide that are under physiological conditions not reached by depolarization or BDNF signaling. PMID:25426021

  4. NMDA-Dependent Switch of proBDNF Actions on Developing GABAergic Synapses

    PubMed Central

    Langlois, Anais; Diabira, Diabe; Ferrand, Nadine; Porcher, Christophe

    2013-01-01

    The brain-derived neurotrophic factor (BDNF) has emerged as an important messenger for activity-dependent development of neuronal network. Recent findings have suggested that a significant proportion of BDNF can be secreted as a precursor (proBDNF) and cleaved by extracellular proteases to yield the mature form. While the actions of proBDNF on maturation and plasticity of excitatory synapses have been studied, the effect of the precursor on developing GABAergic synapses remains largely unknown. Here, we show that regulated secretion of proBDNF exerts a bidirectional control of GABAergic synaptic activity with NMDA receptors driving the polarity of the plasticity. When NMDA receptors are activated during ongoing synaptic activity, regulated Ca2+-dependent secretion of proBDNF signals via p75NTR to depress GABAergic synaptic activity, while in the absence of NMDA receptors activation, secreted proBDNF induces a p75NTR-dependent potentiation of GABAergic synaptic activity. These results revealed a new function for proBDNF-p75NTR signaling in synaptic plasticity and a novel mechanism by which synaptic activity can modulate the development of GABAergic synaptic connections. PMID:22510533

  5. Functional and structural specific roles of activity-driven BDNF within circuits formed by single spiny stellate neurons of the barrel cortex

    PubMed Central

    Sun, Qian-Quan; Zhang, Zhi; Sun, June; Nair, Anand S.; Petrus, Dan P.; Zhang, Chunzhao

    2014-01-01

    Brain derived neurotrophic factor (BDNF) plays key roles in several neurodevelopmental disorders and actions of pharmacological treatments. However, it is unclear how specific BDNF’s effects are on different circuit components. Current studies have largely focused on the role of BDNF in modification of synaptic development. The precise roles of BDNF in the refinement of a functional circuit in vivo remain unclear. Val66Met polymorphism of BDNF may be associated with increased risk for cognitive impairments and is mediated at least in part by activity-dependent trafficking and/or secretion of BDNF. Using mutant mice that lacked activity-driven BDNF expression (bdnf-KIV), we previously reported that experience regulation of the cortical GABAergic network is mediated by activity-driven BDNF expression. Here, we demonstrate that activity-driven BDNF’s effects on circuits formed by the layer IV spiny stellate cells are highly specific. Structurally, dendritic but not axonal morphology was altered in the mutant. Physiologically, GABAergic but not glutamatergic synapses were severely affected. The effects on GABA transmission occurs via presynaptic alteration of calcium-dependent release probability. These results suggest that neuronal activity through activity-driven BDNF expression, can selectively regulate specific features of layer IV circuits in vivo. We postulate that the role of activity-dependent BDNF is to modulate the computational ability of circuits that relate to the gain control (i.e., feed-forward inhibition); whereas the basic wiring of circuits relevant to the sensory pathway is spared. Gain control modulation within cortical circuits has broad impact on cognitive processing and brain state-transitions. Cognitive behavior and mode is determined by brain states, thus the studying of circuit alteration by endogenous BDNF provides insights into the cellular and molecular mechanisms of diseases mediated by BDNF. PMID:25414642

  6. BDNF val66met Polymorphism Affects Aging of Multiple Types of Memory

    PubMed Central

    Kennedy, Kristen M.; Reese, Elizabeth D.; Horn, Marci M.; Sizemore, April N.; Unni, Asha K.; Meerbrey, Michael E.; Kalich, Allan G.; Rodrigue, Karen M.

    2014-01-01

    The BDNF val66met polymorphism (rs6265) influences activity-dependent secretion of brain-derived neurotrophic factor in the synapse, which is crucial for learning and memory. Individuals homozygous or heterozygous for the met allele have lower BDNF secretion than val homozygotes and may be at risk for reduced declarative memory performance, but it remains unclear which types of declarative memory may be affected and how aging of memory across the lifespan is impacted by the BDNF val66met polymorphism. This cross-sectional study investigated the effects of BDNF polymorphism on multiple indices of memory (item, associative, prospective, subjective complaints) in a lifespan sample of 116 healthy adults aged 20-93 years. Advancing age showed a negative effect on item, associative and prospective memory, but not on subjective memory complaints. For item and prospective memory, there were significant age x BDNF group interactions, indicating the adverse effect of age on memory performance across the lifespan was much stronger in the BDNF met carriers than for the val homozygotes. BDNF met carriers also endorsed significantly greater subjective memory complaints, regardless of age, and showed a trend (p < .07) toward poorer associative memory performance compared to val homozygotes. These results suggest that genetic predisposition to the availability of brain-derived neurotrophic factor, by way of the BDNF val66met polymorphism, exerts an influence on multiple indices of episodic memory – in some cases in all individuals regardless of age (subjective memory and perhaps associative memory), in others as an exacerbation of age-related differences in memory across the lifespan (item and prospective memory). PMID:25264352

  7. The functional BDNF Val66Met polymorphism affects functions of pre-attentive visual sensory memory processes.

    PubMed

    Beste, Christian; Schneider, Daniel; Epplen, Jörg T; Arning, Larissa

    2011-01-01

    The brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is involved in nerve growth and survival. Especially, a single nucleotide polymorphism (SNP) in the BDNF gene, Val66Met, has gained a lot of attention, because of its effect on activity-dependent BDNF secretion and its link to impaired memory processes. We hypothesize that the BDNF Val66Met polymorphism may have modulatory effects on the visual sensory (iconic) memory performance. Two hundred and eleven healthy German students (106 female and 105 male) were included in the data analysis. Since BDNF is also discussed to be involved in the pathogenesis of depression, we additionally tested for possible interactions with depressive mood. The BDNF Val66Met polymorphism significantly influenced iconic-memory performance, with the combined Val/Met-Met/Met genotype group revealing less time stability of information stored in iconic memory than the Val/Val group. Furthermore, this stability was positively correlated with depressive mood exclusively in the Val/Val genotype group. Thus, these results show that the BDNF Val66Met polymorphism has an effect on pre-attentive visual sensory memory processes.

  8. 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

  9. Induction of long-term potentiation and depression is reflected by corresponding changes in secretion of endogenous brain-derived neurotrophic factor

    PubMed Central

    Aicardi, Giorgio; Argilli, Emanuela; Cappello, Silvia; Santi, Spartaco; Riccio, Massimo; Thoenen, Hans; Canossa, Marco

    2004-01-01

    Neurotrophins play an important role in modulating activity-dependent neuronal plasticity. In particular, threshold levels of brain-derived neurotrophic factor (BDNF) are required to induce long-term potentiation (LTP) in acute hippocampal slices. Conversely, the administration of exogenous BDNF prevents the induction of long-term depression (LTD) in the visual cortex. A long-standing missing link in the analysis of this modulatory role of BDNF was the determination of the time-course of endogenous BDNF secretion in the same organotypic preparation in which LTP and LTD are elicited. Here, we fulfilled this requirement in slices of perirhinal cortex. Classical theta-burst stimulation patterns evoking LTP lasting >180 min elicited a large increase in BDNF secretion that persisted 5-12 min beyond the stimulation period. Weaker theta-burst stimulation patterns leading only to the initial phase of LTP (≈35 min) were accompanied by a smaller increase in BDNF secretion lasting <1 min. Sequestration of BDNF by TrkB-IgG receptor bodies prevented LTP. Low-frequency stimulations leading to LTD were accompanied by reductions in BDNF secretion that never lasted beyond the duration of the stimulation. PMID:15505222

  10. 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

  11. 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

  12. 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

  13. BDNF deregulation in Rett syndrome

    PubMed Central

    Li, Wei; Pozzo-Miller, Lucas

    2013-01-01

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

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed

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

    2008-01-01

    A functional polymorphism at the val66met locus in the BDNF gene has significant effects on the pro-form of the protein in intracellular trafficking and activity-dependent, but not constitutive, secretion. These differences are thought to underlie several findings in humans related to this polymorphism, including markers of neuronal viability, BOLD activation in medial temporal lobe regions, and some aspects of behavior. However, many important questions remain about the impact of BDNF on various mnemonic subprocesses at the behavioral level. In this study, we examined the impact of the val/met polymorphism in a verbal recognition memory paradigm involving manipulation of depth of encoding and differential delays for recall and analyses of hits for previously presented target words and correct rejections of foils. Twenty-four human val homozygous individuals and 24 met carrier individuals comprised the sample. All were healthy controls. IQ between the groups was equivalent. In the encoding phase of the study, words were presented and encoded either by a decision as to whether they were living or nonliving ("deep") or if they contained the letter "A" (shallow). After this phase, recognition was tested immediately, half an hour, and 24h later. BDNF genotype had significant effects on hits and discriminability (d'), accounting for at least 10% of the variance, but not on correct rejections or beta. BDNF did not interact with level of encoding, nor did it interact with delay. In sum, BDNF genotypes impacted "hits" in a recognition memory paradigm, findings consistent with the general notion that BDNF plays a prominent role in memory subprocesses thought to engage the medial temporal lobe. PMID:17988784

  16. 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

  17. Regulation of hippocampal synaptic plasticity by BDNF.

    PubMed

    Leal, Graciano; Afonso, Pedro M; Salazar, Ivan L; Duarte, Carlos B

    2015-09-24

    The neurotrophin brain-derived neurotrophic factor (BDNF) has emerged as a major regulator of activity-dependent plasticity at excitatory synapses in the mammalian central nervous system. In particular, much attention has been given to the role of the neurotrophin in the regulation of hippocampal long-term potentiation (LTP), a sustained enhancement of excitatory synaptic strength believed to underlie learning and memory processes. In this review we summarize the evidence pointing to a role for BDNF in generating functional and structural changes at synapses required for both early- and late phases of LTP in the hippocampus. The available information regarding the pre- and/or postsynaptic release of BDNF and action of the neurotrophin during LTP will be also reviewed. Finally, we discuss the effects of BDNF on the synaptic proteome, either by acting on the protein synthesis machinery and/or by regulating protein degradation by calpains and possibly by the ubiquitin-proteasome system (UPS). This fine-tuned control of the synaptic proteome rather than a simple upregulation of the protein synthesis may play a key role in BDNF-mediated synaptic potentiation. This article is part of a Special Issue entitled SI: Brain and Memory. PMID:25451089

  18. Selective reduction of striatal mature BDNF without induction of proBDNF in the zQ175 mouse model of Huntington’s disease

    PubMed Central

    Ma, Qian; Yang, Jianmin; Li, Thomas; Milner, Teresa A.; Hempstead, Barbara L.

    2016-01-01

    Huntington’s disease (HD) is a neurodegenerative disorder characterized by massive loss of medium spiny neurons in the striatum. However, the mechanisms by which mutant huntingtin leads to this selective neuronal death remain incompletely understood. Brain-derived neurotrophic factor (BDNF) has been shown to be neuroprotective on HD striatal neurons both in vitro and in vivo. ProBDNF, the precursor of mature BDNF (mBDNF), also can be secreted but promotes apoptosis of neurons expressing p75NTR and sortilin receptors. Although a reduction of total striatal BDNF protein has been reported in HD patients and mouse models, it remains unclear whether conversion of proBDNF to mBDNF is altered in HD, and whether the proBDNF receptors, p75NTR and sortilin are dysregulated, leading to impaired striatal neuron survival. To test these hypotheses, we generated bdnf-HA knock-in (KI) mice on the zQ175 HD background to accurately quantitate the levels of both proBDNF and mBDNF in the HD striatum. In aged zQ175 HD mice, we observed a significant loss of mBDNF and decreased TrkB activation, but no increase of proBDNF or p75NTR levels either in the sensorimotor cortex or the striatum. However, immunoreactivities of p75NTR and sortilin receptor are both increased in immature striatal oligodendrocytes, which associate with significant myelin defects in the HD striatum. Taken together, the present study indicates that diminished mature BDNF trophic signaling through the TrkB receptor, rather than an induction in proBDNF, is a main contributing factor to the vulnerability of striatal neurons in the zQ175 HD mouse model. PMID:26282324

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

    PubMed Central

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

    2015-01-01

    Most growth factors are initially synthesized as precursor proteins and subsequently processed into their mature form by proteolytic cleavage, resulting in simultaneous removal of a pro-peptide. However, compared with that of mature form, the biological role of the pro-peptide is poorly understood. Here, we investigated the biological role of the pro-peptide of brain-derived neurotrophic factor (BDNF) and first showed that the pro-peptide is expressed and secreted in hippocampal tissues and cultures, respectively. Interestingly, we found that the BDNF pro-peptide directly facilitates hippocampal long-term depression (LTD), requiring the activation of GluN2B-containing NMDA receptors and the pan-neurotrophin receptor p75NTR. The BDNF pro-peptide also enhances NMDA-induced α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor endocytosis, a mechanism crucial for LTD expression. Thus, the BDNF pro-peptide is involved in synaptic plasticity that regulates a mechanism responsible for promoting LTD. The well-known BDNF polymorphism valine for methionine at amino acid position 66 (Val66Met) affects human memory function. Here, the BDNF pro-peptide with Met mutation completely inhibits hippocampal LTD. These findings demonstrate functional roles for the BDNF pro-peptide and a naturally occurring human BDNF polymorphism in hippocampal synaptic depression. PMID:26015580

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

    PubMed

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

    2015-06-01

    Most growth factors are initially synthesized as precursor proteins and subsequently processed into their mature form by proteolytic cleavage, resulting in simultaneous removal of a pro-peptide. However, compared with that of mature form, the biological role of the pro-peptide is poorly understood. Here, we investigated the biological role of the pro-peptide of brain-derived neurotrophic factor (BDNF) and first showed that the pro-peptide is expressed and secreted in hippocampal tissues and cultures, respectively. Interestingly, we found that the BDNF pro-peptide directly facilitates hippocampal long-term depression (LTD), requiring the activation of GluN2B-containing NMDA receptors and the pan-neurotrophin receptor p75(NTR). The BDNF pro-peptide also enhances NMDA-induced α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor endocytosis, a mechanism crucial for LTD expression. Thus, the BDNF pro-peptide is involved in synaptic plasticity that regulates a mechanism responsible for promoting LTD. The well-known BDNF polymorphism valine for methionine at amino acid position 66 (Val66Met) affects human memory function. Here, the BDNF pro-peptide with Met mutation completely inhibits hippocampal LTD. These findings demonstrate functional roles for the BDNF pro-peptide and a naturally occurring human BDNF polymorphism in hippocampal synaptic depression. PMID:26015580

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

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

    The benefits of physical exercise on improvements in brain-derived neurotrophic factor (BDNF) levels and cognitive functioning have been reported in the literature. However, the variability of individual responses may be linked to genetic differences. BDNF is considered one of the most plausible factors involved in the cognitive benefits associated with physical activity practice. A single nucleotide polymorphism localized in the gene that codes BDNF results in a missense mutation that promotes an amino acid substitution (Val66Met) in the protein. This process has been associated with decreased levels of BDNF secretion, with corresponding impairments in specific cognitive functions. Therefore, the objective of this study was to analyze the effects of a multimodal physical exercise program on peripheral BDNF levels and cognitive functions in elderly individuals with mild cognitive impairment (MCI). The participants were genotyped for the BDNF Val66Met polymorphism. Cognitive functions were assessed by the Montreal Cognitive Assessment (MoCA) prior to and after the intervention. Forty-five participants were assigned to the control and trained groups. The trained group participated in a multimodal physical training for a 16-week period. The results showed a significant between-subjects interaction (p < 0.05), which indicates the beneficial contribution of training on cognitive functions independent of the BDNF genotype. However, only participants with BDNF-Met genotypes exhibited significant improvements in peripheral BDNF levels. The BDNF genotype appears to modulate the effects of physical exercise on BDNF secretion, but it does not influence cognition. This is the first study that evaluated the influence of a BDNF polymorphism on physical activity and cognition performance in elderly MCI individuals. PMID:25062900

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

    PubMed Central

    Seifert, Bianca; Eckenstaler, Robert; Rönicke, Raik; Leschik, Julia; Lutz, Beat; Reymann, Klaus; Lessmann, Volkmar; Brigadski, Tanja

    2016-01-01

    The neurotrophin brain derived neurotrophic factor (BDNF) is an important growth factor in the CNS. Deficits in transport of this secretory protein could underlie neurodegenerative diseases. Investigation of disease-related changes in BDNF transport might provide insights into the cellular mechanism underlying, for example, Alzheimer's disease (AD). To analyze the role of BDNF transport in AD, live cell imaging of fluorescently labeled BDNF was performed in hippocampal neurons of different AD model systems. BDNF and APP colocalized with low incidence in vesicular structures. Anterograde as well as retrograde transport of BDNF vesicles was reduced and these effects were mediated by factors released from hippocampal neurons into the extracellular medium. Transport of BDNF was altered at a very early time point after onset of human APP expression or after acute amyloid-beta(1-42) treatment, while the activity-dependent release of BDNF remained unaffected. Taken together, extracellular cleavage products of APP induced rapid changes in anterograde and retrograde transport of BDNF-containing vesicles while release of BDNF was unaffected by transgenic expression of mutated APP. These early transport deficits might lead to permanently impaired brain functions in the adult brain. PMID:26881108

  4. Loss of promoter IV-driven BDNF expression impacts oscillatory activity during sleep, sensory information processing and fear regulation

    PubMed Central

    Hill, J L; Hardy, N F; Jimenez, D V; Maynard, K R; Kardian, A S; Pollock, C J; Schloesser, R J; Martinowich, K

    2016-01-01

    Posttraumatic stress disorder is characterized by hyperarousal, sensory processing impairments, sleep disturbances and altered fear regulation; phenotypes associated with changes in brain oscillatory activity. Molecules associated with activity-dependent plasticity, including brain-derived neurotrophic factor (BDNF), may regulate neural oscillations by controlling synaptic activity. BDNF synthesis includes production of multiple Bdnf transcripts, which contain distinct 5′ noncoding exons. We assessed arousal, sensory processing, fear regulation and sleep in animals where BDNF expression from activity-dependent promoter IV is disrupted (Bdnf-e4 mice). Bdnf-e4 mice display sensory hyper-reactivity and impaired electrophysiological correlates of sensory information processing as measured by event-related potentials (ERP). Utilizing electroencephalogram, we identified a decrease in slow-wave activity during non-rapid eye movement sleep, suggesting impaired sleep homeostasis. Fear extinction is controlled by hippocampal–prefrontal cortical BDNF signaling, and neurophysiological communication patterns between the hippocampus (HPC) and medial prefrontal cortex (mPFC) correlate with behavioral performance during extinction. Impaired fear extinction in Bdnf-e4 mice is accompanied by increased HPC activation and decreased HPC–mPFC theta phase synchrony during early extinction, as well as increased mPFC activation during extinction recall. These results suggest that activity-dependent BDNF signaling is critical for regulating oscillatory activity, which may contribute to altered behavior. PMID:27552586

  5. Loss of promoter IV-driven BDNF expression impacts oscillatory activity during sleep, sensory information processing and fear regulation.

    PubMed

    Hill, J L; Hardy, N F; Jimenez, D V; Maynard, K R; Kardian, A S; Pollock, C J; Schloesser, R J; Martinowich, K

    2016-01-01

    Posttraumatic stress disorder is characterized by hyperarousal, sensory processing impairments, sleep disturbances and altered fear regulation; phenotypes associated with changes in brain oscillatory activity. Molecules associated with activity-dependent plasticity, including brain-derived neurotrophic factor (BDNF), may regulate neural oscillations by controlling synaptic activity. BDNF synthesis includes production of multiple Bdnf transcripts, which contain distinct 5' noncoding exons. We assessed arousal, sensory processing, fear regulation and sleep in animals where BDNF expression from activity-dependent promoter IV is disrupted (Bdnf-e4 mice). Bdnf-e4 mice display sensory hyper-reactivity and impaired electrophysiological correlates of sensory information processing as measured by event-related potentials (ERP). Utilizing electroencephalogram, we identified a decrease in slow-wave activity during non-rapid eye movement sleep, suggesting impaired sleep homeostasis. Fear extinction is controlled by hippocampal-prefrontal cortical BDNF signaling, and neurophysiological communication patterns between the hippocampus (HPC) and medial prefrontal cortex (mPFC) correlate with behavioral performance during extinction. Impaired fear extinction in Bdnf-e4 mice is accompanied by increased HPC activation and decreased HPC-mPFC theta phase synchrony during early extinction, as well as increased mPFC activation during extinction recall. These results suggest that activity-dependent BDNF signaling is critical for regulating oscillatory activity, which may contribute to altered behavior. PMID:27552586

  6. 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

  7. 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

  8. 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

  9. 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.

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  12. Pro-region engineering for improved yeast display and secretion of brain derived neurotrophic factor.

    PubMed

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

    2016-03-01

    Brain derived neurotrophic factor (BDNF) is a promising therapeutic candidate for a variety of neurological diseases. However, it is difficult to produce as a recombinant protein. In its native mammalian context, BDNF is first produced as a pro-protein with subsequent proteolytic removal of the pro-region to yield mature BDNF protein. Therefore, in an attempt to improve yeast as a host for heterologous BDNF production, the BDNF pro-region was first evaluated for its effects on BDNF surface display and secretion. Addition of the wild-type pro-region to yeast BDNF production constructs improved BDNF folding both as a surface-displayed and secreted protein in terms of binding its natural receptors TrkB and p75, but titers remained low. Looking to further enhance the chaperone-like functions provided by the pro-region, two rounds of directed evolution were performed, yielding mutated pro-regions that further improved the display and secretion properties of BDNF. Subsequent optimization of the protease recognition site was used to control whether the produced protein was in pro- or mature BDNF forms. Taken together, we have demonstrated an effective strategy for improving BDNF compatibility with yeast protein engineering and secretion platforms. PMID:26580314

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

    PubMed

    Klein, Anders B; Jennum, Poul; Knudsen, Stine; Gammeltoft, Steen; Mikkelsen, Jens D

    2013-06-01

    Narcolepsy is a lifelong sleep disorder characterized by excessive daytime sleepiness, sudden loss of muscle tone (cataplexy), fragmentation of nocturnal sleep and sleep paralysis. The symptoms of the disease strongly correlate with a reduction in hypocretin levels in CSF and a reduction in hypocretin neurons in hypothalamus in post-mortem tissue. Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are important for activity-dependent neuronal function and synaptic modulation and it is considered that these mechanisms are important in sleep regulation. We hypothesized that serum levels of these factors are altered in patients with narcolepsy compared to healthy controls without sleep disturbances. Polysomnography data was obtained and serum BDNF and NGF levels measured using ELISA, while hypocretin was measured using RIA. Serum BDNF levels were significantly higher in narcolepsy patients than in healthy controls (64.2±3.9 ng/ml vs. 47.3±2.6 ng/ml, P<0.01), while there were no significant differences in NGF levels. As expected, narcolepsy patients had higher BMI compared to controls, but BMI did not correlate with the serum BDNF levels. The change in BDNF levels was not related to disease duration and sleep parameters did not correlate with BDNF in narcolepsy patients. The mechanisms behind the marked increase in BDNF levels in narcolepsy patients remain unknown. PMID:23570723

  14. Activation of microglial cells triggers a release of brain-derived neurotrophic factor (BDNF) inducing their proliferation in an adenosine A2A receptor-dependent manner: A2A receptor blockade prevents BDNF release and proliferation of microglia

    PubMed Central

    2013-01-01

    Background Brain-derived neurotrophic factor (BDNF) has been shown to control microglial responses in neuropathic pain. Since adenosine A2A receptors (A2ARs) control neuroinflammation, as well as the production and function of BDNF, we tested to see if A2AR controls the microglia-dependent secretion of BDNF and the proliferation of microglial cells, a crucial event in neuroinflammation. Methods Murine N9 microglial cells were challenged with lipopolysaccharide (LPS, 100 ng/mL) in the absence or in the presence of the A2AR antagonist, SCH58261 (50 nM), as well as other modulators of A2AR signaling. The BDNF cellular content and secretion were quantified by Western blotting and ELISA, A2AR density was probed by Western blotting and immunocytochemistry and cell proliferation was assessed by BrdU incorporation. Additionally, the A2AR modulation of LPS-driven cell proliferation was also tested in primary cultures of mouse microglia. Results LPS induced time-dependent changes of the intra- and extracellular levels of BDNF and increased microglial proliferation. The maximal LPS-induced BDNF release was time-coincident with an LPS-induced increase of the A2AR density. Notably, removing endogenous extracellular adenosine or blocking A2AR prevented the LPS-mediated increase of both BDNF secretion and proliferation, as well as exogenous BDNF-induced proliferation. Conclusions We conclude that A2AR activation plays a mandatory role controlling the release of BDNF from activated microglia, as well as the autocrine/paracrine proliferative role of BDNF. PMID:23363775

  15. NMDA-mediated and self-induced bdnf exon IV transcriptions are differentially regulated in cultured cortical neurons.

    PubMed

    Zheng, Fei; Wang, Hongbing

    2009-01-01

    Activity-dependent transcriptional up-regulation of bdnf (brain-derived neurotrophic factor) is involved in regulating many aspects of neuronal functions. The NMDA (N-methyl-D-aspartic acid)-mediated and BDNF-mediated exon IV transcription may represent mechanistically different responses, and relevant to activity-dependent changes in neurons. We found that the activities of ERK (extracellular signal regulated kinase), CaM KII/IV (calmodulin-dependent protein kinase II and IV), PI3K (phosphoinositide 3-kinase), and PLC (phospholipase C) are required for NMDA receptor-mediated bdnf exon IV transcription in cultured cortical neurons. In contrast, the BDNF-induced and TrkB-dependent exon IV transcription was regulated by ERK and CaM KII/IV, but not by PI3K and PLC. While ERK and CaM KII/IV are separate signaling pathways in BDNF-stimulated neurons, CaM KII/IV appeared to regulate exon IV transcription through ERK in NMDA-stimulated neurons. Similarly, the PI3K and PLC signaling pathways converged on ERK in NMDA- but not BDNF-stimulated neurons. Our results implicate that the NMDA-induced and the self-maintenance of bdnf transcription are differentially regulated.

  16. 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

  17. 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

  18. Stimulation of Synthesis and Release of Brain-Derived Neurotropic Factor (BDNF) from Intestinal Smooth Muscle Cells by Substance P and Pituitary Adenylate Cyclase-Activating Peptide (PACAP)

    PubMed Central

    Al-Qudah, M.; Alkahtani, R.; Akbarali, H.I.; Murthy, K.S.; Grider, J.R.

    2015-01-01

    Background Brain-derived neurotrophic factor (BDNF) is a neurotrophin present in the intestine where it participates in survival and growth of enteric neurons, augmentation of enteric circuits, and stimulation of intestinal peristalsis and propulsion. Previous studies largely focused on the role of neural and mucosal BDNF. The expression and release of BDNF from intestinal smooth muscle and the interaction with enteric neuropeptides has not been studied in gut. Methods The expression and secretion of BDNF from smooth muscle cultured from rabbit longitudinal intestinal muscle in response to substance P and pituitary adenylate cyclase activating peptide (PACAP) was measured by western blot and ELISA. BDNF mRNA was measured by rt-PCR. Key Results The expression of BNDF protein and mRNA was greater in smooth muscle cells from the longitudinal muscle than from circular muscle layer. PACAP and substance P increased the expression of BDNF protein and mRNA in cultured longitudinal smooth muscle cells. PACAP and substance P also stimulated the secretion of BDNF from cultured longitudinal smooth muscle cells. Chelation of intracellular calcium with BAPTA prevented substance P-induced increase in BDNF mRNA and protein expression as well as substance P-induced secretion of BDNF. Conclusions & Inferences Neuropeptides known to be present in enteric neurons innervating the longitudinal layer increase the expression of BDNF mRNA and protein in smooth muscle cells and stimulate the release of BDNF. Considering the ability of BDNF to enhance smooth muscle contraction, this autocrine loop may partially explain the characteristic hypercontractility of longitudinal muscle in inflammatory bowel disease. PMID:26088546

  19. Cleavage of proBDNF to BDNF by a tolloid-like metalloproteinase is required for acquisition of in vitro eyeblink classical conditioning.

    PubMed

    Keifer, Joyce; Sabirzhanov, Boris E; Zheng, Zhaoqing; Li, Wei; Clark, Timothy G

    2009-11-25

    The tolloid/bone morphogenetic protein-1 family of metalloproteinases have an important role in the regulation of embryonic pattern formation and tissue morphogenesis. Studies suggest that they participate in mechanisms of synaptic plasticity in adults, but very little is known about their function. Recently, we isolated a reptilian ortholog of the tolloid gene family designated turtle tolloid-like gene (tTll). Here, we examined the role of tTLL in an in vitro model of eyeblink classical conditioning using an isolated brainstem preparation to assess its role in synaptic plasticity during conditioning. Analysis by real-time reverse transcription-PCR shows that an extracellularly secreted form of tTLL, tTLLs, is transiently expressed in the early stages of conditioning during conditioned response acquisition, whereas a cytosolic form, tTLLc, is not. Short interfering RNA (siRNA)-directed gene knockdown and rescue of tTLL expression demonstrate that it is required for conditioning. Significantly, we show that tTLLs cleaves the precursor proBDNF into mature BDNF in cleavage assay studies, and application of recombinant tTLLs protein alone to preparations results in induction of mature BDNF expression. The mature form of BDNF is minimally expressed in preparations treated with anti-tTLL siRNA, and the synaptic incorporation of both GluR1- and GluR4-containing AMPA receptors is significantly reduced, resulting in suppression of conditioning. This is the first study to demonstrate that expression of an extracellularly secreted tolloid-like metalloproteinase is regulated in the early stages of classical conditioning and functions in the conversion of proBDNF to mature BDNF. The mature form of BDNF is required for synaptic delivery of AMPA receptors and acquisition of conditioned responses.

  20. CLEAVAGE OF proBDNF TO BDNF BY A TOLLOID-LIKE METALLOPROTEINASE (tTLL) IS REQUIRED FOR ACQUISITION OF IN VITRO EYEBLINK CLASSICAL CONDITIONING

    PubMed Central

    Keifer, Joyce; Sabirzhanov, Boris E.; Zheng, Zhaoqing; Li, Wei; Clark, Timothy G.

    2010-01-01

    The tolloid/bone morphogenetic protein-1 (BMP-1) family of metalloproteinases have an important role in the regulation of embryonic pattern formation and tissue morphogenesis. Studies suggest they participate in mechanisms of synaptic plasticity in adults, but very little is known about their function. Recently, we isolated a reptilian orthologue of the tolloid gene family designated turtle tolloid-like gene (tTll). Here, we examined the role of tTLL in an in vitro model of eyeblink classical conditioning using an isolated brain stem preparation to assess its role in synaptic plasticity during conditioning. Analysis by real-time RT-PCR shows that an extracellularly secreted form of tTLL, tTLLs, is transiently expressed in the early stages of conditioning during CR acquisition while a cytosolic form, tTLLc, is not. siRNA-directed gene knockdown and rescue of tTLL expression demonstrate that it is required for conditioning. Significantly, we show that tTLLs cleaves the precursor proBDNF into mature BDNF in cleavage assay studies and application of recombinant tTLLs protein alone to preparations results in induction of mature BDNF expression. The mature form of BDNF is minimally expressed in preparations treated with anti-tTLL siRNA, and the synaptic incorporation of both GluR1- and GluR4-containing AMPARs is significantly reduced resulting in suppression of conditioning. This is the first study to demonstrate that expression of an extracellularly secreted tolloid-like metalloproteinase is regulated in the early stages of classical conditioning and functions in the conversion of proBDNF to mature BDNF. The mature form of BDNF is required for synaptic delivery of AMPARs and acquisition of conditioned responses. PMID:19940191

  1. Brain-derived neurotrophic factor in arterial baroreceptor pathways: implications for activity-dependent plasticity at baroafferent synapses.

    PubMed

    Martin, Jessica L; Jenkins, Victoria K; Hsieh, Hui-ya; Balkowiec, Agnieszka

    2009-01-01

    Functional characteristics of the arterial baroreceptor reflex change throughout ontogenesis, including perinatal adjustments of the reflex gain and adult resetting during hypertension. However, the cellular mechanisms that underlie these functional changes are not completely understood. Here, we provide evidence that brain-derived neurotrophic factor (BDNF), a neurotrophin with a well-established role in activity-dependent neuronal plasticity, is abundantly expressed in vivo by a large subset of developing and adult rat baroreceptor afferents. Immunoreactivity to BDNF is present in the cell bodies of baroafferent neurons in the nodose ganglion, their central projections in the solitary tract, and terminal-like structures in the lower brainstem nucleus tractus solitarius. Using ELISA in situ combined with electrical field stimulation, we show that native BDNF is released from cultured newborn nodose ganglion neurons in response to patterns that mimic the in vivo activity of baroreceptor afferents. In particular, high-frequency bursting patterns of baroreceptor firing, which are known to evoke plastic changes at baroreceptor synapses, are significantly more effective at releasing BDNF than tonic patterns of the same average frequency. Together, our study indicates that BDNF expressed by first-order baroreceptor neurons is a likely mediator of both developmental and post-developmental modifications at first-order synapses in arterial baroreceptor pathways.

  2. 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

  3. Sex Steroids Influence Brain-Derived Neurotropic Factor Secretion From Human Airway Smooth Muscle Cells.

    PubMed

    Wang, Sheng-Yu; Freeman, Michelle R; Sathish, Venkatachalem; Thompson, Michael A; Pabelick, Christina M; Prakash, Y S

    2016-07-01

    Brain derived neurotropic factor (BDNF) is emerging as an important player in airway inflammation, remodeling, and hyperreactivity. Separately, there is increasing evidence that sex hormones contribute to pathophysiology in the lung. BDNF and sex steroid signaling are thought to be intricately linked in the brain. There is currently little information on BDNF and sex steroid interactions in the airway but is relevant to understanding growth factor signaling in the context of asthma in men versus women. In this study, we assessed the effect of sex steroids on BDNF expression and secretion in human airway smooth muscle (ASM). Human ASM was treated with estrogen (E2 ) or testosterone (T, 10 nM each) and intracellular BDNF and secreted BDNF measured. E2 and T significantly reduced secretion of BDNF; effects prevented by estrogen and androgen receptor inhibitor, ICI 182,780 (1 μM), and flutamide (10 μM), respectively. Interestingly, no significant changes were observed in intracellular BDNF mRNA or protein expression. High affinity BDNF receptor, TrkB, was not altered by E2 or T. E2 (but not T) significantly increased intracellular cyclic AMP levels. Notably, Epac1 and Epac2 expression were significantly reduced by E2 and T. Furthermore, SNARE complex protein SNAP25 was decreased. Overall, these novel data suggest that physiologically relevant concentrations of E2 or T inhibit BDNF secretion in human ASM, suggesting a potential interaction of sex steroids with BDNF in the airway that is different from brain. The relevance of sex steroid-BDNF interactions may lie in their overall contribution to airway diseases such as asthma. PMID:26566264

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

    PubMed Central

    Ambigapathy, Ganesh; Zheng, Zhaoqing; Keifer, Joyce

    2015-01-01

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

  5. SNAREs controlling vesicular release of BDNF and development of callosal axons

    PubMed Central

    Shimojo, Masafumi; Courchet, Julien; Pieraut, Simon; Torabi-Rander, Nina; Sando, Richard; Polleux, Franck; Maximov, Anton

    2015-01-01

    SUMMARY At presynaptic active zones, exocytosis of neurotransmitter vesicles (SVs) is driven by SNARE complexes that recruit Syb2 and SNAP25. However, it remains unknown which SNAREs promote the secretion of neuronal proteins, including those essential for circuit development and experience-dependent plasticity. Here, we demonstrate that Syb2 and SNAP25 mediate the vesicular release of BDNF in axons and dendrites of cortical neurons, suggesting these SNAREs act in multiple spatially-segregated secretory pathways. Remarkably, axonal secretion of BDNF is also strongly regulated by SNAP47 which interacts with SNAP25 but appears to be dispensable for exocytosis of SVs. Cell-autonomous ablation of SNAP47 disrupts the layer-specific branching of callosal axons of projection cortical neurons in vivo, and this phenotype is recapitulated by ablation of BDNF or its receptor, TrkB. Our results provide insights into the molecular mechanisms of protein secretion and define the functions of SNAREs in BDNF signaling and regulation of neuronal connectivity. PMID:25959820

  6. 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

  7. Spatiotemporal resolution of BDNF neuroprotection against glutamate excitotoxicity in cultured hippocampal neurons.

    PubMed

    Melo, C V; Okumoto, S; Gomes, J R; Baptista, M S; Bahr, B A; Frommer, W B; Duarte, C B

    2013-05-01

    Brain-derived neurotrophic factor (BDNF) protects hippocampal neurons from glutamate excitotoxicity as determined by analysis of chromatin condensation, through activation of extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3-K) signaling pathways. However, it is still unknown whether BDNF also prevents the degeneration of axons and dendrites, and the functional demise of synapses, which would be required to preserve neuronal activity. Herein, we have studied the time-dependent changes in several neurobiological markers, and the regulation of proteolytic mechanisms in cultured rat hippocampal neurons, through quantitative western blot and immunocytochemistry. Calpain activation peaked immediately after the neurodegenerative input, followed by a transient increase in ubiquitin-conjugated proteins and increased abundance of cleaved-caspase-3. Proteasome and calpain inhibition did not reproduce the protective effect of BDNF and caspase inhibition in preventing chromatin condensation. However, proteasome and calpain inhibition did protect the neuronal markers for dendrites (MAP-2), axons (Neurofilament-H) and the vesicular glutamate transporters (VGLUT1-2), whereas caspase inhibition was unable to mimic the protective effect of BDNF on neurites and synaptic markers. BDNF partially prevented the downregulation of synaptic activity measured by the KCl-evoked glutamate release using a Förster (Fluorescence) resonance energy transfer (FRET) glutamate nanosensor. These results translate a time-dependent activation of proteases and spatial segregation of these mechanisms, where calpain activation is followed by proteasome deregulation, from neuronal processes to the soma, and finally by caspase activation in the cell body. Moreover, PI3-K and PLCγ small molecule inhibitors significantly blocked the protective action of BDNF, suggesting an activity-dependent mechanism of neuroprotection. Ultimately, we hypothesize that neuronal repair after a

  8. Activity dependent CAM cleavage and neurotransmission

    PubMed Central

    Conant, Katherine; Allen, Megan; Lim, Seung T.

    2015-01-01

    Spatially localized proteolysis represents an elegant means by which neuronal activity dependent changes in synaptic structure, and thus experience dependent learning and memory, can be achieved. In vitro and in vivo studies suggest that matrix metalloproteinase and adamalysin activity is concentrated at the cell surface, and emerging evidence suggests that increased peri-synaptic expression, release and/or activation of these proteinases occurs with enhanced excitatory neurotransmission. Synaptically expressed cell adhesion molecules (CAMs) could therefore represent important targets for neuronal activity-dependent proteolysis. Several CAM subtypes are expressed at the synapse, and their cleavage can influence the efficacy of synaptic transmission through a variety of non-mutually exclusive mechanisms. In the following review, we discuss mechanisms that regulate neuronal activity-dependent synaptic CAM shedding, including those that may be calcium dependent. We also highlight CAM targets of activity-dependent proteolysis including neuroligin and intercellular adhesion molecule-5 (ICAM-5). We include discussion focused on potential consequences of synaptic CAM shedding, with an emphasis on interactions between soluble CAM cleavage products and specific pre- and post-synaptic receptors. PMID:26321910

  9. 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…

  10. 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.

  11. Ebbinghaus revisited: influences of the BDNF Val66Met polymorphism on backward serial recall are modulated by human aging.

    PubMed

    Li, Shu-Chen; Chicherio, Christian; Nyberg, Lars; von Oertzen, Timo; Nagel, Irene E; Papenberg, Goran; Sander, Thomas; Heekeren, Hauke R; Lindenberger, Ulman; Bäckman, Lars

    2010-10-01

    The brain-derived neurotrophic factor (BDNF) plays an important role in activity-dependent synaptic plasticity, which underlies learning and memory. In a sample of 948 younger and older adults, we investigated whether a common Val66Met missense polymorphism (rs6265) in the BDNF gene affects the serial position curve--a fundamental phenomenon of associative memory identified by Hermann Ebbinghaus more than a century ago. We found a BDNF polymorphism effect for backward recall in older adults only, with Met-allele carriers (i.e., individuals with reduced BDNF signaling) recalling fewer items than Val homozygotes. This effect was specific to the primacy and middle portions of the serial position curve, where intralist interference and associative demands are especially high. The poorer performance of older Met-allele carriers reflected transposition errors, whereas no genetic effect was found for omissions. These findings indicate that effects of the BDNF polymorphism on episodic memory are most likely to be observed when the associative and executive demands are high. Furthermore, the findings are in line with the hypothesis that the magnitude of genetic effects on cognition is greater when brain resources are reduced, as is the case in old age.

  12. Ebbinghaus revisited: influences of the BDNF Val66Met polymorphism on backward serial recall are modulated by human aging.

    PubMed

    Li, Shu-Chen; Chicherio, Christian; Nyberg, Lars; von Oertzen, Timo; Nagel, Irene E; Papenberg, Goran; Sander, Thomas; Heekeren, Hauke R; Lindenberger, Ulman; Bäckman, Lars

    2010-10-01

    The brain-derived neurotrophic factor (BDNF) plays an important role in activity-dependent synaptic plasticity, which underlies learning and memory. In a sample of 948 younger and older adults, we investigated whether a common Val66Met missense polymorphism (rs6265) in the BDNF gene affects the serial position curve--a fundamental phenomenon of associative memory identified by Hermann Ebbinghaus more than a century ago. We found a BDNF polymorphism effect for backward recall in older adults only, with Met-allele carriers (i.e., individuals with reduced BDNF signaling) recalling fewer items than Val homozygotes. This effect was specific to the primacy and middle portions of the serial position curve, where intralist interference and associative demands are especially high. The poorer performance of older Met-allele carriers reflected transposition errors, whereas no genetic effect was found for omissions. These findings indicate that effects of the BDNF polymorphism on episodic memory are most likely to be observed when the associative and executive demands are high. Furthermore, the findings are in line with the hypothesis that the magnitude of genetic effects on cognition is greater when brain resources are reduced, as is the case in old age. PMID:19925205

  13. New insight in expression, transport, and secretion of brain-derived neurotrophic factor: Implications in brain-related diseases

    PubMed Central

    Adachi, Naoki; Numakawa, Tadahiro; Richards, Misty; Nakajima, Shingo; Kunugi, Hiroshi

    2014-01-01

    Brain-derived neurotrophic factor (BDNF) attracts increasing attention from both research and clinical fields because of its important functions in the central nervous system. An adequate amount of BDNF is critical to develop and maintain normal neuronal circuits in the brain. Given that loss of BDNF function has been reported in the brains of patients with neurodegenerative or psychiatric diseases, understanding basic properties of BDNF and associated intracellular processes is imperative. In this review, we revisit the gene structure, transcription, translation, transport and secretion mechanisms of BDNF. We also introduce implications of BDNF in several brain-related diseases including Alzheimer’s disease, Huntington’s disease, depression and schizophrenia. PMID:25426265

  14. 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

  15. Comparing brain-derived neurotrophic factor and ciliary neurotrophic factor secretion of induced neurotrophic factor secreting cells from human adipose and bone marrow-derived stem cells.

    PubMed

    Razavi, Shahnaz; Razavi, Mohamad Reza; Zarkesh Esfahani, Hamid; Kazemi, Mohammad; Mostafavi, Fatemeh Sadat

    2013-08-01

    Adipose derived stem cells (ADSCs) and bone marrow stem cells (BMSCs) may be equally beneficial in treating neurodegenerative diseases. However, ADSCs have practical advantages. In this study, we aimed to induce neurotrophic factors secreting cells in human ADSCs. Then, we compared the level of brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) secretion in neurotrophic factors secreting cells from human adipose and bone marrow-derived stem cells. Isolated human ADSCs and BMSCs were induced to neurotrophic factor (NTF)-secreting cells. The levels of expression and secretion of BDNF and CTNF of induced cells were assessed using immunocytochemical, Real-Time polymerase chain reaction, and enzyme linked immunosorbent assay (ELISA). The level of BDNF significantly increased in both the induced mesenchymal stem cells (MSCs) relative to ADSCs and the BMSCs (P < 0.01). Moreover, ELISA analysis showed that the release of BDNF in the induced BMSCs was almost twofold more than the induced ADSCs. Overall, NTF-secreting factor cells derived BMSCs and ADSCs could secret a range of different growth factors. Therefore, the variation in neurotrophic factors of different induced MSC populations suggest the possible beneficial effect of each specific kind of neurotrophic factor secreting cells for the treatment of a particular neurodegenerative disease. PMID:23944834

  16. 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...

  17. 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

  18. Enhanced BDNF signalling following chronic hypoxia potentiates catecholamine release from cultured rat adrenal chromaffin cells

    PubMed Central

    Scott, Angela L; Zhang, Min; Nurse, Colin A

    2015-01-01

    Environmental stressors, including chronic hypoxia, enhance the ability of adrenomedullary chromaffin cells (AMCs) to secrete catecholamines; however, the underlying molecular mechanisms remain unclear. Here, we investigated the role of brain-derived neurotrophic factor (BDNF) signalling in rat AMCs exposed to chronic hypoxia. In rat adrenal glands, BDNF and its tropomyosin-related kinase B (TrkB) receptor are highly expressed in the cortex and medulla, respectively. Exposure of AMCs to chronic hypoxia (2% O2; 48 h) in vitro caused a significant increase to TrkB mRNA expression. A similar increase was observed in an immortalized chromaffin cell line (MAH cells); however, it was absent in MAH cells deficient in the transcription factor HIF-2α. A specific TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF), stimulated quantal catecholamine secretion from chronically hypoxic (CHox; 2% O2) AMCs to a greater extent than normoxic (Nox; 21% O2) controls. Activation of TrkB by BDNF or 7,8-DHF increased intracellular Ca2+ ([Ca2+]i), an effect that was significantly larger in CHox cells. The 7,8-DHF-induced [Ca2+]i rise was sensitive to the tyrosine kinase inhibitor K252a and nickel (2 mm), but not the Ca2+ store-depleting agent cyclopiazonic acid. Blockade of T-type calcium channels with TTA-P2 (1 μm) or voltage-gated Na+ channels with TTX inhibited BDNF-induced [Ca2+]i increases. BDNF also induced a dose-dependent enhancement of action potential firing in CHox cells. These data demonstrate that during chronic hypoxia, enhancement of BDNF-TrkB signalling increases voltage-dependent Ca2+ influx and catecholamine secretion in chromaffin cells, and that T-type Ca2+ channels play a key role in the signalling pathway. Key points We investigated the role of the neurotrophin BDNF signalling via the TrkB receptor in rat adrenomedullary chromaffin cells (AMCs) exposed to normoxia (Nox; 21% O2) and chronic hypoxia (CHox; 2% O2) in vitro for ∼48 h. TrkB receptor expression was

  19. 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.

  20. Progressive loss of BDNF in a mouse model of Huntington's disease and rescue by BDNF delivery.

    PubMed

    Zuccato, Chiara; Liber, Daniel; Ramos, Catarina; Tarditi, Alessia; Rigamonti, Dorotea; Tartari, Marzia; Valenza, Marta; Cattaneo, Elena

    2005-08-01

    Huntingtin is a protein of 348 kDa that is mutated in Huntington's disease (HD), a dominantly inherited neurodegenerative disorder. Previous data have led us to propose that aspects of the disease arise from both a loss of the neuroprotective function of the wild-type protein, and a toxic activity gained by the mutant protein. In particular, we have shown that wild-type huntingtin stimulates the production of brain-derived neurotrophic factor (BDNF), a pro-survival factor for the striatal neurons that die in the pathology. Wild-type huntingtin controls BDNF gene transcription in cerebral cortex, which is then delivered to its striatal targets. In the disease state, supply of cortical BDNF to the striatum is strongly reduced, possibly leading to striatal vulnerability. Here we show that a reduction in cortical BDNF messenger level correlates with the progression of the disease in a mouse model of HD. In particular, we show that the progressive loss of mRNAs transcribed from BDNF exon II, III and IV follows a different pattern that may reflect different upstream mechanisms impaired by mutation in huntingtin. On this basis, we also discuss the possibility that delivery of BDNF may represent an useful strategy for Huntington's disease treatment. PMID:15967378

  1. Hippocampal--prefrontal BDNF and memory for fear extinction.

    PubMed

    Rosas-Vidal, Luis E; Do-Monte, Fabricio H; Sotres-Bayon, Francisco; Quirk, Gregory J

    2014-08-01

    Infusing brain-derived neurotrophic factor (BDNF) into the infralimbic (IL) prefrontal cortex is capable of inducing extinction. Little is known, however, about the circuits mediating BDNF effects on extinction or the extent to which extinction requires BDNF in IL. Using local pharmacological infusion of BDNF protein, or an antibody against BDNF, we found that BDNF in the IL, but not prelimbic (PL) prefrontal cortex, is both necessary and sufficient for fear extinction. Furthermore, we report that BDNF in IL can induce extinction of older fear memories (14 days) as well as recent fear memories (1 day). Using immunocytochemistry, we show that BDNF is increased in the ventral hippocampus (vHPC), but not IL or PL, following extinction training. Finally, we observed that infusing BDNF into the vHPC increased the firing rate of IL, but not PL neurons in fear conditioned rats. These findings indicate that an extinction-induced increase in BDNF within the vHPC enhances excitability in IL targets, thereby supporting extinction memories.

  2. BDNF Pretreatment of Human Embryonic-Derived Neural Stem Cells Improves Cell Survival and Functional Recovery After Transplantation in Hypoxic-Ischemic Stroke.

    PubMed

    Rosenblum, Sahar; Smith, Tenille N; Wang, Nancy; Chua, Joshua Y; Westbroek, Erick; Wang, Kendrick; Guzman, Raphael

    2015-01-01

    Intra-arterial neural stem cell (NSC) therapy has the potential to improve long-term outcomes after stroke. Here we evaluate if pretreatment of NSCs with brain-derived neurotrophic factor (BDNF) prior to transplantation improves cell engraftment and functional recovery following hypoxic-ischemic (HI) stroke. Human embryonic-derived NSCs with or without BDNF pretreatment (1 h, 100 ng/ml) were transplanted 3 days after HI stroke. Functional recovery was assessed using the horizontal ladder test. Cell engraftment was evaluated using bioluminescence imaging (BLI) and histological counts of SC121(+) cells. Fluoro-Jade C (FJC) and NeuN stains were used to evaluate neuroprotection. The effect of BDNF on NSCs was analyzed using a migration assay, immunocytochemistry, Luminex proteomic assay, and RT-qPCR.BLI analysis demonstrated significantly higher photon flux in the BDNF-treated NSC group compared to untreated NSC (p = 0.049) and control groups (p = 0.0021) at 1 week after transplantation. Immunohistochemistry confirmed increased transplanted cell survival in the cortex (p = 0.0126) and hippocampus (p = 0.0098) of animals injected with BDNF-treated NSCs compared to untreated NSCs. Behavioral testing revealed that the BDNF-treated NSC group demonstrated increased sensorimotor recovery compared to the untreated NSC and control groups (p < 0.001) over the 1-month period (p < 0.001) following transplantation. A significant improvement in performance was found in the BDNF-treated NSC group compared to the control group at 14, 21, and 28 (p < 0.05) days after transplantation. The cortex and hippocampus of the BDNF-treated NSC group had significantly more SC121(+) NSCs (p = 0.0125, p = 0.0098), fewer FJC(+) neurons (p = 0.0370, p = 0.0285), and a higher percentage of NeuN(+) expression (p = 0.0354) in the cortex compared to the untreated NSC group. BDNF treatment of NSCs resulted in significantly greater migration to SDF-1, secretion of M-CSF, VEGF, and expression of CXCR4

  3. 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

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

    PubMed

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

    2015-04-01

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

  5. Role for Endogenous BDNF in Endocannabinoid-Mediated Long-Term Depression at Neocortical Inhibitory Synapses1,2,3

    PubMed Central

    Zhao, Liangfang; Li-Wen Yeh, Mason

    2015-01-01

    Abstract The endogenous cannabinoid (endocannabinoid) system is an important regulator of synaptic function. Endocannabinoids acutely modulate inhibitory and excitatory transmission, and also mediate long-term depression at GABAergic and glutamatergic synapses. Typically, endocannabinoid synthesis and release is stimulated by depolarization-induced calcium influx and/or activation of phospholipase-C (PLC) signaling triggered by mGluR activation. Recently it has been shown that brain-derived neurotrophic factor (BDNF) can also induce endocannabinoid release. Although there is growing evidence for cross-talk between BDNF and endocannabinoid signaling, little is known about the functional relevance of these interactions. In the present studies, we examined BDNF−endocannabinoid interactions in regulating activity-dependent long-term depression at inhibitory synapses (iLTD). We found that theta burst stimulation (TBS) in layer 2/3 of mouse somatosensory cortical slices can induce a form of endocannabinoid-mediated iLTD that is independent of metabotropic glutamate receptor (mGluR) activation. This endocannabinoid-dependent iLTD, however, requires endogenous BDNF-trkB signaling, as it is blocked by a trk tyrosine kinase inhibitor and by a trkB receptor antagonist, and also requires activation of diacylglycerol lipase (DAG-lipase, DGL). In addition, endocannabinoid-mediated iLTD can be induced by combining a subthreshold concentration of exogenous BDNF with weak TBS stimulation that by itself is insufficient to induce iLTD. Taken together, our results suggest that TBS can induce the release of endogenous BDNF, which triggers DGL-dependent endocannabinoid mobilization and cannabinoid receptor-dependent iLTD at layer 2/3 cortical synapses. PMID:25938134

  6. 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

  7. 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

  8. Impaired reelin processing and secretion by Cajal-Retzius cells contributes to granule cell dispersion in a mouse model of temporal lobe epilepsy.

    PubMed

    Duveau, Venceslas; Madhusudan, Amrita; Caleo, Matteo; Knuesel, Irene; Fritschy, Jean-Marc

    2011-09-01

    Cajal-Retzius cells play a crucial role during ontogeny in regulating cortical lamination via release of reelin. In adult brain, they comprise small calretinin-positive interneurons located in the marginal zone of the cerebral cortex and in the hippocampal fissure. Alterations of reelin signaling or expression have been involved in major neurological disorders, and they underlie granule cell dispersion (GCD) in mesial temporal lobe epilepsy (TLE). Here, we investigated in a mouse model of TLE the contribution of Cajal-Retzius cells to reelin production in epileptic hippocampus and the molecular mechanisms underlying GCD. Following unilateral intrahippocampal Kainic acid injection in adult mice to induce an epileptic focus, we observed that Cajal-Retzius cells gradually became strongly immunopositive for reelin, due to intracellular accumulation. This phenotype resembled the morphology of Cajal-Retzius cells in reeler Orleans (reln (orl/orl) ) mice, which express a secretion-deficient 310-kDa reelin fragment. The possibility that GCD might result from abnormal reelin processing in Cajal-Retzius cells, leading to a lack of reelin secretion, was confirmed by KA injection in reln (orl/+) mice, which induced severe GCD. Furthermore, Western blot analysis in KA-treated wildtype mice revealed increased production of ∼300-kDa reelin fragments, confirming abnormal proteolytic processing. This effect was not seen upon treatment with Botulinum neurotoxin E (BoNT/E), which prevents GCD in KA-lesioned hippocampus by chronic blockade of synaptic transmission. Furthermore, BoNT/E blocked upregulation of TrkB in Cajal-Retzius cells, suggesting that production of truncated reelin in KA-treated hippocampus is activity-dependent and regulated by BDNF. Altogether, these data reveal that GCD results from abnormal reelin processing in Cajal-Retzius cells under the control of BDNF. Our findings highlight the critical role played by Cajal-Retzius cells for hippocampal neuronal

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

    PubMed

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

    2014-05-15

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

  10. The activity-dependent transcription factor NPAS4 regulates domain-specific inhibition

    PubMed Central

    Bloodgood, Brenda L.; Sharma, Nikhil; Browne, Heidi Adlman; Trepman, Alissa Z.; Greenberg, Michael E.

    2014-01-01

    A heterogeneous population of inhibitory neurons controls the flow of information through a neural circuit1–3. Inhibitory synapses that form on pyramidal neuron dendrites modulate the summation of excitatory synaptic potentials4–6 and prevent the generation of dendritic calcium spikes7,8. Precisely timed somatic inhibition limits both the number of action potentials and the time window during which firing can occur8,9. The activity-dependent transcription factor NPAS4 regulates inhibitory synapse number and function in cell culture10, but how this transcription factor affects the inhibitory inputs that form on distinct domains of a neuron in vivo was unclear. Here we show that in the mouse hippocampus behaviourally driven expression of NPAS4 coordinates the redistribution of inhibitory synapses made onto a CA1 pyramidal neuron, simultaneously increasing inhibitory synapse number on the cell body while decreasing the number of inhibitory synapses on the apical dendrites. This rearrangement of inhibition is mediated in part by the NPAS4 target gene brain derived neurotrophic factor (Bdnf), which specifically regulates somatic, and not dendritic, inhibition. These findings indicate that sensory stimuli, by inducing NPAS4 and its target genes, differentially control spatial features of neuronal inhibition in a way that restricts the output of the neuron while creating a dendritic environment that is permissive for plasticity. PMID:24201284

  11. Toward a unified biological hypothesis for the BDNF Val66Met-associated memory deficits in humans: a model of impaired dendritic mRNA trafficking

    PubMed Central

    Baj, Gabriele; Carlino, Davide; Gardossi, Lucia; Tongiorgi, Enrico

    2013-01-01

    Brain-derived neurotrophic factor (BDNF) represents promotesa key molecule for the survival and differentiation of specific populations of neurons in the central nervous system. BDNF also regulates plasticity-related processes underlying memory and learning. A common single nucleotide polymorphism (SNP) rs6265 has been identified on the coding sequence of human BDNF located at 11p13. The SNP rs6265 is a single base mutation with an adenine instead of a guanine at position 196 (G196A), resulting in the amino acid substitution Val66Met. This polymorphism only exists in humans and has been associated with a plethora of effects ranging from molecular, cellular and brain structural modifications in association with deficits in social and cognitive functions. To date, the literature on Val66Met polymorphism describes a complex and often conflicting pattern of effects. In this review, we attempt to provide a unifying model of the Val66Met effects. We discuss the clinical evidence of the association between Val66Met and memory deficits, as well as the molecular mechanisms involved including the reduced transport of BDNF mRNA to the dendrites as well as the reduced processing and secretion of BDNF protein through the regulated secretory pathway. PMID:24198753

  12. 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

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

    PubMed Central

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

    2016-01-01

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

  14. 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

  15. 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

  16. Neonatal propofol anesthesia modifies activity-dependent processes and induces transient hyperlocomotor response to d-amphetamine during adolescence in rats.

    PubMed

    Pešić, Vesna; Milanović, Desanka; Popić, Jelena; Smiljanić, Kosara; Tešić, Vesna; Kanazir, Selma; Jevtović-Todorović, Vesna; Ruždijić, Sabera

    2015-12-01

    This study examined the influence of propofol anesthesia on the expression of activity-regulated molecules (BDNF and c-Fos) and synaptic plasticity markers (synaptophysin, GAP-43, drebrin) in the frontal cortex and thalamus of 7-day-old (P7) rats. Although these brain regions are the main targets of anesthetic action, they are contained in the cortico-striato-thalamo-cortical feedback loops, involved in naturally occurring and drug-induced psychoses. Therefore, functional integrity of these loops was examined in adolescent and adult rats through d-amphetamine-induced hyperactivity. Propofol treatment (25mg/kg) decreased exon-specific and total BDNF mRNA expression in the frontal cortex and thalamus, in a time-dependent manner. BDNF protein level was increased in the frontal cortex and decreased in the thalamus, which was accompanied by the change of phospho-TrkB expression. Similarly to BDNF, the expression of c-Fos was decreased in the frontal cortex while it was changed only at the protein level in the thalamus. Synaptic plasticity markers changed in a time- and region-specific manner, indicating increased synaptogenesis in the frontal cortex and synapse elimination in the thalamus in P7 rats after the propofol anesthesia exposure. These early molecular changes were followed by time-related, increased motor reaction to d-amphetamine in adolescent, but not in adult rats. Our study revealed that exposure of immature brain to propofol anesthesia during the critical phase of development provoked immediate changes in activity-dependent processes and synaptic adjustment, influencing brain capacity to integrate later developmental events and resulting in temporary altered response to acute psychotropic stimulation during adolescence.

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

    ERIC Educational Resources Information Center

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

    2011-01-01

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

  18. Acute Administration of Branched-Chain Amino Acids Increases the Pro-BDNF/Total-BDNF Ratio in the Rat Brain.

    PubMed

    Scaini, Giselli; Morais, Meline O S; Furlanetto, Camila B; Kist, Luiza W; Pereira, Talita C B; Schuck, Patrícia F; Ferreira, Gustavo C; Pasquali, Matheus A B; Gelain, Daniel P; Moreira, José Cláudio F; Bogo, Maurício R; Streck, Emilio L

    2015-05-01

    Maple syrup urine disease (MSUD) is caused by an inborn error in metabolism resulting from a deficiency in the branched-chain α-keto acid dehydrogenase complex activity. This blockage leads to accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine and valine, as well as their corresponding α-keto acids and α-hydroxy acids. High levels of BCAAs are associated with neurological dysfunction and the role of pro- and mature brain-derived neurotrophic factor (BDNF) in the neurological dysfunction of MSUD is still unclear. Thus, in the present study we investigated the effect of an acute BCAA pool administration on BDNF levels and on the pro-BDNF cleavage-related proteins S100A10 and tissue plasminogen activator (tPA) in rat brains. Our results demonstrated that acute Hyper-BCAA (H-BCAA) exposure during the early postnatal period increases pro-BDNF and total-BDNF levels in the hippocampus and striatum. Moreover, tPA levels were significantly decreased, without modifications in the tPA transcript levels in the hippocampus and striatum. On the other hand, the S100A10 mRNA and S100A10 protein levels were not changed in the hippocampus and striatum. In the 30-day-old rats, we observed increased pro-BDNF, total-BDNF and tPA levels only in the striatum, whereas the tPA and S100A10 mRNA expression and the immunocontent of S100A10 were not altered. In conclusion, we demonstrated that acute H-BCAA administration increases the pro-BDNF/total-BDNF ratio and decreases the tPA levels in animals, suggesting that the BCAA effect may depend, at least in part, on changes in BDNF post-translational processing. PMID:25681161

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

    PubMed

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

    2011-08-01

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

  20. 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.

  1. Activity-dependent release of transforming growth factor-beta in a neuronal network in vitro.

    PubMed

    Lacmann, A; Hess, D; Gohla, G; Roussa, E; Krieglstein, K

    2007-12-12

    For neurotrophins and also for members of the transforming growth factor beta (TGF-beta) family an activity-dependent regulation of synthesis and release has been proposed. Together with the observation that the secretion of neurotransmitters is initiated by neurotrophic factors, it is reasonable to assume that they might act as retrograde modulators enhancing the efficacy and stabilization of synapses. In the present study, we have tested this hypothesis and studied the release and regulation of TGF-beta in vitro using mouse primary hippocampal neurons at embryonic day E16.5 as model. We show that neuronal activity regulates TGF-beta release and TGF-beta expression in vitro. Treatment of the cultures with KCl, 3-veratroylveracevine (veratridine), glutamate or carbamylcholine chloride (carbachol) increased the levels of secreted TGF-beta, as assessed by the MLEC/plasminogen activator inhibitor (PAI)-luciferase-assay, whereas TGF-beta release stimulated by KCl or veratridine was reduced in the presence of tetrodotoxin or 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). In addition, application of glutamate significantly upregulated expression of TGF-beta2 and TGF-beta3 in the culture. Notably, KCl stimulation caused Smad (composite term from SMA (C. elegans) and MAD=mothers against dpp (Drosophila)) translocation into the nucleus and upregulated TGF-beta inducible early gene (Tieg1) expression, demonstrating that activity-dependent released TGF-beta may exert autocrine actions and thereby activate the TGF-beta-dependent signaling pathway. Together, these results suggest an activity-dependent release and gene transcription of TGF-beta from mouse hippocampal neurons in vitro as well as subsequent autocrine functions of the released TGF-beta within the hippocampal network.

  2. Decreased Plasma BDNF Levels of Patients with Somatization Disorder

    PubMed Central

    Kang, Nam-In; Park, Jong-Il

    2016-01-01

    Objective Brain-derived neurotrophic factor (BDNF), one of the most abundant and important neurotrophins, is known to be involved in the development, survival, maintenance, and plasticity of neurons in the nervous system. Some studies have suggested that BDNF may play a role in the pathophysiology of several psychiatric illnesses such as depression and schizophrenia. Similarly, it is likely that the alteration of BDNF may be associated with the neuro-modulation that contributes to the development of somatization disorder. Methods The purpose of this study was to determine whether there is an abnormality of plasma BDNF levels in patients with somatization disorder, and to analyze the nature of the alteration after pharmacotherapy using an enzyme-linked immunosorbent assay (ELISA). Results The plasma BDNF levels of the patients with a somatization disorder were significantly lower compared with those of the control volunteers (83.61±89.97 pg/mL vs. 771.36±562.14 pg/mL); moreover, the plasma BDNF levels of those patients who received an antidepressant were significantly increased after the treatment (118.13±91.45 pg/mL vs. 72.92±88.21 pg/mL). Conclusion These results suggest that BDNF may play a role in the pathophysiology of somatization disorder. PMID:27757131

  3. Synapse Maturation by Activity-Dependent Ectodomain Shedding of SIRPα

    PubMed Central

    Toth, Anna B.; Terauchi, Akiko; Zhang, Lily Y.; Johnson-Venkatesh, Erin M.; Larsen, David J.; Sutton, Michael A.; Umemori, Hisashi

    2013-01-01

    Formation of appropriate synaptic connections is critical for proper functioning of the brain. After initial synaptic differentiation, active synapses are stabilized by neural activity-dependent signals to establish functional synaptic connections. However, the molecular mechanisms underlying activity-dependent synapse maturation remain to be elucidated. Here we show that activity-dependent ectodomain shedding of SIRPα mediates presynaptic maturation. Two target-derived molecules, FGF22 and SIRPα, sequentially organize the glutamatergic presynaptic terminals during the initial synaptic differentiation and synapse maturation stages, respectively, in the mouse hippocampus. SIRPα drives presynaptic maturation in an activity-dependent fashion. Remarkably, neural activity cleaves the extracellular domain of SIRPα, and the shed ectodomain, in turn, promotes the maturation of the presynaptic terminal. This process involves CaM kinase, matrix metalloproteinases, and the presynaptic receptor CD47. Finally, SIRPα-dependent synapse maturation has significant impacts on synaptic function and plasticity. Thus, ectodomain shedding of SIRPα is an activity-dependent trans-synaptic mechanism for the maturation of functional synapses. PMID:24036914

  4. Nobiletin Ameliorates the Deficits in Hippocampal BDNF, TrkB, and Synapsin I Induced by Chronic Unpredictable Mild Stress.

    PubMed

    Li, Jing; Zhou, Ying; Liu, Bin-Bin; Liu, Qing; Geng, Di; Weng, Lian-Jin; Yi, Li-Tao

    2013-01-01

    Background. Our previous study has demonstrated that nobiletin could reverse the behavioral alterations in stressed mice. However, the relation of its antidepressant-like action with neurotrophic molecular expression remains unknown. This study aimed to explore the antidepressant-like mechanism of nobiletin related to the neurotrophic system in rats exposed to chronic unpredictable mild stress (CUMS). Methods. Depressive-like anhedonia (assessed by sucrose preference) and serum corticosterone secretion were evaluated in the CUMS, followed by brain-derived neurotrophic factor (BDNF), its tropomyosin-related kinase receptor B (TrkB), and the downstream target synapsin I expressions in the hippocampus. Results. Anhedonia, which occurred within week 2, was rapidly ameliorated by nobiletin. While fluoxetine needed additional 2 weeks to improve the anhedonia. In addition, nobiletin administration for 5 weeks significantly ameliorated CUMS-induced increase in serum corticosterone levels. Furthermore, we also found that CUMS-induced deficits of hippocampal BDNF, TrkB, and synapsin I were ameliorated by nobiletin. Conclusions. Taken together, these findings suggest that nobiletin produces rapidly acting antidepressant-like responses in the CUMS and imply that BDNF-TrkB pathway may play an important role in the antidepressant-like effect of nobiletin.

  5. The Physiology of BDNF and Its Relationship with ADHD.

    PubMed

    Liu, De-Yi; Shen, Xue-Mei; Yuan, Fang-Fen; Guo, Ou-Yang; Zhong, Yan; Chen, Jian-Guo; Zhu, Ling-Qiang; Wu, Jing

    2015-12-01

    Brain-derived neurotrophic factor (BDNF) is a major neurotrophin in the central nervous system that plays a critical role in the physiological brain functions via its two independent receptors: tropomyosin-related kinase B (TrkB) and p75, especially in the neurodevelopment. Disrupting of BDNF and its downstream signals has been found in many neuropsychological diseases, including attention-deficit hyperactivity disorder (ADHD), a common mental disorder which is prevalent in childhood. Understanding the physiological functions of BDNF during neural development and its potential relationship with ADHD will help us to elucidate the possible mechanisms of ADHD and to develop therapeutic approaches for this disease. In this review, we summarized the important literatures for the physiological functions of BDNF in the neurodevelopment. We also performed an association study on the functional genetic variation of BDNF and ADHD by a case-control study in the Chinese mainland population and revealed the potential correlation between BDNF and ADHD which needs further research to confirm.

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

    PubMed

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

    2015-04-22

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

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

    PubMed Central

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

    2015-01-01

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

  8. Serum pro-BDNF/BDNF as a treatment biomarker for response to docosahexaenoic acid in traumatized people vulnerable to developing psychological distress: a randomized controlled trial

    PubMed Central

    Matsuoka, Y; Nishi, D; Tanima, Y; Itakura, M; Kojima, M; Hamazaki, K; Noguchi, H; Hamazaki, T

    2015-01-01

    Our open-label pilot study showed that supplementation with docosahexaenoic acid (DHA) increased serum brain-derived neurotrophic factor (BDNF) levels and that there might be an association between changes in serum BDNF levels and reduced psychological distress. Animal research has indicated that a DHA-enriched diet increases BDNF in the brain. In this randomized double-blind controlled trial of severely injured patients vulnerable to posttraumatic stress disorder (PTSD) and depression, we examined whether DHA increases serum BDNF levels and whether changes in BDNF levels are associated with subsequent symptoms of PTSD and depression. Patients received 1470 mg per day of DHA plus 147 mg per day of eicosapentaenoic acid (EPA; n=53) or placebo (n=57) for 12 weeks. Serum levels of mature BDNF and precursor pro-BDNF at baseline and 12-week follow-up were measured using enzyme-linked immunosorbent assay kits. At 12 weeks, we used the Clinician-Administered PTSD Scale to assess PTSD symptoms and depressive symptoms by the Montgomery–Åsberg Depression Rating Scale. We found a significant increase in serum BDNF levels during the trial in the DHA and placebo groups with no interaction between time and group. Changes in BDNF levels were not associated with PTSD severity but negatively associated with depression severity (Spearman's ρ=−0.257, P=0.012). Changes in pro-BDNF were also negatively associated with depression severity (Spearman's ρ=−0.253, P=0.013). We found no specific effects of DHA on increased serum levels of BDNF and pro-BDNF; however, evidence in this study suggests that increased BDNF and pro-BDNF have a protective effect by minimizing depression severity. PMID:26151924

  9. Activity-dependent plasticity of hippocampal place maps

    PubMed Central

    Schoenenberger, Philipp; O'Neill, Joseph; Csicsvari, Jozsef

    2016-01-01

    Hippocampal neurons encode a cognitive map of space. These maps are thought to be updated during learning and in response to changes in the environment through activity-dependent synaptic plasticity. Here we examine how changes in activity influence spatial coding in rats using halorhodopsin-mediated, spatially selective optogenetic silencing. Halorhoposin stimulation leads to light-induced suppression in many place cells and interneurons; some place cells increase their firing through disinhibition, whereas some show no effect. We find that place fields of the unaffected subpopulation remain stable. On the other hand, place fields of suppressed place cells were unstable, showing remapping across sessions before and after optogenetic inhibition. Disinhibited place cells had stable maps but sustained an elevated firing rate. These findings suggest that place representation in the hippocampus is constantly governed by activity-dependent processes, and that disinhibition may provide a mechanism for rate remapping. PMID:27282121

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

    PubMed

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

    2011-03-15

    Brain-derived neurotrophic factor (BDNF) plays a key role in learning and memory, but its effects on the fiber architecture of the living brain are unknown. We genotyped 455 healthy adult twins and their non-twin siblings (188 males/267 females; age: 23.7±2.1 years, mean±SD) and scanned them with high angular resolution diffusion tensor imaging (DTI), to assess how the BDNF Val66Met polymorphism affects white matter microstructure. By applying genetic association analysis to every 3D point in the brain images, we found that the Val-BDNF genetic variant was associated with lower white matter integrity in the splenium of the corpus callosum, left optic radiation, inferior fronto-occipital fasciculus, and superior corona radiata. Normal BDNF variation influenced the association between subjects' performance intellectual ability (as measured by Object Assembly subtest) and fiber integrity (as measured by fractional anisotropy; FA) in the callosal splenium, and pons. BDNF gene may affect the intellectual performance by modulating the white matter development. This combination of genetic association analysis and large-scale diffusion imaging directly relates a specific gene to the fiber microstructure of the living brain and to human intelligence. PMID:21195196

  11. 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

  12. BDNF polymorphisms are associated with schizophrenia onset and positive symptoms.

    PubMed

    Zhang, Xiang Yang; Chen, Da-Chun; Tan, Yun-Long; Tan, Shu-Ping; Luo, Xingguang; Zuo, Lingjun; Soares, Jair C

    2016-01-01

    Numerous studies have showed that brain-derived neurotrophic factor (BDNF) may be involved in the pathogenesis and pathophysiology of schizophrenia. The purposes of this study were to investigate the potential association of BDNF gene polymorphisms with susceptibility to schizophrenia and the psychopathological symptoms in patients with schizophrenia in a Han Chinese population. Four polymorphisms (rs6265, rs12273539, rs10835210 and rs2030324) of the BDNF gene were analyzed in a case-control study of 1887 Han Chinese individuals (844 patients and 1043 controls). We assessed 825 patients for psychopathology using the Positive and Negative Syndrome Scale. In single marker analyses the BDNF rs10835210 mutant A allele was significantly associated with schizophrenia. Haplotype analyses revealed higher frequencies of haplotypes containing the mutant A allele of the rs10835210 in schizophrenia than controls. We also found that this polymorphism rs10835210 was associated with positive symptoms, and the patients carrying the mutational allele A showed more positive symptoms. These findings suggest the role of these BDNF gene variants in both susceptibility to schizophrenia and in clinical symptom severity.

  13. 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

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

    PubMed Central

    Huie, J. Russell

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophic factor family of signaling molecules. Since its discovery over three decades ago, BDNF has been identified as an important regulator of neuronal development, synaptic transmission, and cellular and synaptic plasticity and has been shown to function in the formation and maintenance of certain forms of memory. Neural plasticity that underlies learning and memory in the hippocampus shares distinct characteristics with spinal cord nociceptive plasticity. Research examining the role BDNF plays in spinal nociception and pain overwhelmingly suggests that BDNF promotes pronociceptive effects. BDNF induces synaptic facilitation and engages central sensitization-like mechanisms. Also, peripheral injury-induced neuropathic pain is often accompanied with increased spinal expression of BDNF. Research has extended to examine how spinal cord injury (SCI) influences BDNF plasticity and the effects BDNF has on sensory and motor functions after SCI. Functional recovery and adaptive plasticity after SCI are typically associated with upregulation of BDNF. Although neuropathic pain is a common consequence of SCI, the relation between BDNF and pain after SCI remains elusive. This article reviews recent literature and discusses the diverse actions of BDNF. We also highlight similarities and differences in BDNF-induced nociceptive plasticity in naïve and SCI conditions. PMID:27721996

  15. [The relationship between BDNF gene polymorphisms and alcoholics in Japan].

    PubMed

    Narita, Shin; Nagahori, Kenta; Yoshihara, Eiji; Nishizawa, Daisuke; Ikeda, Kazutaka; Kawai, Atsuko; Iwahashi, Kazuhiko

    2013-12-01

    As a help of the mechanism elucidation of alcoholism, we studied the relationship between brain-derived neurotrophic factor (BDNF) rs6265, 270 C/T (ID number has not yet been determined), and rs10835210 gene polymorphisms, which are reported to be related to bipolar disorder, and alcoholics. We genotyped the three polymorphisms in the BDNF gene using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) in 65 alcoholics and 71 healthy controls. In this study, there was no significant difference in the frequency of rs6265 and 270 C/T polymorphisms between alcoholics and controls (P > 0.05). However, there was a significant difference in the genotype frequency of rs10835210 polymorphism between alcoholics and controls (P < 0.05), in which the CA heterozygote genotype and A allele frequency was higher in alcoholics than in the controls. It suggests the possibility that the BDNF rs10835210 gene polymorphism affects the etiology of alcoholism.

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

    PubMed

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

    2016-02-01

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

  17. A memristor SPICE model accounting for synaptic activity dependence.

    PubMed

    Li, Qingjiang; Serb, Alexander; Prodromakis, Themistoklis; Xu, Hui

    2015-01-01

    In this work, we propose a new memristor SPICE model that accounts for the typical synaptic characteristics that have been previously demonstrated with practical memristive devices. We show that this model could account for both volatile and non-volatile memristance changes under distinct stimuli. We then demonstrate that our model is capable of supporting typical STDP with simple non-overlapping digital pulse pairs. Finally, we investigate the capability of our model to simulate the activity dependence dynamics of synaptic modification and present simulated results that are in excellent agreement with biological results. PMID:25785597

  18. A memristor SPICE model accounting for synaptic activity dependence.

    PubMed

    Li, Qingjiang; Serb, Alexander; Prodromakis, Themistoklis; Xu, Hui

    2015-01-01

    In this work, we propose a new memristor SPICE model that accounts for the typical synaptic characteristics that have been previously demonstrated with practical memristive devices. We show that this model could account for both volatile and non-volatile memristance changes under distinct stimuli. We then demonstrate that our model is capable of supporting typical STDP with simple non-overlapping digital pulse pairs. Finally, we investigate the capability of our model to simulate the activity dependence dynamics of synaptic modification and present simulated results that are in excellent agreement with biological results.

  19. A Memristor SPICE Model Accounting for Synaptic Activity Dependence

    PubMed Central

    Li, Qingjiang; Serb, Alexander; Prodromakis, Themistoklis; Xu, Hui

    2015-01-01

    In this work, we propose a new memristor SPICE model that accounts for the typical synaptic characteristics that have been previously demonstrated with practical memristive devices. We show that this model could account for both volatile and non-volatile memristance changes under distinct stimuli. We then demonstrate that our model is capable of supporting typical STDP with simple non-overlapping digital pulse pairs. Finally, we investigate the capability of our model to simulate the activity dependence dynamics of synaptic modification and present simulated results that are in excellent agreement with biological results. PMID:25785597

  20. 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

  1. MeCP2 is required for activity-dependent refinement of olfactory circuits

    PubMed Central

    Degano, Alicia L.; Park, Min Jung; Penati, Judy; Li, Qun; Ronnett, Gabriele V.

    2014-01-01

    MeCP2 in activity-dependent maturation of olfactory circuitry, with implications for understanding the mechanism of MeCP2 mutations in the development of neural connectivity. PMID:24472844

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

    PubMed

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

    2012-12-01

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

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

    PubMed

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

    2015-10-01

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

  4. 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.

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

    PubMed

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

    2015-09-15

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

  6. Epibranchial placode-derived neurons produce BDNF required for early sensory neuron development.

    PubMed

    Harlow, Danielle E; Yang, Hui; Williams, Trevor; Barlow, Linda A

    2011-02-01

    In mice, BDNF provided by the developing taste epithelium is required for gustatory neuron survival following target innervation. However, we find that expression of BDNF, as detected by BDNF-driven β-galactosidase, begins in the cranial ganglia before its expression in the central (hindbrain) or peripheral (taste papillae) targets of these sensory neurons, and before gustatory ganglion cells innervate either target. To test early BDNF function, we examined the ganglia of bdnf null mice before target innervation, and found that while initial neuron survival is unaltered, early neuron development is disrupted. In addition, fate mapping analysis in mice demonstrates that murine cranial ganglia arise from two embryonic populations, i.e., epibranchial placodes and neural crest, as has been described for these ganglia in non-mammalian vertebrates. Only placodal neurons produce BDNF, however, which indicates that prior to innervation, early ganglionic BDNF produced by placode-derived cells promotes gustatory neuron development.

  7. Brain-derived neurotrophic factor (BDNF) Val(66)Met polymorphism differentially predicts hippocampal function in medication-free patients with schizophrenia.

    PubMed

    Eisenberg, D P; Ianni, A M; Wei, S-M; Kohn, P D; Kolachana, B; Apud, J; Weinberger, D R; Berman, K F

    2013-06-01

    A Val(66)Met single-nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene impairs activity-dependent BDNF release in cultured hippocampal neurons and predicts impaired memory and exaggerated basal hippocampal activity in healthy humans. Several clinical genetic association studies along with multi-modal evidence for hippocampal dysfunction in schizophrenia indirectly suggest a relationship between schizophrenia and genetically determined BDNF function in the hippocampus. To directly test this hypothesized relationship, we studied 47 medication-free patients with schizophrenia or schizoaffective disorder and 74 healthy comparison individuals with genotyping for the Val(66)Met SNP and [(15)O]H(2)O positron emission tomography (PET) to measure resting and working memory-related hippocampal regional cerebral blood flow (rCBF). In patients, harboring a Met allele was associated with significantly less hippocampal rCBF. This finding was opposite to the genotype effect seen in healthy participants, resulting in a significant diagnosis-by-genotype interaction. Exploratory analyses of interregional resting rCBF covariation revealed a specific and significant diagnosis-by-genotype interaction effect on hippocampal-prefrontal coupling. A diagnosis-by-genotype interaction was also found for working memory-related hippocampal rCBF change, which was uniquely attenuated in Met allele-carrying patients. Thus, both task-independent and task-dependent hippocampal neurophysiology accommodates a Met allelic background differently in patients with schizophrenia than in control subjects. Potentially consistent with the hypothesis that cellular sequelae of the BDNF Val(66)Met SNP interface with aspects of schizophrenic hippocampal and frontotemporal dysfunction, these results warrant future investigation to understand the contributions of unique patient trait or state variables to these robust interactions.

  8. Brain-Derived Neurotrophic Factor (BDNF) Val66Met Polymorphism Differentially Predicts Hippocampal Function in Medication-Free Patients with Schizophrenia

    PubMed Central

    Eisenberg, Daniel Paul; Ianni, Angela M.; Wei, Shau-Ming; Kohn, Philip D.; Kolachana, Bhaskar; Apud, José; Weinberger, Daniel R.; Berman, Karen F.

    2012-01-01

    A Val66Met single nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene impairs activity-dependent BDNF release in cultured hippocampal neurons and predicts impaired memory and exaggerated basal hippocampal activity in healthy humans. Several clinical genetic association studies, along with multi-modal evidence for hippocampal dysfunction in schizophrenia indirectly suggest a relationship between schizophrenia and genetically-determined BDNF function in the hippocampus. To directly test this hypothesized relationship, we studied 47 medication-free patients with schizophrenia or schizoaffective disorder and 74 healthy comparison individuals with genotyping for the Val66Met SNP and [15O]H2O positron emission tomography (PET) to measure resting and working memory-related hippocampal regional cerebral blood flow (rCBF). In patients, harboring a Met allele was associated with significantly less hippocampal rCBF. This finding was opposite to the genotype effect seen in healthy participants, resulting in a significant diagnosis-by-genotype interaction. Exploratory analyses of interregional resting rCBF covariation revealed a specific and significant diagnosis-by-genotype interaction effect on hippocampal-prefrontal coupling. A diagnosis-by-genotype interaction was also found for working-memory related hippocampal rCBF change, which was uniquely attenuated in Met allele-carrying patients. Thus, both task-independent and task-dependent hippocampal neurophysiology accommodates a Met allelic background differently in patients with schizophrenia than in control subjects. Potentially consistent with the hypothesis that cellular sequelae of the BDNF Val66Met SNP interface with aspects of schizophrenic hippocampal and frontotemporal dysfunction, these results warrant future investigation to understand the contributions of unique patient trait or state variables to these robust interactions. PMID:23319002

  9. Bilateral Activity-Dependent Interactions in the Developing Corticospinal System

    PubMed Central

    Friel, Kathleen M.; Martin, John H.

    2009-01-01

    Activity-dependent competition between the corticospinal (CS) systems in each hemisphere drives postnatal development of motor skills and stable CS tract connections with contralateral spinal motor circuits. Unilateral restriction of motor cortex (M1) activity during an early postnatal critical period impairs contralateral visually guided movements later in development and in maturity. Silenced M1 develops aberrant connections with the contralateral spinal cord whereas the initially active M1, in the other hemisphere, develops bilateral connections. In this study, we determined whether the aberrant pattern of CS tract terminations and motor impairments produced by early postnatal M1 activity restriction could be abrogated by reducing activity-dependent synaptic competition from the initially active M1 later in development. We first inactivated M1 unilaterally between postnatal weeks 5–7. We next inactivated M1 on the other side from weeks 7–11 (alternate inactivation), to reduce the competitive advantage that this side may have over the initially inactivated side. Alternate inactivation redirected aberrant contralateral CS tract terminations from the initially silenced M1 to their normal spinal territories and reduced the density of aberrant ipsilateral terminations from the initially active side. Normal movement endpoint control during visually guided locomotion was fully restored. This reorganization of CS terminals reveals an unsuspected late plasticity after the critical period for establishing the pattern of CS terminations in the spinal cord. Our findings show that robust bilateral interactions between the developing CS systems on each side are important for achieving balance between contralateral and ipsilateral CS tract connections and visuomotor control. PMID:17928450

  10. 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

  11. 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.

  12. Infanticide secrets

    PubMed Central

    Barr, Jennieffer A.; Beck, Cheryl T.

    2008-01-01

    ABSTRACT OBJECTIVE To explore thoughts of infanticide that did not lead to the act among mothers with postpartum depression. DESIGN A phenomenologic hermeneutic study in which women were invited to share their experiences of having thoughts of infanticide. SETTING Community setting in a large metropolitan city, Brisbane, Australia. PARTICIPANTS Fifteen women who had been diagnosed as clinically depressed with postpartum onset whose babies were 12 months of age or younger. METHOD Audiotaped, in-depth interviews were transcribed verbatim. Thematic analysis commenced immediately after the first interview, and data collection continued until saturation was achieved. A questioning approach that reflected hermeneutics was facilitated by use of journals by the researchers. MAIN FINDINGS Six themes emerged from the data: imagined acts of infanticide, the experience of horror, distorted sense of responsibility, consuming negativity, keeping secrets, and managing the crisis. CONCLUSION Women who experienced nonpsychotic depression preferred not to disclose their thoughts of infanticide to health professionals, including trusted general practitioners or psychiatrists. These women were more likely to mention their suicidal thoughts than their infanticidal thoughts in order to obtain health care. General practitioners and other health professionals should directly ask about whether a woman has been experiencing thoughts of harming herself or her baby, regardless of the reason why she has presented. PMID:19074717

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

    PubMed

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

    2016-01-01

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

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

    PubMed

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

    2016-09-20

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

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

    PubMed Central

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

    2016-01-01

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

  16. Astrocyte-Derived BDNF Supports Myelin Protein Synthesis after Cuprizone-Induced Demyelination

    PubMed Central

    Fulmer, Clifton G.; VonDran, Melissa W.; Stillman, Althea A.; Huang, Yangyang; Hempstead, Barbara L.

    2014-01-01

    It is well established that BDNF may enhance oligodendrocyte differentiation following a demyelinating lesion, however, the endogenous sources of BDNF that may be harnessed to reverse deficits associated with such lesions are poorly defined. Here, we investigate roles of astrocytes in synthesizing and releasing BDNF. These cells are known to express BDNF following injury in vivo. In culture, they increase BDNF synthesis and release in response to glutamate metabotropic stimulation. Following cuprizone-elicited demyelination in mice, astrocytes contain BDNF and increase levels of metabotropic receptors. The metabotropic agonist, trans-(1S,3R)-1-amino-1,3-cyclopentanedicarboxylic acid (ACPD), was therefore injected into the demyelinating lesion. Increases in BDNF, as well as myelin proteins, were observed. Effects of ACPD were eliminated by coinjection of trkB-Fc to locally deplete BDNF and by deletion of astrocyte-derived BDNF. The data indicate that astrocyte-derived BDNF may be a source of trophic support that can be used to reverse deficits elicited following demyelination. PMID:24920623

  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. 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

    2016-07-15

    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.

  19. 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

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

    PubMed

    Cardenas-Aguayo, Maria del Carmen; Kazim, Syed Faraz; Grundke-Iqbal, Inge; Iqbal, Khalid

    2013-01-01

    The level of brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is down regulated in Alzheimer's disease (AD), Parkinson's disease (PD), depression, stress, and anxiety; conversely the level of this neurotrophin is increased in autism spectrum disorders. Thus, modulating the level of BDNF can be a potential therapeutic approach for nervous system pathologies. In the present study, we designed five different tetra peptides (peptides B-1 to B-5) corresponding to different active regions of BDNF. These tetra peptides were found to be non-toxic, and they induced the expression of neuronal markers in mouse embryonic day 18 (E18) primary hippocampal neuronal cultures. Additionally, peptide B-5 induced the expression of BDNF and its receptor, TrkB, suggesting a positive feedback mechanism. The BDNF peptides induced only a moderate activation (phosphorylation at Tyr 706) of the TrkB receptor, which could be blocked by the Trk's inhibitor, K252a. Peptide B-3, when combined with BDNF, potentiated the survival effect of this neurotrophin on H(2)O(2)-treated E18 hippocampal cells. Peptides B-3 and B-5 were found to work as partial agonists and as partial antagonists competing with BDNF to activate the TrkB receptor in a dose-dependent manner. Taken together, these results suggest that the described BDNF tetra peptides are neurotrophic, can modulate BDNF signaling in a partial agonist/antagonist way, and offer a novel therapeutic approach to neural pathologies where BDNF levels are dysregulated. PMID:23320097

  1. 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

  2. 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

  3. Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition.

    PubMed

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

    2004-11-01

    We found that a short exercise period enhanced cognitive function on the Morris water maze (MWM), such that exercised animals were significantly better than sedentary controls at learning and recalling the location of the platform. The finding that exercise increased brain-derived neurotrophic factor (BDNF), a molecule important for synaptic plasticity and learning and memory, impelled us to examine whether a BDNF-mediated mechanism subserves the capacity of exercise to improve hippocampal-dependent learning. A specific immunoadhesin chimera (TrkB-IgG), that mimics the BDNF receptor, TrkB, to selectively bind BDNF molecules, was used to block BDNF in the hippocampus during a 1-week voluntary exercise period. After this, a 2-trial-per-day MWM was performed for 5 consecutive days, succeeded by a probe trial 2 days later. By inhibiting BDNF action we blocked the benefit of exercise on cognitive function, such that the learning and recall abilities of exercising animals receiving the BDNF blocker were reduced to sedentary control levels. Inhibiting BDNF action also blocked the effect of exercise on downstream systems regulated by BDNF and important for synaptic plasticity, cAMP response-element-binding protein (CREB) and synapsin I. Specific to exercise, we found an association between CREB and BDNF expression and cognitive function, such that animals who were the fastest learners and had the best recall showed the highest expression of BDNF and associated CREB mRNA levels. These findings suggest a functional role for CREB under the control of BDNF in mediating the exercise-induced enhancement in learning and memory. Our results indicate that synapsin I might also contribute to this BDNF-mediated mechanism.

  4. Peripheral Blood Leukocyte Production of BDNF following Mitogen Stimulation in Early Onset and Regressive Autism

    PubMed Central

    Enstrom, Amanda; Onore, Charity; Tarver, Angela; Hertz-Picciotto, Irva; Hansen, Robin; Croen, Lisa; Van de Water, Judy; Ashwood, Paul

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) is critical for neuronal differentiation and synaptic development. BDNF is also implicated in the development of psychological disorders including depression, bipolar disorder and schizophrenia. Previously, elevated BDNF levels were observed in neonatal blood samples from infants who were later diagnosed with autism when compared with children who developed normally, suggesting that BDNF may be involved in the development of autism. BDNF is produced by activated brain microglial cells, a cellular phenotype that shares several features with peripheral macrophages, suggesting an important role for the immune system in BDNF production. We hypothesized that under mitogenic stimulation, peripheral blood mononuclear cells obtained from children with autism may have altered BDNF production compared with age-matched typically developing control subjects. In addition, we examined the differences between the production of BDNF in classic/early-onset autism and children who had a regressive form of autism. We show here that plasma levels of BDNF levels are increased in children with autism, especially in early onset autism subjects. Furthermore, under mitogenic stimulation with PHA and LPS, BDNF production is significantly increased in children with autism compared with typically developing subjects. However, stimulation with tetanus toxoid results in a decreased response in children with autism. This data suggest that immune cell-derived production of BDNF could be an important source for the increased BDNF that is detected in some subjects with autism. As a neurotrophic factor produced by immune cells, BDNF could help elucidate the role of the immune system in neurodevelopment and neuronal maintenance, which may be dysregulated in autism.

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

    PubMed

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

    2014-01-17

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

  6. Solar activity dependence of nightside aurora in winter conditions

    NASA Astrophysics Data System (ADS)

    Zhou, Su; Luan, Xiaoli; Dou, Xiankang

    2016-02-01

    The dependence of the nightside (21:00-03:00 MLT; magnetic local time) auroral energy flux on solar activity was quantitatively studied for winter/dark and geomagnetically quiet conditions. Using data combined from Thermosphere, Ionosphere, Mesosphere Energetics and Dynamics/Global Ultraviolet Imager and Defense Meteorological Satellite Program/Special Sensor Ultraviolet Spectrographic Imager observations, we separated the effects of geomagnetic activity from those of solar flux on the nightside auroral precipitation. The results showed that the nightside auroral power was reduced by ~42% in solar maximum (F10.7 = 200 sfu; solar flux unit 1 sfu = 10-22 W m-2 Hz-1) with respect to that under solar minimum (F10.7 = 70 sfu) for the Kp = 1 condition, and this change rate became less (~21%) for the Kp = 3 condition. In addition, the solar cycle dependence of nightside auroral power was similar with that from both the premidnight (21:00-23:00 MLT) and postmidnight (01:00-03:00 MLT) sectors. These results indicated that as the ionospheric ionization increases with the enhanced auroral and geomagnetic activities, the solar activity dependences of nightside auroral power become weaker, at least under geomagnetically quiet conditions.

  7. Shaping inhibition: activity dependent structural plasticity of GABAergic synapses

    PubMed Central

    Flores, Carmen E.; Méndez, Pablo

    2014-01-01

    Inhibitory transmission through the neurotransmitter γ-aminobutyric acid (GABA) shapes network activity in the mammalian cerebral cortex by filtering synaptic incoming information and dictating the activity of principal cells. The incredibly diverse population of cortical neurons that use GABA as neurotransmitter shows an equally diverse range of mechanisms that regulate changes in the strength of GABAergic synaptic transmission and allow them to dynamically follow and command the activity of neuronal ensembles. Similarly to glutamatergic synaptic transmission, activity-dependent functional changes in inhibitory neurotransmission are accompanied by alterations in GABAergic synapse structure that range from morphological reorganization of postsynaptic density to de novo formation and elimination of inhibitory contacts. Here we review several aspects of structural plasticity of inhibitory synapses, including its induction by different forms of neuronal activity, behavioral and sensory experience and the molecular mechanisms and signaling pathways involved. We discuss the functional consequences of GABAergic synapse structural plasticity for information processing and memory formation in view of the heterogenous nature of the structural plasticity phenomena affecting inhibitory synapses impinging on somatic and dendritic compartments of cortical and hippocampal neurons. PMID:25386117

  8. Shaping inhibition: activity dependent structural plasticity of GABAergic synapses.

    PubMed

    Flores, Carmen E; Méndez, Pablo

    2014-01-01

    Inhibitory transmission through the neurotransmitter γ-aminobutyric acid (GABA) shapes network activity in the mammalian cerebral cortex by filtering synaptic incoming information and dictating the activity of principal cells. The incredibly diverse population of cortical neurons that use GABA as neurotransmitter shows an equally diverse range of mechanisms that regulate changes in the strength of GABAergic synaptic transmission and allow them to dynamically follow and command the activity of neuronal ensembles. Similarly to glutamatergic synaptic transmission, activity-dependent functional changes in inhibitory neurotransmission are accompanied by alterations in GABAergic synapse structure that range from morphological reorganization of postsynaptic density to de novo formation and elimination of inhibitory contacts. Here we review several aspects of structural plasticity of inhibitory synapses, including its induction by different forms of neuronal activity, behavioral and sensory experience and the molecular mechanisms and signaling pathways involved. We discuss the functional consequences of GABAergic synapse structural plasticity for information processing and memory formation in view of the heterogenous nature of the structural plasticity phenomena affecting inhibitory synapses impinging on somatic and dendritic compartments of cortical and hippocampal neurons. PMID:25386117

  9. Effects of pregnane glycosides on food intake depend on stimulation of the melanocortin pathway and BDNF in an animal model.

    PubMed

    Komarnytsky, Slavko; Esposito, Debora; Rathinasabapathy, Thirumurugan; Poulev, Alexander; Raskin, Ilya

    2013-02-27

    Pregnane glycosides appear to modulate food intake by possibly affecting the hypothalamic feeding circuits; however, the mechanisms of the appetite-regulating effect of pregnane glycosides remain obscure. Here, we show that pregnane glycoside-enriched extracts from swamp milkweed Asclepias incarnata at 25-100 mg/kg daily attenuated food intake (up to 47.1 ± 8.5% less than controls) and body weight gain in rats (10% for males and 9% for females, respectively) by activating melanocortin signaling and inhibiting gastric emptying. The major milkweed pregnane glycoside, ikemagenin, exerted its appetite-regulating effect by decreasing levels of agouti-related protein (0.6-fold) but not NPY satiety peptides. Ikemagenin treatment also increased secretion of brain-derived neurotropic factor (BDNF) downstream of melanocortin receptors in the hypothalamus (1.4-fold) and in the C6 rat glioma cell culture in vitro (up to 6-fold). These results support the multimodal effects of pregnane glycosides on feeding regulation, which depends on the activity of the melanocortin signaling pathway and BDNF. PMID:23308358

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

    PubMed

    Tikhonova, Maria; Kulikov, Alexander V

    2012-08-31

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

  11. BDNF is associated with SFRP1 expression in luminal and basal-like breast cancer cell lines and primary breast cancer tissues: a novel role in tumor suppression?

    PubMed

    Huth, Laura; Rose, Michael; Kloubert, Veronika; Winkens, Wiebke; Schlensog, Martin; Hartmann, Arndt; Knüchel, Ruth; Dahl, Edgar

    2014-01-01

    Secreted frizzled related protein 1 (SFRP1) functions as an important inhibitor of the Wnt pathway and is a known tumor suppressor gene, which is epigenetically silenced in a variety of tumors e.g. in breast cancer. However, it is still unclear how SFRP1 exactly affects the Wnt pathway. Our aim was to decipher SFRP1 involvement in biochemical signaling in dependency of different breast cancer subtypes and to identify novel SFRP1-regulated genes. We generated SFRP1 over-expressing in vitro breast cancer models, reflecting the two major subtypes by using basal-like BT20 and luminal-like HER2-positive SKBR3 cells. DNA microarray expression profiling of these models revealed that SFRP1 expression potentially modulates Bone morphogenetic protein- and Smoothened signaling (p<0.01), in addition to the known impact on Wnt signaling. Importantly, further statistical analysis revealed that in dependency of the cancer subtype model SFRP1 may affect the canonical and non-canonical Wnt pathway (p<0.01), respectively. While SFRP1 re-expression generally mediated distinct patterns of transcriptionally induced or repressed genes in BT20 and SKBR3 cells, brain derived neurotrophic factor (BDNF) was identified as a SFRP1 induced gene in both cell lines. Although BDNF has been postulated as a putative oncogene, the co-regulation with SFRP1 indicates a potential suppressive function in breast cancer. Indeed, a positive correlation between SFRP1 and BDNF protein expression could be shown (p<0.001) in primary breast cancer samples. Moreover, TCGA dataset based analysis clearly underscores that BDNF mRNA is down-regulated in primary breast cancer samples predicting a poor prognosis of these patients. In line, we functionally provide evidence that stable BDNF re-expression in basal-like BT20 breast cancer cells blocks tumor cell proliferation. Hence, our results suggest that BDNF might rather mediate suppressive than promoting function in human breast cancer whose mode of action should be

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

    PubMed

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

    2012-09-01

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

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

    PubMed

    Thomas, Ajay X; Cruz Del Angel, Yasmin; Gonzalez, Marco I; Carrel, Andrew J; Carlsen, Jessica; Lam, Philip M; Hempstead, Barbara L; Russek, Shelley J; Brooks-Kayal, Amy R

    2016-01-01

    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.

  14. 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

  15. Working memory deficits, increased anxiety-like traits, and seizure susceptibility in BDNF overexpressing mice.

    PubMed

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

    2011-08-01

    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 anxiety-like scores, high self-grooming, impaired prepulse inhibition, and higher susceptibility to seizures when placed in a new empty cage, as compared with wild-type (WT) littermate controls. Control measures of general health, locomotor activity, motor coordination, depression-related behaviors, and sociability did not differ between genotypes. The present findings, indicating detrimental effects of life-long increased BDNF in mice, may inform human studies evaluating the role of BDNF functional genetic variations on cognitive abilities and vulnerability to psychiatric disorders. PMID:21791566

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

    PubMed

    Levada, O A; Cherednichenko, N V

    2015-01-01

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

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

    PubMed

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

    2000-10-20

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

  18. Working memory deficits, increased anxiety-like traits, and seizure susceptibility in BDNF overexpressing mice

    PubMed Central

    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 anxiety-like scores, high self-grooming, impaired prepulse inhibition, and higher susceptibility to seizures when placed in a new empty cage, as compared with wild-type (WT) littermate controls. Control measures of general health, locomotor activity, motor coordination, depression-related behaviors, and sociability did not differ between genotypes. The present findings, indicating detrimental effects of life-long increased BDNF in mice, may inform human studies evaluating the role of BDNF functional genetic variations on cognitive abilities and vulnerability to psychiatric disorders. PMID:21791566

  19. Stress and CRF gate neural activation of BDNF in the mesolimbic reward pathway.

    PubMed

    Walsh, Jessica J; Friedman, Allyson K; Sun, Haosheng; Heller, Elizabeth A; Ku, Stacy M; Juarez, Barbara; Burnham, Veronica L; Mazei-Robison, Michelle S; Ferguson, Deveroux; Golden, Sam A; Koo, Ja Wook; Chaudhury, Dipesh; Christoffel, Daniel J; Pomeranz, Lisa; Friedman, Jeffrey M; Russo, Scott J; Nestler, Eric J; Han, Ming-Hu

    2014-01-01

    Mechanisms controlling release of brain-derived neurotrophic factor (BDNF) in the mesolimbic dopamine reward pathway remain unknown. We report that phasic optogenetic activation of this pathway increases BDNF amounts in the nucleus accumbens (NAc) of socially stressed mice but not of stress-naive mice. This stress gating of BDNF signaling is mediated by corticotrophin-releasing factor (CRF) acting in the NAc. These results unravel a stress context-detecting function of the brain's mesolimbic circuit.

  20. 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

  1. Circadian variations in behaviors, BDNF and cell proliferation in depressive mice.

    PubMed

    Yi, Li-Tao; Luo, Liu; Wu, Yong-Jing; Liu, Bin-Bin; Liu, Xiao-Long; Geng, Di; Liu, Qing

    2015-12-01

    Neurotrophic factors are well-known to be involved in the pathophysiology of depression and treatment of antidepressants. Brain-derived neurotrophic factor (BDNF), one of the most widely distributed and the most highly studied neurotrophic factors, has been demonstrated to play an important role in the pathophysiology of depression and the mechanism of antidepressants. According to the previous studies, we found that animal tissues were dissected for BDNF measurement mainly in daytime. Considering the circadian rhythm of BDNF expression, our present study evaluated the circadian variations in behaviors, serum corticosterone concentrations, hippocampal BDNF expression and neuronal cell proliferation in mice exposed to chronic mild stress (CMS), one of the most widely used depression-like animal models. Our results provided the first evidence that the difference of BDNF expression and neuronal cell proliferation between CMS and control mice underwent an oscillation related to the circadian variations (maximum at 20:00 h, minimum at 12:00 h or 16:00 h), while the difference of sucrose preference and first feeding latency was not affected by circadian rhythm. This oscillation difference was attributed to the relative constant BDNF expression and cell proliferation in CMS mice and the fluctuating BDNF expression and cell proliferation in control mice. CMS exposure might destroy the circadian rhythm of BDNF expression and cell proliferation in hippocampus of normal individual. Our present study suggests that animal decapitation at 20:00 h is the best time for BDNF-related measurement in CMS experiment, since the difference reaches the maximum.

  2. 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.

  3. 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

  4. BDNF and NT-3 Modulate Neurotransmitter Receptor Expressions on Developing Spiral Ganglion Neurons

    PubMed Central

    Sun, Wei; Salvi, Richard J.

    2009-01-01

    Cochlear spiral ganglion neurons (SGN) provide the only pathway for transmitting sound evoked activity from the hair cells to the central auditory system. Neurotrophic factor-3 (NT-3) and brain derived neurotrophic factor (BDNF) released from hair cells and supporting cells exert a profound effect on SGN survival and neural firing patterns; however, it is unclear what the effects NT-3 and BDNF have on the type of neurotransmitter receptors expressed on SGN. To address this question, the whole-cell patch clamp recording technique was used to determine what effect NT-3 and BDNF had on the function and expression of glutamate, GABA and glycine receptors on postnatal SGN. Receptor currents induced by the agonist of each receptor were recorded from SGN cultured with or without BDNF or NT-3. NT-3 and BDNF exerted different effects. NT-3, and to a lesser extent BDNF, enhanced the expression of GABA receptors and had comparatively little effect on glutamate receptors. Absence of BDNF and NT-3 resulted in the emergence of glycine-induced currents; however, glycine receptor currents were absent from the short term cultured SGN. In contrast, NT-3 and BDNF suppressed glycine receptor expression on SGN. These results indicate that NT-3 and BDNF exert a profound effect on the types of neurotransmitter receptors expressed on postnatal SGN, results that may have important implications for neural development and plasticity. PMID:19778585

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

    PubMed

    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

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

    PubMed

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

    2015-04-01

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

  7. 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.

  8. Activity-Dependent Rapid Local RhoA Synthesis Is Required for Hippocampal Synaptic Plasticity

    PubMed Central

    Briz, Victor; Zhu, Guoqi; Wang, Yubin; Liu, Yan; Avetisyan, Mariam; Bi, Xiaoning

    2015-01-01

    Dendritic protein synthesis and actin cytoskeleton reorganization are important events required for the consolidation of hippocampal LTP and memory. However, the temporal and spatial relationships between these two processes remain unclear. Here, we report that treatment of adult rat hippocampal slices with BDNF or with tetraethylammonium (TEA), which induces a chemical form of LTP, produces a rapid and transient increase in RhoA protein levels. Changes in RhoA were restricted to dendritic spines of CA3 and CA1 and require de novo protein synthesis regulated by mammalian target of rapamycin (mTOR). BDNF-mediated stimulation of RhoA activity, cofilin phosphorylation, and actin polymerization were completely suppressed by protein synthesis inhibitors. Furthermore, intrahippocampal injections of RhoA antisense oligodeoxynucleotides inhibited theta burst stimulation (TBS)-induced RhoA upregulation in dendritic spines and prevented LTP consolidation. Addition of calpain inhibitors after BDNF or TEA treatment maintained RhoA levels elevated and prolonged the effects of BDNF and TEA on actin polymerization. Finally, the use of isoform-selective calpain inhibitors revealed that calpain-2 was involved in RhoA synthesis, whereas calpain-1 mediated RhoA degradation. Overall, this mechanism provides a novel link between dendritic protein synthesis and reorganization of the actin cytoskeleton in hippocampal dendritic spines during LTP consolidation. PMID:25653381

  9. Activity-dependent rapid local RhoA synthesis is required for hippocampal synaptic plasticity.

    PubMed

    Briz, Victor; Zhu, Guoqi; Wang, Yubin; Liu, Yan; Avetisyan, Mariam; Bi, Xiaoning; Baudry, Michel

    2015-02-01

    Dendritic protein synthesis and actin cytoskeleton reorganization are important events required for the consolidation of hippocampal LTP and memory. However, the temporal and spatial relationships between these two processes remain unclear. Here, we report that treatment of adult rat hippocampal slices with BDNF or with tetraethylammonium (TEA), which induces a chemical form of LTP, produces a rapid and transient increase in RhoA protein levels. Changes in RhoA were restricted to dendritic spines of CA3 and CA1 and require de novo protein synthesis regulated by mammalian target of rapamycin (mTOR). BDNF-mediated stimulation of RhoA activity, cofilin phosphorylation, and actin polymerization were completely suppressed by protein synthesis inhibitors. Furthermore, intrahippocampal injections of RhoA antisense oligodeoxynucleotides inhibited theta burst stimulation (TBS)-induced RhoA upregulation in dendritic spines and prevented LTP consolidation. Addition of calpain inhibitors after BDNF or TEA treatment maintained RhoA levels elevated and prolonged the effects of BDNF and TEA on actin polymerization. Finally, the use of isoform-selective calpain inhibitors revealed that calpain-2 was involved in RhoA synthesis, whereas calpain-1 mediated RhoA degradation. Overall, this mechanism provides a novel link between dendritic protein synthesis and reorganization of the actin cytoskeleton in hippocampal dendritic spines during LTP consolidation.

  10. LPS-induced microglial secretion of TNFα increases activity-dependent neuronal apoptosis in the neonatal cerebral cortex.

    PubMed

    Nimmervoll, Birgit; White, Robin; Yang, Jenq-Wei; An, Shuming; Henn, Christopher; Sun, Jyh-Jang; Luhmann, Heiko J

    2013-07-01

    During the pre- and neonatal period, the cerebral cortex reveals distinct patterns of spontaneous synchronized activity, which is critically involved in the formation of early networks and in the regulation of neuronal survival and programmed cell death (apoptosis). During this period, the cortex is also highly vulnerable to inflammation and in humans prenatal infection may have a profound impact on neurodevelopment causing long-term neurological deficits. Using in vitro and in vivo multi-electrode array recordings and quantification of caspase-3 (casp-3)-dependent apoptosis, we demonstrate that lipopolysaccharide-induced inflammation causes rapid alterations in the pattern of spontaneous burst activities, which subsequently leads to an increase in apoptosis. We show that these inflammatory effects are specifically initiated by the microglia-derived pro-inflammatory cytokine tumor necrosis factor α and the chemokine macrophage inflammatory protein 2. Our data demonstrate that inflammation-induced modifications in spontaneous network activities influence casp-3-dependent cell death in the developing cerebral cortex.

  11. Modulation of the NMDA Receptor Through Secreted Soluble Factors.

    PubMed

    Cerpa, Waldo; Ramos-Fernández, Eva; Inestrosa, Nibaldo C

    2016-01-01

    Synaptic activity is a critical determinant in the formation and development of excitatory synapses in the central nervous system (CNS). The excitatory current is produced and regulated by several ionotropic receptors, including those that respond to glutamate. These channels are in turn regulated through several secreted factors that function as synaptic organizers. Specifically, Wnt, brain-derived neurotrophic factor (BDNF), fibroblast growth factor (FGF), and transforming growth factor (TGF) particularly regulate the N-methyl-D-aspartate receptor (NMDAR) glutamatergic channel. These factors likely regulate early embryonic development and directly control key proteins in the function of important glutamatergic channels. Here, we review the secreted molecules that participate in synaptic organization and discuss the cell signaling behind of this fine regulation. Additionally, we discuss how these factors are dysregulated in some neuropathologies associated with glutamatergic synaptic transmission in the CNS. PMID:25429903

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

    PubMed Central

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

    2016-01-01

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

  13. 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

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

    PubMed

    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

  15. 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

  16. 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.

  17. Investigating the Role of Hippocampal BDNF in Anxiety Vulnerability Using Classical Eyeblink Conditioning

    PubMed Central

    Janke, Kellie L.; Cominski, Tara P.; Kuzhikandathil, Eldo V.; Servatius, Richard J.; Pang, Kevin C. H.

    2015-01-01

    Dysregulation of brain-derived neurotrophic factor (BDNF), behavioral inhibition temperament (BI), and small hippocampal volume have been linked to anxiety disorders. Individuals with BI show facilitated acquisition of the classically conditioned eyeblink response (CCER) as compared to non-BI individuals, and a similar pattern is seen in an animal model of BI, the Wistar-Kyoto (WKY) rat. The present study examined the role of hippocampal BDNF in the facilitated delay CCER of WKY rats. Consistent with earlier work, acquisition was facilitated in WKY rats compared to the Sprague Dawley (SD) rats. Facilitated acquisition was associated with increased BDNF, TrkB, and Arc mRNA in the dentate gyrus of SD rats, but learning-induced increases in BDNF and Arc mRNA were significantly smaller in WKY rats. To determine whether reduced hippocampal BDNF in WKY rats was a contributing factor for their facilitated CCER, BDNF or saline infusions were given bilaterally into the dentate gyrus region 1 h prior to training. BDNF infusion did not alter the acquisition of SD rats, but significantly dampened the acquisition of CCER in the WKY rats, such that acquisition was similar to SD rats. Together, these results suggest that inherent differences in the BDNF system play a critical role in the facilitated associative learning exhibited by WKY rats, and potentially individuals with BI. Facilitated associative learning may represent a vulnerability factor in the development of anxiety disorders. PMID:26257661

  18. PLD1 participates in BDNF-induced signalling in cortical neurons

    PubMed Central

    Ammar, Mohamed Raafet; Thahouly, Tamou; Hanauer, André; Stegner, David; Nieswandt, Bernhard; Vitale, Nicolas

    2015-01-01

    The brain-derived neurotrophic factor BDNF plays a critical role in neuronal development and the induction of L-LTP at glutamatergic synapses in several brain regions. However, the cellular and molecular mechanisms underlying these BDNF effects have not been firmly established. Using in vitro cultures of cortical neurons from knockout mice for Pld1 and Rsk2, BDNF was observed to induce a rapid RSK2-dependent activation of PLD and to stimulate BDNF ERK1/2-CREB and mTor-S6K signalling pathways, but these effects were greatly reduced in Pld1−/− neurons. Furthermore, phospho-CREB did not accumulate in the nucleus, whereas overexpression of PLD1 amplified the BDNF-dependent nuclear recruitment of phospho-ERK1/2 and phospho-CREB. This BDNF retrograde signalling was prevented in cells silenced for the scaffolding protein PEA15, a protein which complexes with PLD1, ERK1/2, and RSK2 after BDNF treatment. Finally PLD1, ERK1/2, and RSK2 partially colocalized on endosomal structures, suggesting that these proteins are part of the molecular module responsible for BDNF signalling in cortical neurons. PMID:26437780

  19. PLD1 participates in BDNF-induced signalling in cortical neurons.

    PubMed

    Ammar, Mohamed Raafet; Thahouly, Tamou; Hanauer, André; Stegner, David; Nieswandt, Bernhard; Vitale, Nicolas

    2015-01-01

    The brain-derived neurotrophic factor BDNF plays a critical role in neuronal development and the induction of L-LTP at glutamatergic synapses in several brain regions. However, the cellular and molecular mechanisms underlying these BDNF effects have not been firmly established. Using in vitro cultures of cortical neurons from knockout mice for Pld1 and Rsk2, BDNF was observed to induce a rapid RSK2-dependent activation of PLD and to stimulate BDNF ERK1/2-CREB and mTor-S6K signalling pathways, but these effects were greatly reduced in Pld1(-/-) neurons. Furthermore, phospho-CREB did not accumulate in the nucleus, whereas overexpression of PLD1 amplified the BDNF-dependent nuclear recruitment of phospho-ERK1/2 and phospho-CREB. This BDNF retrograde signalling was prevented in cells silenced for the scaffolding protein PEA15, a protein which complexes with PLD1, ERK1/2, and RSK2 after BDNF treatment. Finally PLD1, ERK1/2, and RSK2 partially colocalized on endosomal structures, suggesting that these proteins are part of the molecular module responsible for BDNF signalling in cortical neurons. PMID:26437780

  20. BDNF mediates improvements in executive function following a 1-year exercise intervention

    PubMed Central

    Leckie, Regina L.; Oberlin, Lauren E.; Voss, Michelle W.; Prakash, Ruchika S.; Szabo-Reed, Amanda; Chaddock-Heyman, Laura; Phillips, Siobhan M.; Gothe, Neha P.; Mailey, Emily; Vieira-Potter, Victoria J.; Martin, Stephen A.; Pence, Brandt D.; Lin, Mingkuan; Parasuraman, Raja; Greenwood, Pamela M.; Fryxell, Karl J.; Woods, Jeffrey A.; McAuley, Edward; Kramer, Arthur F.; Erickson, Kirk I.

    2014-01-01

    Executive function declines with age, but engaging in aerobic exercise may attenuate decline. One mechanism by which aerobic exercise may preserve executive function is through the up-regulation of brain-derived neurotropic factor (BDNF), which also declines with age. The present study examined BDNF as a mediator of the effects of a 1-year walking intervention on executive function in 90 older adults (mean age = 66.82). Participants were randomized to a stretching and toning control group or a moderate intensity walking intervention group. BDNF serum levels and performance on a task-switching paradigm were collected at baseline and follow-up. We found that age moderated the effect of intervention group on changes in BDNF levels, with those in the highest age quartile showing the greatest increase in BDNF after 1-year of moderate intensity walking exercise (p = 0.036). The mediation analyses revealed that BDNF mediated the effect of the intervention on task-switch accuracy, but did so as a function of age, such that exercise-induced changes in BDNF mediated the effect of exercise on task-switch performance only for individuals over the age of 71. These results demonstrate that both age and BDNF serum levels are important factors to consider when investigating the mechanisms by which exercise interventions influence cognitive outcomes, particularly in elderly populations. PMID:25566019

  1. BDNF val66met genotype and schizotypal personality traits interact to influence probabilistic association learning.

    PubMed

    Skilleter, Ashley Jayne; Weickert, Cynthia Shannon; Moustafa, Ahmed Abdelhalim; Gendy, Rasha; Chan, Mico; Arifin, Nur; Mitchell, Philip Bowden; Weickert, Thomas Wesley

    2014-11-01

    The brain derived neurotrophic factor (BDNF) val66met polymorphism rs6265 influences learning and may represent a risk factor for schizophrenia. Healthy people with high schizotypal personality traits display cognitive deficits that are similar to but not as severe as those observed in schizophrenia and they can be studied without confounds of antipsychotics or chronic illness. How genetic variation in BDNF may impact learning in individuals falling along the schizophrenia spectrum is unknown. We predicted that schizotypal personality traits would influence learning and that schizotypal personality-based differences in learning would vary depending on the BDNF val66met genotype. Eighty-nine healthy adults completed the Schizotypal Personality Questionnaire (SPQ) and a probabilistic association learning test. Blood samples were genotyped for the BDNF val66met polymorphism. An ANOVA was performed with BDNF genotype (val homozygotes and met-carriers) and SPQ score (high/low) as grouping variables and probabilistic association learning as the dependent variable. Participants with low SPQ scores (fewer schizotypal personality traits) showed significantly better learning than those with high SPQ scores. BDNF met-carriers displaying few schizotypal personality traits performed best, whereas BDNF met-carriers displaying high schizotypal personality traits performed worst. Thus, the BDNF val66met polymorphism appears to influence probabilistic association learning differently depending on the extent of schizotypal personality traits displayed.

  2. Association of testosterone and BDNF serum levels with craving during alcohol withdrawal.

    PubMed

    Heberlein, Annemarie; Lenz, Bernd; Opfermann, Birgitt; Gröschl, Michael; Janke, Eva; Stange, Katrin; Groh, Adrian; Kornhuber, Johannes; Frieling, Helge; Bleich, Stefan; Hillemacher, Thomas

    2016-08-01

    Preclinical and clinical studies show associations between testosterone and brain-derived neurotrophic growth factor (BDNF) serum levels. BDNF and testosterone have been independently reported to influence alcohol consumption. Therefore, we aimed to investigate a possible interplay of testosterone and BDNF contributing to alcohol dependence. Regarding possible interplay of testosterone and BDNF and the activity of the hypothalamic pituitary axis (HPA), we included cortisol serum levels in our research. We investigated testosterone and BDNF serum levels in a sample of 99 male alcohol-dependent patients during alcohol withdrawal (day 1, 7, and 14) and compared them to a healthy male control group (n = 17). The testosterone serum levels were significantly (p < 0.001) higher in the patients' group than in the control group and decreased significantly during alcohol withdrawal (p < 0.001). The decrease of testosterone serum levels during alcohol withdrawal (days 1-7) was significantly associated with the BDNF serum levels (day 1: p = 0.008). In a subgroup of patients showing high cortisol serum levels (putatively mirroring high HPA activity), we found a significant association of BDNF and testosterone as well as with alcohol craving measured by the Obsessive and Compulsive Drinking Scale (OCDS). Our data suggest a possible association of BDNF and testosterone serum levels, which may be relevant for the symptomatology of alcohol dependence. Further studies are needed to clarify our results. PMID:27514572

  3. 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…

  4. 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...

  5. 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...

  6. Computer Simulations Support a Morphological Contribution to BDNF Enhancement of Action Potential Generation.

    PubMed

    Galati, Domenico F; Hiester, Brian G; Jones, Kevin R

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) regulates both action potential (AP) generation and neuron morphology. However, whether BDNF-induced changes in neuron morphology directly impact AP generation is unclear. We quantified BDNF's effect on cultured cortical neuron morphological parameters and found that BDNF stimulates dendrite growth and addition of dendrites while increasing both excitatory and inhibitory presynaptic inputs in a spatially restricted manner. To gain insight into how these combined changes in neuron structure and synaptic input impact AP generation, we used the morphological parameters we gathered to generate computational models. Simulations suggest that BDNF-induced neuron morphologies generate more APs under a wide variety of conditions. Synapse and dendrite addition have the greatest impact on AP generation. However, subtle alterations in excitatory/inhibitory synapse ratio and strength have a significant impact on AP generation when synaptic activity is low. Consistent with these simulations, BDNF rapidly enhances spontaneous activity in cortical cultures. We propose that BDNF promotes neuron morphologies that are intrinsically more efficient at translating barrages of synaptic activity into APs, which is a previously unexplored aspect of BDNF's function. PMID:27683544

  7. Investigating the Role of Hippocampal BDNF in Anxiety Vulnerability Using Classical Eyeblink Conditioning.

    PubMed

    Janke, Kellie L; Cominski, Tara P; Kuzhikandathil, Eldo V; Servatius, Richard J; Pang, Kevin C H

    2015-01-01

    Dysregulation of brain-derived neurotrophic factor (BDNF), behavioral inhibition temperament (BI), and small hippocampal volume have been linked to anxiety disorders. Individuals with BI show facilitated acquisition of the classically conditioned eyeblink response (CCER) as compared to non-BI individuals, and a similar pattern is seen in an animal model of BI, the Wistar-Kyoto (WKY) rat. The present study examined the role of hippocampal BDNF in the facilitated delay CCER of WKY rats. Consistent with earlier work, acquisition was facilitated in WKY rats compared to the Sprague Dawley (SD) rats. Facilitated acquisition was associated with increased BDNF, TrkB, and Arc mRNA in the dentate gyrus of SD rats, but learning-induced increases in BDNF and Arc mRNA were significantly smaller in WKY rats. To determine whether reduced hippocampal BDNF in WKY rats was a contributing factor for their facilitated CCER, BDNF or saline infusions were given bilaterally into the dentate gyrus region 1 h prior to training. BDNF infusion did not alter the acquisition of SD rats, but significantly dampened the acquisition of CCER in the WKY rats, such that acquisition was similar to SD rats. Together, these results suggest that inherent differences in the BDNF system play a critical role in the facilitated associative learning exhibited by WKY rats, and potentially individuals with BI. Facilitated associative learning may represent a vulnerability factor in the development of anxiety disorders.

  8. ProBDNF negatively regulates neuronal remodeling, synaptic transmission and synaptic plasticity in hippocampus

    PubMed Central

    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.

    2014-01-01

    Summary 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 p75NTR. 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 knock-in mouse. Our results demonstrate that proBDNF negatively regulates hippocampal dendritic complexity and spine density through p75NTR. 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 mature BDNF. PMID:24746813

  9. 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

  10. Cooperation between BDNF and glutamate in the regulation of synaptic transmission and neuronal development.

    PubMed

    Martin, Jean-Luc; Finsterwald, Charles

    2011-01-01

    Ample evidence supports a role of brain-derived neurotrophic factor (BDNF) in the survival and differentiation of selective populations of neurons in the peripheral and central nervous systems. In addition to its trophic actions, BDNF exerts acute effects on synaptic transmission and plasticity. In particular, BDNF enhances excitatory synaptic transmission through pre- and postsynaptic mechanisms. In this regard, BDNF enhances glutamate release, the frequency of miniature excitatory postsynaptic currents (mEPSCs), NMDA receptor activity and the phosphorylation of NMDA receptor subunits. Our recent studies revealed a novel cooperative interaction between BDNF and glutamate in the regulation of dendritic development. Indeed, we found that the effects of BDNF on dendritic growth of cortical neurons require both the stimulation of cAMP response element-binding protein (CREB) phosphorylation by BDNF and the activation of the CREB-regulated transcription coactivator 1 (CRTC1) by glutamate. Together, these studies highlight the importance of the cooperation between BDNF and glutamate in the regulation of synaptic transmission and neuronal development.

  11. Systematic assessment of BDNF and its receptor levels in human cortices affected by Huntington's disease.

    PubMed

    Zuccato, Chiara; Marullo, Manuela; Conforti, Paola; MacDonald, Marcy E; Tartari, Marzia; Cattaneo, Elena

    2008-04-01

    One cardinal feature of Huntington's disease (HD) is the degeneration of striatal neurons, whose survival greatly depends on the binding of cortical brain-derived neurotrophic factor (BDNF) with high-affinity (TrkB) and low-affinity neurotrophin receptors [p75 pan-neurotrophin receptor (p75(NTR))]. With a few exceptions, results obtained in HD mouse models demonstrate a reduction in cortical BDNF mRNA and protein, although autopsy data from a limited number of human HD cortices are conflicting. These studies indicate the presence of defects in cortical BDNF gene transcription and transport to striatum. We provide new evidence indicating a significant reduction in BDNF mRNA and protein in the cortex of 20 HD subjects in comparison with 17 controls, which supports the hypothesis of impaired BDNF production in human HD cortex. Analyses of the BDNF isoforms show that transcription from BDNF promoter II and IV is down-regulated in human HD cortex from an early symptomatic stage. We also found that TrkB mRNA levels are reduced in caudate tissue but not in the cortex, whereas the mRNA levels of T-Shc (a truncated TrkB isoform) and p75(NTR) are increased in the caudate. This indicates that, in addition to the reduction in BDNF mRNA, there is also unbalanced neurotrophic receptor signaling in HD. PMID:18093249

  12. Role of BDNF in bipolar and unipolar disorder: clinical and theoretical implications.

    PubMed

    Post, Robert M

    2007-12-01

    A number of lines of converging evidence suggest that brain-derived neurotrophic factor (BDNF) may play a role in the onset and treatment of bipolar disorder. We review pertinent data on BDNF from several different areas of preclinical and clinical investigation that suggest novel theoretical and treatment implications for the recurrent affective disorders. Data from several recent studies have also converged showing that the val66met allele of BDNF, a common single nucleotide polymorphism (SNP), is associated with selective minor deficits in cognitive functioning in subjects with schizophrenia, bipolar illness, and normal controls. Yet, paradoxically, the better functioning val66val allele of BDNF appears to be associated with an increased risk for bipolar disorder and perhaps early onset or rapid cycling. All the primary antidepressant modalities, as well as the mood stabilizers lithium and valproate, increase BDNF. Stressors decrease BDNF and this effect can be blocked by antidepressants. Serum BDNF is low in proportion to the severity of mania and depression and increases with clinical improvement. Assessment of the val66val BDNF allele and a range of other SNPs as potential vulnerability factors for bipolar illness and its early onset could facilitate studies of early intervention, help reduce long delays between the onset of first symptoms and the first treatment, and help in the prediction of individual patient's likelihood of responding to a given treatment.

  13. Loss of BDNF or Its Receptors in Three Mouse Models Has Unpredictable Consequences for Anxiety and Fear Acquisition

    ERIC Educational Resources Information Center

    Olsen, Ditte; Kaas, Mathias; Schwartz, Ole; Nykjaer, Anders; Glerup, Simon

    2013-01-01

    BDNF-induced signaling is essential for the development of the central nervous system and critical for plasticity in adults. Mature BDNF signals through TrkB, while its precursor proBDNF employs p75[superscript NTR], resulting in activation of signaling cascades with opposite effects on neuronal survival, growth cone decisions, and synaptic…

  14. Possible role of brain-derived neurotrophic factor (BDNF) in autism spectrum disorder: current status.

    PubMed

    Halepoto, Dost Muhammad; Bashir, Shahid; A L-Ayadhi, Laila

    2014-04-01

    Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family of survival-promoting molecules, plays a vital role in the growth, development, maintenance, and function of several neuronal systems. The purpose of this review is to document the support for the involvement of this molecule in the maintenance of normal cognitive, emotional functioning, and to outline recent developments in the content of Autism spectrum disorder (ASD). Current and future treatment development can be guided by developing understanding of this molecule's actions in the brain and the ways the expression of BDNF can be planned. Over the years, research findings suggested a critical role played by BDNF in the development of autism including increased serum concentrations of BDNF in children with autism and identification of different forms of BDNF in families of autistic individuals. PMID:24709243

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

    PubMed

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

    2016-09-01

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

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

    PubMed Central

    Vanevski, Filip; Xu, Baoji

    2013-01-01

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

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

    PubMed

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

    2016-09-01

    Serum BDNF levels are significantly decreased in transsexual Brazilian women when compared to cis-sexual men. Since transsexual men are also exposed to chronic social stress and have a high prevalence of associated psychopathologies, it is plausible to inquire if BDNF serum levels are altered in transsexual men as well. Therefore, our objective was to evaluate differences in BDNF serum level of transsexual men when compared to cis-sexual men and women. Our sample comprises 27 transsexual men, 31 cis-sexual women and 30 cis-sexual men recruited between 2011 and 2015. We observed that BDNF serum concentration is decreased in transsexual men comparing to cis-sexual men and women. Cross-sex hormone treatment, chronic social stress or long-term gender dysphoria (GD) could explain the variation found in BDNF serum levels. PMID:27473941

  18. BDNF: the career of a multifaceted neurotrophin in spinal cord injury.

    PubMed

    Weishaupt, N; Blesch, A; Fouad, K

    2012-12-01

    Brain-derived neurotrophic factor (BDNF) has been identified as a potent promoter of neurite growth, a finding that has led to an ongoing exploration of this neurotrophin as a potential treatment for spinal cord injury. BDNF's many effects in the nervous system make it an excellent candidate for neuroprotective strategies as well as for promoting axonal regeneration, plasticity and re-myelination. In addition, neuronal activity and physical exercise can modulate the expression of BDNF, suggesting that non-invasive means to increase BDNF levels might exist. Nonetheless, depending on the location, amount and duration of BDNF delivery, this potent neurotrophin can also have adverse effects, such as modulation of nociceptive pathways or contribution to spasticity. Taken together, the benefits and possible risks require careful assessment when considering this multifaceted neurotrophin as a treatment option for spinal cord injury.

  19. BDNF Polymorphism Predicts General Intelligence after Penetrating Traumatic Brain Injury

    PubMed Central

    Rostami, Elham; Krueger, Frank; Zoubak, Serguei; Dal Monte, Olga; Raymont, Vanessa; Pardini, Matteo; Hodgkinson, Colin A.; Goldman, David; Risling, Mårten; Grafman, Jordan

    2011-01-01

    Neuronal plasticity is a fundamental factor in cognitive outcome following traumatic brain injury. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, plays an important role in this process. While there are many ways to measure cognitive outcome, general cognitive intelligence is a strong predictor of everyday decision-making, occupational attainment, social mobility and job performance. Thus it is an excellent measure of cognitive outcome following traumatic brain injury (TBI). Although the importance of the single-nucleotide polymorphisms polymorphism on cognitive function has been previously addressed, its role in recovery of general intelligence following TBI is unknown. We genotyped male Caucasian Vietnam combat veterans with focal penetrating TBI (pTBI) (n = 109) and non-head injured controls (n = 38) for 7 BDNF single-nucleotide polymorphisms. Subjects were administrated the Armed Forces Qualification Test (AFQT) at three different time periods: pre-injury on induction into the military, Phase II (10–15 years post-injury, and Phase III (30–35 years post-injury). Two single-nucleotide polymorphisms, rs7124442 and rs1519480, were significantly associated with post-injury recovery of general cognitive intelligence with the most pronounced effect at the Phase II time point, indicating lesion-induced plasticity. The genotypes accounted for 5% of the variance of the AFQT scores, independently of other significant predictors such as pre-injury intelligence and percentage of brain volume loss. These data indicate that genetic variations in BDNF play a significant role in lesion-induced recovery following pTBI. Identifying the underlying mechanism of this brain-derived neurotrophic factor effect could provide insight into an important aspect of post-traumatic cognitive recovery. PMID:22087305

  20. Brain BDNF levels are dependent on cerebrovascular endothelium-derived nitric oxide.

    PubMed

    Banoujaafar, Hayat; Monnier, Alice; Pernet, Nicolas; Quirié, Aurore; Garnier, Philippe; Prigent-Tessier, Anne; Marie, Christine

    2016-09-01

    Scientific evidence continues to demonstrate a link between endothelial function and cognition. Besides, several studies have identified a complex interplay between nitric oxide (NO) and brain-derived neurotrophic factor (BDNF), a neurotrophin largely involved in cognition. Therefore, this study investigated the link between cerebral endothelium-derived NO and BDNF signaling. For this purpose, levels of BDNF and the phosphorylated form of endothelial NO synthase at serine 1177 (p-eNOS) were simultaneously measured in the cortex and hippocampus of rats subjected to either bilateral common carotid occlusion (n = 6), physical exercise (n = 6) or a combination of both (n = 6) as experimental approaches to modulate flow-induced NO production by the cerebrovasculature. Tropomyosin-related kinase type B (TrkB) receptors and its phosphorylated form at tyrosine 816 (p-TrkB) were also measured. Moreover, we investigated BDNF synthesis in brain slices exposed to the NO donor glyceryl trinitrate. Our results showed increased p-eNOS and BDNF levels after exercise and decreased levels after vascular occlusion as compared to corresponding controls, with a positive correlation between changes in p-eNOS and BDNF (r = 0.679). Exercise after vascular occlusion did not change levels of these proteins. Gyceryl trinitrate increased proBDNF and BDNF levels in brain slices, thus suggesting a possible causal relationship between NO and BDNF. Moreover, vascular occlusion, like exercise, resulted in increased TrkB and p-TrkB levels, whereas no change was observed with the combination of both. These results suggest that brain BDNF signaling may be dependent on cerebral endothelium-derived NO production. PMID:27306299

  1. Postnatal reduction of BDNF regulates the developmental remodeling of taste bud innervation.

    PubMed

    Huang, Tao; Ma, Liqun; Krimm, Robin F

    2015-09-15

    The refinement of innervation is a common developmental mechanism that serves to increase the specificity of connections following initial innervation. In the peripheral gustatory system, the extent to which innervation is refined and how refinement might be regulated is unclear. The initial innervation of taste buds is controlled by brain-derived neurotrophic factor (BDNF). Following initial innervation, taste receptor cells are added and become newly innervated. The connections between the taste receptor cells and nerve fibers are likely to be specific in order to retain peripheral coding mechanisms. Here, we explored the possibility that the down-regulation of BDNF regulates the refinement of taste bud innervation during postnatal development. An analysis of BDNF expression in Bdnf(lacZ/+) mice and real-time reverse transcription polymerase chain reaction (RT-PCR) revealed that BDNF was down-regulated between postnatal day (P) 5 and P10. This reduction in BDNF expression was due to a loss of precursor/progenitor cells that express BDNF, while the expression of BDNF in the subpopulations of taste receptor cells did not change. Gustatory innervation, which was identified by P2X3 immunohistochemistry, was lost around the perimeter where most progenitor/precursor cells are located. In addition, the density of innervation in the taste bud was reduced between P5 and P10, because taste buds increase in size without increasing innervation. This reduction of innervation density was blocked by the overexpression of BDNF in the precursor/progenitor population of taste bud cells. Together these findings indicate that the process of BDNF restriction to a subpopulation of taste receptor cells between P5 and P10, results in a refinement of gustatory innervation. We speculate that this refinement results in an increased specificity of connections between neurons and taste receptor cells during development.

  2. High-intensity interval training evokes larger serum BDNF levels compared with intense continuous exercise.

    PubMed

    Saucedo Marquez, Cinthia Maria; Vanaudenaerde, Bart; Troosters, Thierry; Wenderoth, Nicole

    2015-12-15

    Exercise can have a positive effect on the brain by activating brain-derived neurotrophic factor (BDNF)-related processes. In healthy humans there appears to be a linear relationship between exercise intensity and the positive short-term effect of acute exercise on BDNF levels (i.e., the highest BDNF levels are reported after high-intensity exercise protocols). Here we performed two experiments to test the effectiveness of two high-intensity exercise protocols, both known to improve cardiovascular health, to determine whether they have a similar efficacy in affecting BDNF levels. Participants performed a continuous exercise (CON) protocol at 70% of maximal work rate and a high-intensity interval-training (HIT) protocol at 90% of maximal work rate for periods of 1 min alternating with 1 min of rest (both protocols lasted 20 min). We observed similar BDNF kinetics in both protocols, with maximal BDNF concentrations being reached toward the end of training (experiment 1). We then showed that both exercise protocols significantly increase BDNF levels compared with a rest condition (CON P = 0.04; HIT P < 0.001), with HIT reaching higher BDNF levels than CON (P = 0.035) (experiment 2). These results suggest that shorter bouts of high intensity exercise are slightly more effective than continuous high-intensity exercise for elevating serum BDNF. Additionally, 73% of the participants preferred the HIT protocol (P = 0.02). Therefore, we suggest that the HIT protocol might represent an effective and preferred intervention for elevating BDNF levels and potentially promoting brain health.

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

    PubMed

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

    2016-01-01

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

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

    PubMed

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

    2014-08-01

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

  5. BDNF increases homotypic olivocerebellar reinnervation and associated fine motor and cognitive skill.

    PubMed

    Willson, Melina L; McElnea, Catriona; Mariani, Jean; Lohof, Ann M; Sherrard, Rachel M

    2008-04-01

    Recovery of complex neural function after injury to the adult CNS is limited by minimal spontaneous axonal regeneration and/or sprouting from remaining pathways. In contrast, the developing CNS displays spontaneous reorganization following lesion, in which uninjured axons can develop new projections to appropriate target neurons and provide partial recovery of complex behaviours. Similar pathways can be induced in the mature CNS, providing models to optimize post-injury recovery of complex neural functions. After unilateral transection of a developing olivocerebellar path (pedunculotomy), remaining inferior olivary axons topographically reinnervate the denervated hemicerebellum and compensate functional deficits. Brain-derived neurotrophic factor (BDNF) partly recreates such reinnervation in the mature cerebellum. However the function of this incomplete reinnervation and any unwanted behavioural effects of BDNF remain unknown. We measured olivocerebellar reinnervation and tested rotarod and navigation skills in Wistar rats treated with BDNF/vehicle and pedunculotomized on day 3 (Px3; with reinnervation) or 11 (Px11; without spontaneous reinnervation). BDNF treatment did not affect motor or spatial behaviour in normal (control) animals. Px11-BDNF animals equalled controls on the rotarod, outperforming Px11-vehicle animals. Moreover, Px3-BDNF and Px11-BDNF animals achieved spatial learning and memory tasks as well as controls, with Px11-BDNF animals showing better spatial orientation than Px11-vehicle counterparts. BDNF slightly increased olivocerebellar reinnervation in Px3 animals and induced sparse (22% Purkinje cells) yet widespread reinnervation in Px11 animals. As reinnervation correlated with spatial function, these data imply that after injury even a small amount of reinnervation that is homotypic to correct target neurons compensates deficits in appropriate complex motor and spatial skills. As there was no effect in control animals, BDNF effectively induces

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

    PubMed Central

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

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) has been found to produce pro- but also anti-epileptic effects. Thus, its validity as a therapeutic target must be verified using advanced tools designed to block or to enhance its signal. The aim of this study was to develop tools to silence the BDNF signal. We generated Herpes simplex virus type 1 (HSV-1) derived amplicon vectors, i.e. viral particles containing a genome of 152 kb constituted of concatameric repetitions of an expression cassette, enabling the expression of the gene of interest in multiple copies. HSV-1 based amplicon vectors are non-pathogenic and have been successfully employed in the past for gene delivery into the brain of living animals. Therefore, amplicon vectors should represent a logical choice for expressing a silencing cassette, which, in multiple copies, is expected to lead to an efficient knock-down of the target gene expression. Here, we employed two amplicon-based BDNF silencing strategies. The first, antisense, has been chosen to target and degrade the cytoplasmic mRNA pool of BDNF, whereas the second, based on the convergent transcription technology, has been chosen to repress transcription at the BDNF gene. Both these amplicon vectors proved to be effective in down-regulating BDNF expression in vitro, in BDNF-expressing mesoangioblast cells. However, only the antisense strategy was effective in vivo, after inoculation in the hippocampus in a model of status epilepticus in which BDNF mRNA levels are strongly increased. Interestingly, the knocking down of BDNF levels induced with BDNF-antisense was sufficient to produce significant behavioral effects, in spite of the fact that it was produced only in a part of a single hippocampus. In conclusion, this study demonstrates a reliable effect of amplicon vectors in knocking down gene expression in vitro and in vivo. Therefore, this approach may find broad applications in neurobiological studies. PMID:26954758

  7. Postnatal reduction of BDNF regulates the developmental remodeling of taste bud innervation.

    PubMed

    Huang, Tao; Ma, Liqun; Krimm, Robin F

    2015-09-15

    The refinement of innervation is a common developmental mechanism that serves to increase the specificity of connections following initial innervation. In the peripheral gustatory system, the extent to which innervation is refined and how refinement might be regulated is unclear. The initial innervation of taste buds is controlled by brain-derived neurotrophic factor (BDNF). Following initial innervation, taste receptor cells are added and become newly innervated. The connections between the taste receptor cells and nerve fibers are likely to be specific in order to retain peripheral coding mechanisms. Here, we explored the possibility that the down-regulation of BDNF regulates the refinement of taste bud innervation during postnatal development. An analysis of BDNF expression in Bdnf(lacZ/+) mice and real-time reverse transcription polymerase chain reaction (RT-PCR) revealed that BDNF was down-regulated between postnatal day (P) 5 and P10. This reduction in BDNF expression was due to a loss of precursor/progenitor cells that express BDNF, while the expression of BDNF in the subpopulations of taste receptor cells did not change. Gustatory innervation, which was identified by P2X3 immunohistochemistry, was lost around the perimeter where most progenitor/precursor cells are located. In addition, the density of innervation in the taste bud was reduced between P5 and P10, because taste buds increase in size without increasing innervation. This reduction of innervation density was blocked by the overexpression of BDNF in the precursor/progenitor population of taste bud cells. Together these findings indicate that the process of BDNF restriction to a subpopulation of taste receptor cells between P5 and P10, results in a refinement of gustatory innervation. We speculate that this refinement results in an increased specificity of connections between neurons and taste receptor cells during development. PMID:26164656

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

    PubMed

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

    2014-05-21

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

  9. Impact of an additional chronic BDNF reduction on learning performance in an Alzheimer mouse model.

    PubMed

    Psotta, Laura; Rockahr, Carolin; Gruss, Michael; Kirches, Elmar; Braun, Katharina; Lessmann, Volkmar; Bock, Jörg; Endres, Thomas

    2015-01-01

    There is increasing evidence that brain-derived neurotrophic factor (BDNF) plays a crucial role in Alzheimer's disease (AD) pathology. A number of studies demonstrated that AD patients exhibit reduced BDNF levels in the brain and the blood serum, and in addition, several animal-based studies indicated a potential protective effect of BDNF against Aβ-induced neurotoxicity. In order to further investigate the role of BDNF in the etiology of AD, we created a novel mouse model by crossing a well-established AD mouse model (APP/PS1) with a mouse exhibiting a chronic BDNF deficiency (BDNF(+/-)). This new triple transgenic mouse model enabled us to further analyze the role of BDNF in AD in vivo. We reasoned that in case BDNF has a protective effect against AD pathology, an AD-like phenotype in our new mouse model should occur earlier and/or in more severity than in the APP/PS1-mice. Indeed, the behavioral analysis revealed that the APP/PS1-BDNF(+/-)-mice show an earlier onset of learning impairments in a two-way active avoidance task in comparison to APP/PS1- and BDNF(+/-)-mice. However in the Morris water maze (MWM) test, we could not observe an overall aggrevated impairment in spatial learning and also short-term memory in an object recognition task remained intact in all tested mouse lines. In addition to the behavioral experiments, we analyzed the amyloid plaque pathology in the APP/PS1 and APP/PS1-BDNF(+/-)-mice and observed a comparable plaque density in the two genotypes. Moreover, our results revealed a higher plaque density in prefrontal cortical compared to hippocampal brain regions. Our data reveal that higher cognitive tasks requiring the recruitment of cortical networks appear to be more severely affected in our new mouse model than learning tasks requiring mainly sub-cortical networks. Furthermore, our observations of an accelerated impairment in active avoidance learning in APP/PS1-BDNF(+/-)-mice further supports the hypothesis that BDNF deficiency

  10. TrkB/BDNF signalling patterns the sympathetic nervous system.

    PubMed

    Kasemeier-Kulesa, Jennifer C; Morrison, Jason A; Lefcort, Frances; Kulesa, Paul M

    2015-01-01

    The sympathetic nervous system is essential for maintaining mammalian homeostasis. How this intricately connected network, composed of preganglionic neurons that reside in the spinal cord and post-ganglionic neurons that comprise a chain of vertebral sympathetic ganglia, arises developmentally is incompletely understood. This problem is especially complex given the vertebral chain of sympathetic ganglia derive secondarily from the dorsal migration of 'primary' sympathetic ganglia that are initially located several hundred microns ventrally from their future pre-synaptic partners. Here we report that the dorsal migration of discrete ganglia is not a simple migration of individual cells but a much more carefully choreographed process that is mediated by extensive interactions of pre-and post-ganglionic neurons. Dorsal migration does not occur in the absence of contact with preganglionic axons, and this is mediated by BDNF/TrkB signalling. Thus BDNF released by preganglionic axons acts chemotactically on TrkB-positive sympathetic neurons, to pattern the developing peripheral nervous system. PMID:26404565

  11. Intracerebral Administration of BDNF Protects Rat Brain Against Oxidative Stress Induced by Ouabain in an Animal Model of Mania.

    PubMed

    Valvassori, Samira S; Arent, Camila O; Steckert, Amanda V; Varela, Roger B; Jornada, Luciano K; Tonin, Paula T; Budni, Josiane; Mariot, Edemilson; Kapczinski, Flávio; Quevedo, João

    2015-08-01

    Several studies have suggested that alterations in brain-derived neurotrophic factor (BDNF) and increased oxidative stress have a central role in bipolar disorder (BD). Intracerebroventricular (ICV) injection of ouabain (OUA) in rats alters oxidative stress parameters and decreases BDNF levels in the brain. In this context, the present study aims to investigate the effects of BDNF ICV administration on BDNF levels and oxidative stress parameters in brains of rats submitted to animal model of mania induced by OUA. Wistar rats received an ICV injection of OUA, artificial cerebrospinal fluid (ACSF), OUA plus BDNF, or ACSF plus BDNF. Locomotor activity and risk-taking behavior in the rats were measured using the open-field test. In addition, we analyzed the BDNF levels and oxidative stress parameters (TBARS, Carbonyl, CAT, SOD, GR, and GPx) in the frontal cortex and hippocampus of rats. The BDNF was unable to reverse the ouabain-induced hyperactivity and risk-taking behavior. Nevertheless, BDNF treatment increased BDNF levels, modulated the antioxidant enzymes, and protected the OUA-induced oxidative damage in the brain of rats. These results suggest that BDNF alteration observed in BD patients may be associated with oxidative damage, both seen in this disorder. PMID:25164569

  12. Agonistic approach of omega-3, omega-6 and its metabolites with BDNF: An in-silico study.

    PubMed

    Kumar, Yadla Phani; Srinivas, G Sri Shanmukha; E, Yadu Mitravinda; Malla, Lalitha; Rao, Allam Appa

    2013-01-01

    Brain derived neurotrophic factor (BDNF) is a member of neurotrophic family of growth factors, mainly found in the hippocampus and cerebral cortex of brain. Studies have shown that there is a link between BDNF and cognitive dysfunction, as well as there is a relationship between the PUFAs intake and their effect on BDNF production. Intake of PUFAs, mainly omega-3 and omega-6 has show increase in production of BDNF in brain. In our study we performed docking studies on PUFAs and their metabolites with BDNF using MVD (Molegro Virtual Docker), this has shown that the metabolites of the PUFAs mainly LXA_4, NPD1, HDHA have shown more binding affinity towards BDNF. These metabolites of PUFAs are responsible for modulation of BDNF activity. PMID:24307768

  13. Combining restricted diet with forced or voluntary exercises improves hippocampal BDNF and cognitive function in rats.

    PubMed

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

    2016-01-01

    Dietary restriction (RDt) and exercise (Ex) enhances cognitive function due, at least in part, levels of neurotrophins such as brain-derived neurotrophic factor (BDNF). This study examined changes in BDNF levels and data acquisition and retention following every-other-day RDt alone, and combined with either voluntary wheel (VxRDt) or forced swimming Exs (FxRDt) in rats. Hippocampal BDNF was measured using ELISA while learning and memory formation were assessed with the radial arm water maze (RAWM) paradigm. After 6 weeks, VxRDt and FxRDt enhanced BDNF levels, and short- and long-term memories (p < 0.05). The magnitude of the increase in BDNF was significantly higher in VxRDt group than in other groups (p < 0.05). However, no differences were found in learning and memory formation between the Ex regiments (VxRDt versus FxRDt). Additionally, RDt alone neither modulated BDNF level nor enhanced learning and memory formation (p > 0.05). These results suggest more important role of Ex, as opposed to RDt, in enhancing learning and memory formation. In addition, VxRDt appears to be more potent in enhancing brain BDNF levels than FxRDt, when combined with RDt in rats. PMID:26000806

  14. 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

  15. Hippocampal BDNF signaling restored with chronic asiaticoside treatment in depression-like mice.

    PubMed

    Luo, Liu; Liu, Xiao-Long; Mu, Rong-Hao; Wu, Yong-Jing; Liu, Bin-Bin; Geng, Di; Liu, Qing; Yi, Li-Tao

    2015-05-01

    Brain-derived neurotrophic factor (BDNF) plays a key role in the regulation of depression in the brain. Recently, increasing studies have focused on the antidepressant-like mechanism of BDNF and its downstream signaling pathway. A previous study has shown that asiaticoside produced an antidepressant-like action in the mouse tail suspension test and forced swimming test. However, the neurotrophic mechanism that is affected by asiaticoside is unclear. Our present study aimed to verify whether asiaticoside produces an antidepressant-like effect through the activation of BDNF signaling in chronic unpredictable mild stress (CUMS). The results showed that mice treated with asiaticoside for four weeks reversed the decreased sucrose preference and increased immobility time that was observed in CUMS mice. In addition, we found that asiaticoside up-regulated BDNF, PSD-95 and synapsin I expression only in the hippocampus but not in the frontal cortex in both non-stressed and CUMS mice. However, K252a, an inhibitor of BDNF receptor tropomyosin-related kinase receptor B (TrkB), completely abolished the antidepressant-like effect of asiaticoside. Moreover, the expression of hippocampal BDNF, PSD-95 and synapsin I that had increased with asiaticoside also declined with K252a pretreatment. In conclusion, our study implies that it is possible that asiaticoside exerts its antidepressant-like action by activating BDNF signaling in the hippocampus.

  16. Post-weaning environmental enrichment improves BDNF response of adult male rats.

    PubMed

    Mosaferi, Belal; Babri, Shirin; Mohaddes, Gisou; Khamnei, Saeed; Mesgari, Mehran

    2015-11-01

    The environment could have long lasting effects on the individual phenotype through developmental plasticity. Early environmental enrichment exerts profound biological effects, most of which are quite beneficial ones. To explore the enduring effects of rearing condition quality on BDNF(1) responses, we reared male Wistar rats from weaning to young-adulthood in three different environmental conditions: 1. Enriched 2. Standard, and 3. Isolated. Then, at the age of 16 weeks, 10 rats from each group were randomly chosen and allocated to six common mix cages. They were kept together for 14 weeks. At the end of the experiment, each rat received ten inescapable foot-shocks. Twelve hours later, the BDNF contents of the amygdala and CA1 sub-region of the dorsal hippocampus were measured. The serum BDNF levels, hematocrit values as well as brain and testis weights were also measured. Results showed that the environmental enrichment led to stronger dorsal hippocampal BDNF response and higher serum BDNF levels, while rats from standard laboratory condition showed higher amygdala BDNF response. Also, enriched animals showed higher brain weight compared to isolation reared rats as well as higher testis weight and hematocrit value compared to animals reared in standard laboratory condition. Rats showed less body weights in isolated condition. In conclusion, the BDNF profile of enriched animals might represent the neurobiological correlate of resilience phenotype under a stressful situation.

  17. Hippocampal BDNF content in response to short- and long-term exercise.

    PubMed

    Sheikhzadeh, Farzam; Etemad, Asieh; Khoshghadam, Sahar; Asl, Naser Ahmadi; Zare, Peyman

    2015-07-01

    The hippocampus is a region in the brain that is crucial for learning and memory. Previous researches proved that brain-derived neurotrophic factor (BDNF) is a probable responsible protein in the learning and memory formation process. BDNF content is thought to be affected by environmental enrichment and physical activity. The purpose of this research was to identify the effect of short- and long-term forced exercise on hippocampal BDNF levels. A total of 30 Wistar rats were randomly divided into three groups (control, short-term exercise and long-term exercise) and treated by treadmill running based on their group. As the treadmill running period finished, the animals were anesthetized. The hippocampus was dissected out immediately and BDNF content of the samples was assessed by ELISA. None of the exercise paradigms did make any significant change on hippocampal BDNF levels. Although exercise was proposed to up-regulate BDNF levels, these results show that the intensity or the duration of running paradigm used in forced exercise protocols here was not enough to affect BDNF levels in the hippocampus significantly.

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

    PubMed

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

    2014-03-01

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

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

    PubMed

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

    2014-02-01

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

  20. Enhancement of synaptic transmission induced by BDNF in cultured cortical neurons

    NASA Astrophysics Data System (ADS)

    He, Jun; Gong, Hui; Zeng, Shaoqun; Li, Yanling; Luo, Qingming

    2005-03-01

    Brain-derived neurotrophic factor (BDNF), like other neurotrophins, has long-term effects on neuronal survival and differentiation; furthermore, BDNF has been reported to exert an acute potentiation of synaptic activity and are critically involved in long-term potentiation (LTP). We found that BDNF rapidly induced potentiation of synaptic activity and an increase in the intracellular Ca2+ concentration in cultured cortical neurons. Within minutes of BDNF application to cultured cortical neurons, spontaneous firing rate was dramatically increased as were the frequency and amplitude of excitatory spontaneous postsynaptic currents (EPSCs). Fura-2 recordings showed that BDNF acutely elicited an increase in intracellular calcium concentration ([Ca2+]c). This effect was partially dependent on [Ca2+]o; The BDNF-induced increase in [Ca2+]c can not be completely blocked by Ca2+-free solution. It was completely blocked by K252a and partially blocked by Cd2+ and TTX. The results demonstrate that BDNF can enhances synaptic transmission and that this effect is accompanied by a rise in [Ca2+]c that requires two route: the release of Ca2+ from intracellular calcium stores and influx of extracellular Ca2+ through voltage-dependent Ca2+ channels in cultured cortical neurons.

  1. Hippocampal BDNF content in response to short- and long-term exercise.

    PubMed

    Sheikhzadeh, Farzam; Etemad, Asieh; Khoshghadam, Sahar; Asl, Naser Ahmadi; Zare, Peyman

    2015-07-01

    The hippocampus is a region in the brain that is crucial for learning and memory. Previous researches proved that brain-derived neurotrophic factor (BDNF) is a probable responsible protein in the learning and memory formation process. BDNF content is thought to be affected by environmental enrichment and physical activity. The purpose of this research was to identify the effect of short- and long-term forced exercise on hippocampal BDNF levels. A total of 30 Wistar rats were randomly divided into three groups (control, short-term exercise and long-term exercise) and treated by treadmill running based on their group. As the treadmill running period finished, the animals were anesthetized. The hippocampus was dissected out immediately and BDNF content of the samples was assessed by ELISA. None of the exercise paradigms did make any significant change on hippocampal BDNF levels. Although exercise was proposed to up-regulate BDNF levels, these results show that the intensity or the duration of running paradigm used in forced exercise protocols here was not enough to affect BDNF levels in the hippocampus significantly. PMID:25860428

  2. The Role of BDNF as a Mediator of Neuroplasticity in Bipolar Disorder

    PubMed Central

    Grande, Iria; Fries, Gabriel Rodrigo; Kunz, Mauricio

    2010-01-01

    The cognitive impairment and neuroanatomical changes that takes place among patients with bipolar disorder (BD) patients has been well described. Recent data suggest that changes in neuroplasticity, cell resilience and connectivity are the main neuropathological findings in BD. Data from differential lines of research converges to the brain-derived neurotrophic factor (BDNF) as an important contributor to the neuroplasticity changes described among BD patients. BDNF serum levels have been shown to be decreased in depressive and manic episodes, returning to normal levels in euthymia. BDNF has also been shown to decrease as the disorder progresses. Moreover, factors that negatively influence the course of BD, such as life stress and trauma have been shown to be associated with a decrease in BDNF serum levels. These findings suggest that BDNF plays a central role in the progression of BD. The present review discusses the role of BDNF as a mediator of the neuroplastic changes that occur in portion with mood episodes and the potential use of serum BDNF as a biomarker in BD. PMID:21253407

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

    PubMed

    Andero, R; Ressler, K J

    2012-07-01

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

  4. Rescue of retinal function by BDNF in a mouse model of glaucoma.

    PubMed

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

    2014-01-01

    Vision loss in glaucoma is caused by progressive dysfunction of retinal ganglion cells (RGCs) and optic nerve atrophy. Here, we investigated the effectiveness of BDNF treatment to preserve vision in a glaucoma experimental model. As an established experimental model, we used the DBA/2J mouse, which develops chronic intraocular pressure (IOP) elevation that mimics primary open-angle glaucoma (POAG). IOP was measured at different ages in DBA/2J mice. Visual function was monitored using the steady-state Pattern Electroretinogram (P-ERG) and visual cortical evoked potentials (VEP). RGC alterations were assessed using Brn3 immunolabeling, and confocal microscope analysis. Human recombinant BDNF was dissolved in physiological solution (0.9% NaCl); the effects of repeated intravitreal injections and topical eye BDNF applications were independently evaluated in DBA/2J mice with ocular hypertension. BDNF level was measured in retinal homogenate by ELISA and western blot. We found a progressive decline of P-ERG and VEP responses in DBA/2J mice between 4 and 7 months of age, in relationship with the development of ocular hypertension and the reduction of Brn3 immunopositive RGCs. Conversely, repeated intravitreal injections (BDNF concentration = 2 µg/µl, volume = 1 µl, for each injection; 1 injection every four days, three injections over two weeks) and topical eye application of BDNF eye-drops (12 µg/µl, 5 µl eye-drop every 48 h for two weeks) were able to rescue visual responses in 7 month DBA/2J mice. In particular, BDNF topical eye treatment recovered P-ERG and VEP impairment increasing the number of Brn3 immunopositive RGCs. We showed that BDNF effects were independent of IOP reduction. Thus, topical eye treatment with BDNF represents a promisingly safe and feasible strategy to preserve visual function and diminish RGC vulnerability to ocular hypertension. PMID:25536045

  5. BDNF-estrogen interactions in hippocampal mossy fiber pathway: implications for normal brain function and disease

    PubMed Central

    Harte-Hargrove, Lauren; MacLusky, Neil J.; Scharfman, Helen E.

    2013-01-01

    The neurotrophin BDNF and the steroid hormone estrogen exhibit potent effects on hippocampal neurons during development and in adulthood. BDNF and estrogen have also been implicated in the etiology of diverse types of neurological disorders or psychiatric illnesses, or have been discussed as potentially important in treatment. Although both are typically studied independently, it has been suggested that BDNF mediates several of the effects of estrogen in hippocampus, and that these interactions play a role in the normal brain as well as disease. Here we focus on the mossy fiber (MF) pathway of the hippocampus, a critical pathway in normal hippocampal function, and a prime example of a location where numerous studies support an interaction between BDNF and estrogen in the rodent brain. We first review the temporal and spatially-regulated expression of BDNF and estrogen in the MFs, as well as their receptors. Then we consider the results of studies that suggest that 17β-estradiol alters hippocampal function by its influence on BDNF expression in the MF pathway. We also address the hypothesis that estrogen influences hippocampus by mechanisms related not only to the mature form of BDNF, acting at trkB receptors, but also by regulating the precursor, proBDNF, acting at p75NTR. We suggest that the interactions between BDNF and 17β-estradiol in the MFs are potentially important in the normal function of the hippocampus, and have implications for sex differences in functions that depend on the MFs and in diseases where MF plasticity has been suggested to play an important role, Alzheimer’s disease, epilepsy and addiction. PMID:23276673

  6. Rescue of retinal function by BDNF in a mouse model of glaucoma.

    PubMed

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

    2014-01-01

    Vision loss in glaucoma is caused by progressive dysfunction of retinal ganglion cells (RGCs) and optic nerve atrophy. Here, we investigated the effectiveness of BDNF treatment to preserve vision in a glaucoma experimental model. As an established experimental model, we used the DBA/2J mouse, which develops chronic intraocular pressure (IOP) elevation that mimics primary open-angle glaucoma (POAG). IOP was measured at different ages in DBA/2J mice. Visual function was monitored using the steady-state Pattern Electroretinogram (P-ERG) and visual cortical evoked potentials (VEP). RGC alterations were assessed using Brn3 immunolabeling, and confocal microscope analysis. Human recombinant BDNF was dissolved in physiological solution (0.9% NaCl); the effects of repeated intravitreal injections and topical eye BDNF applications were independently evaluated in DBA/2J mice with ocular hypertension. BDNF level was measured in retinal homogenate by ELISA and western blot. We found a progressive decline of P-ERG and VEP responses in DBA/2J mice between 4 and 7 months of age, in relationship with the development of ocular hypertension and the reduction of Brn3 immunopositive RGCs. Conversely, repeated intravitreal injections (BDNF concentration = 2 µg/µl, volume = 1 µl, for each injection; 1 injection every four days, three injections over two weeks) and topical eye application of BDNF eye-drops (12 µg/µl, 5 µl eye-drop every 48 h for two weeks) were able to rescue visual responses in 7 month DBA/2J mice. In particular, BDNF topical eye treatment recovered P-ERG and VEP impairment increasing the number of Brn3 immunopositive RGCs. We showed that BDNF effects were independent of IOP reduction. Thus, topical eye treatment with BDNF represents a promisingly safe and feasible strategy to preserve visual function and diminish RGC vulnerability to ocular hypertension.

  7. Exogenous t-PA Administration Increases Hippocampal Mature BDNF Levels. Plasmin- or NMDA-Dependent Mechanism?

    PubMed Central

    Rodier, Marion; Prigent-Tessier, Anne; Béjot, Yannick; Jacquin, Agnès; Mossiat, Claude; Marie, Christine; Garnier, Philippe

    2014-01-01

    Brain-derived neurotrophic factor (BDNF) through TrkB activation is central for brain functioning. Since the demonstration that plasmin is able to process pro-BDNF to mature BDNF and that these two forms have opposite effects on neuronal survival and plasticity, a particular attention has been paid to the link between tissue plasminogen activator (tPA)/plasmin system and BDNF metabolism. However, t-PA via its action on different N-methyl-D-aspartate (NMDA) receptor subunits is also considered as a neuromodulator of glutamatergic transmission. In this context, the aim of our study was to investigate the effect of recombinant (r)t-PA administration on brain BDNF metabolism in rats. In the hippocampus, we found that rt-PA (10 mg/kg) administration induced a progressive increase in mature BDNF levels associated with TrkB activation. In order to delineate the mechanistic involved, plasmin activity was assessed and its inhibition was attempted using tranexamic acid (30 or 300 mg/kg, i.v.) while NMDA receptors were antagonized with MK801 (0.3 or 3 mg/kg, i.p.) in combination with rt-PA treatment. Our results showed that despite a rise in rt-PA activity, rt-PA administration failed to increase hippocampal plasmin activity suggesting that the plasminogen/plasmin system is not involved whereas MK801 abrogated the augmentation in mature BDNF levels observed after rt-PA administration. All together, our results show that rt-PA administration induces increase in hippocampal mature BDNF expression and suggests that rt-PA contributes to the control of brain BDNF synthesis through a plasmin-independent potentiation of NMDA receptors signaling. PMID:24670989

  8. Postnatal reduction of BDNF regulates the developmental remodeling of taste bud innervation

    PubMed Central

    Huang, Tao; Ma, Liqun; Krimm, Robin F

    2015-01-01

    The refinement of innervation is a common developmental mechanism that serves to increase the specificity of connections following initial innervation. In the peripheral gustatory system, the extent to which innervation is refined and how refinement might be regulated is unclear. The initial innervation of taste buds is controlled by brain-derived neurotrophic factor (BDNF). Following initial innervation, taste receptor cells are added and become newly innervated. The connections between the taste receptor cells and nerve fibers are likely to be specific in order to retain peripheral coding mechanisms. Here, we explored the possibility that the down-regulation of BDNF regulates the refinement of taste bud innervation during postnatal development. An analysis of BDNF expression in BdnflacZ/+ mice and real-time reverse transcription polymerase chain reaction (RT-PCR) revealed that BDNF was down-regulated between postnatal day (P) 5 and P10. This reduction in BDNF expression was due to a loss of precursor/progenitor cells that express BDNF, while the expression of BDNF in the subpopulations of taste receptor cells did not change. Gustatory innervation, which was identified by P2X3 immunohistochemistry, was lost around the perimeter where most progenitor/precursor cells are located. In addition, the density of innervation in the taste bud was reduced between P5 and P10, because taste buds increase in size without increasing innervation. This reduction of innervation density was blocked by the overexpression of BDNF in the precursor/progenitor population of taste bud cells. Together these findings indicate that the process of BDNF restriction to a subpopulation of taste receptor cells between P5 and P10, results in a refinement of gustatory innervation. We speculate that this refinement results in an increased specificity of connections between neurons and taste receptor cells during development. PMID:26164656

  9. BDNF and its TrkB receptor in human fracture healing.

    PubMed

    Kilian, Olaf; Hartmann, Sonja; Dongowski, Nicole; Karnati, Srikanth; Baumgart-Vogt, Eveline; Härtel, Frauke V; Noll, Thomas; Schnettler, Reinhard; Lips, Katrin Susanne

    2014-09-01

    Fracture healing is a physiological process of repair which proceeds in stages, each characterized by a different predominant tissue in the fracture gap. Matrix reorganization is regulated by cytokines and growth factors. Neurotrophins and their receptors might be of importance to osteoblasts and endothelial cells during fracture healing. The aim of this study was to examine the presence of brain-derived neurotrophic factor (BDNF) and its tropomyosin-related kinase B receptor (TrkB) during human fracture healing. BDNF and TrkB were investigated in samples from human fracture gaps and cultured cells using RT-PCR, Western blot, and immunohistochemistry. Endothelial cells and osteoblastic cell lines demonstrated a cytoplasmic staining pattern of BDNF and TrkB in vitro. At the mRNA level, BDNF and TrkB were expressed in the initial and osteoid formation phase of human fracture healing. In the granulation tissue of fracture gap, both proteins--BDNF and TrkB--are concentrated in endothelial and osteoblastic cells at the margins of woven bone suggesting their involvement in the formation of new vessels. There was no evidence of BDNF or TrkB during fracture healing in chondrocytes of human enchondral tissue. Furthermore, BDNF is absent in mature bone. Taken together, BDNF and TrkB are involved in vessel formation and osteogenic processes during human fracture healing. The detection of BDNF and its TrkB receptor during various stages of the bone formation process in human fracture gap tissue were shown for the first time. The current study reveals that both proteins are up-regulated in human osteoblasts and endothelial cells in fracture healing. PMID:24984919

  10. Fyn is an intermediate kinase that BDNF utilizes to promote oligodendrocyte myelination.

    PubMed

    Peckham, Haley; Giuffrida, Lauren; Wood, Rhiannon; Gonsalvez, David; Ferner, Anita; Kilpatrick, Trevor J; Murray, Simon S; Xiao, Junhua

    2016-02-01

    Fyn, a member of the Src family of nonreceptor tyrosine kinases, promotes central nervous system myelination during development; however the mechanisms mediating this effect remain unknown. Here we show that Fyn phosphorylation is modulated by BDNF in vivo. Concordant with this, we find that BDNF stimulates Fyn phosphorylation in myelinating cocultures, an effect dependent on oligodendroglial expression of TrkB. Importantly, PP2, a pharmacological inhibitor of Src family kinases, not only abrogated the promyelinating influence of BDNF in vitro, but also attenuated BDNF-induced phosphorylation of Erk1/2 in oligodendrocytes. Over-expression of Fyn in oligodendrocytes significantly promotes phosphorylation of Erk1/2, and promotes myelination to the extent that exogenous BDNF exerts no additive effect in vitro. In contrast, expression of a kinase-dead mutant of Fyn in oligodendrocytes significantly inhibited BDNF-induced activation of Erk1/2 and abrogated the promyelinating effect of BDNF. Analysis of white matter tracts in vivo revealed that phosphorylated Fyn primarily colocalized with mature oligodendrocytes, and was rarely observed in oligodendrocyte progenitor cells, a profile that closely parallels the detection of phosphorylated Erk1/2 in the developing central nervous system. Taken together, these data identify that Fyn kinase exerts a key role in mediating the promyelinating influence of BDNF. Here we identify a pathway in which BDNF activation of oligodendroglial TrkB receptors stimulates the phosphorylation of Fyn, a necessary step required to potentiate the phosphorylation of Erk1/2, which in turn regulates oligodendrocyte myelination.

  11. Prenatal Exposure to Polycyclic Aromatic Hydrocarbons /Aromatics, BDNF and Child Development

    PubMed Central

    Perera, Frederica; Phillips, David H.; Wang, Ya; Roen, Emily; Herbstman, Julie; Rauh, Virginia; Wang, Shuang; Tang, Deliang

    2015-01-01

    Objectives Within a New York City (NYC) birth cohort, we assessed the associations between polycyclic aromatic hydrocarbon (PAH) and other aromatic DNA adducts and brain derived neurotrophic factor (BDNF) concentrations in umbilical cord blood, and neurodevelopment at age 2 years and whether BDNF is a mediator of the associations between PAH/aromatic-DNA adducts and neurodevelopment. Methods PAH/aromatic-DNA adduct concentrations in cord blood were measured in 505 children born to nonsmoking African-American and Dominican women residing in NYC, and a subset was assessed for neurodevelopment at 2 years using the Bayley Scales of Infant Development Mental Development Index (MDI). A spectrum of PAH/aromatic-DNA adducts was measured using the 32P-postlabeling assay; DNA adducts formed by benzo[a]pyrene (B[a]P), a representative PAH, were measured by High Performance Liquid Chromatography (HPLC)/fluorescence. BDNF mature protein in cord blood plasma was quantified by an ELISA. Multivariate regression analysis, adjusting for potential confounders, was conducted. Results PAH/aromatic-DNA adduct concentration measured by postlabeling was inversely associated with BDNF concentration (p=0.02) and with MDI scores at 2 years (p=0.04). BDNF level was positively associated with MDI scores (p=0.003). Restricting to subjects having all three measures (PAH/aromatic-DNA adducts by postlabeling, MDI, and BDNF), results were similar but attenuated (p=0.13, p=0.05, p=0.01, respectively). Associations between B[a]P-DNA adducts and BDNF and B[a]P-DNA adducts and MDI at age 2 years were not significant. At age 3 years, the positive association of BDNF with MDI was not observed. Conclusions The results at age 2 suggest that prenatal exposure to a spectrum of PAH/aromatic pollutants may adversely affect early neurodevelopment, in part by reducing BDNF levels during the fetal period. However, the same relationship was not seen at age 3. PMID:26301740

  12. Exogenous t-PA administration increases hippocampal mature BDNF levels. plasmin- or NMDA-dependent mechanism?

    PubMed

    Rodier, Marion; Prigent-Tessier, Anne; Béjot, Yannick; Jacquin, Agnès; Mossiat, Claude; Marie, Christine; Garnier, Philippe

    2014-01-01

    Brain-derived neurotrophic factor (BDNF) through TrkB activation is central for brain functioning. Since the demonstration that plasmin is able to process pro-BDNF to mature BDNF and that these two forms have opposite effects on neuronal survival and plasticity, a particular attention has been paid to the link between tissue plasminogen activator (tPA)/plasmin system and BDNF metabolism. However, t-PA via its action on different N-methyl-D-aspartate (NMDA) receptor subunits is also considered as a neuromodulator of glutamatergic transmission. In this context, the aim of our study was to investigate the effect of recombinant (r)t-PA administration on brain BDNF metabolism in rats. In the hippocampus, we found that rt-PA (10 mg/kg) administration induced a progressive increase in mature BDNF levels associated with TrkB activation. In order to delineate the mechanistic involved, plasmin activity was assessed and its inhibition was attempted using tranexamic acid (30 or 300 mg/kg, i.v.) while NMDA receptors were antagonized with MK801 (0.3 or 3 mg/kg, i.p.) in combination with rt-PA treatment. Our results showed that despite a rise in rt-PA activity, rt-PA administration failed to increase hippocampal plasmin activity suggesting that the plasminogen/plasmin system is not involved whereas MK801 abrogated the augmentation in mature BDNF levels observed after rt-PA administration. All together, our results show that rt-PA administration induces increase in hippocampal mature BDNF expression and suggests that rt-PA contributes to the control of brain BDNF synthesis through a plasmin-independent potentiation of NMDA receptors signaling.

  13. Novel activity-dependent approaches to therapeutic hypnosis and psychotherapy: the general waking trance.

    PubMed

    Rossi, Ernest; Erickson-Klein, Roxanna; Rossi, Kathryn

    2008-10-01

    This paper presents a highly edited version of a videotape made in 1980 by Marion Moore, M.D., showing Milton H. Erickson and Moore demonstrating novel, activity-dependent approaches to hand-levitation and therapeutic hypnosis on their subject, Ernest Rossi. Erickson's naturalistic and utilization approach is described in his very direct and surprising induction in a trance challenged patient. These novel, and surprising inductions are examples of how Erickson was prescient in developing activity-dependent approaches to therapeutic hypnosis and psychotherapy several generations before modern neuroscience documented the activity-dependent molecular-genomic mechanisms of memory, learning, and behavior change. Erickson describes a case where he utilized what he called, "The General Waking Trance" when he "dared" not use an obvious hypnotic induction. It is proposed that the states of intense mental absorption and response attentiveness that are facilitated by the general waking trance are functionally related to the three conditions neuroscientists have identified as novelty, enrichment, and exercise (both mental and physical), which can turn on activity-dependent gene expression and activity-dependent brain plasticity, that are the molecular-genomic and neural basis ofmemory, learning, consciousness, and behavior change. We recommend that the next step in investigating the efficacy of therapeutic hypnosis will be in partnering with neuroscientists to explore the possibilities and limitations of utilizing the activity-dependent approaches to hypnotic induction and the general waking trance in facilitating activity-dependent gene expression and brain plasticity.

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

    PubMed

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

    2014-07-30

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

  15. Dendritic targeting of short and long 3′ UTR BDNF mRNA is regulated by BDNF or NT-3 and distinct sets of RNA-binding proteins

    PubMed Central

    Vicario, Annalisa; Colliva, Andrea; Ratti, Antonia; Davidovic, Laetitia; Baj, Gabriele; Gricman, Łukasz; Colombrita, Claudia; Pallavicini, Alberto; Jones, Kevin R.; Bardoni, Barbara; Tongiorgi, Enrico

    2015-01-01

    Sorting of mRNAs in neuronal dendrites relies upon inducible transport mechanisms whose molecular bases are poorly understood. We investigated here the mechanism of inducible dendritic targeting of rat brain-derived neurotrophic factor (BDNF) mRNAs as a paradigmatic example. BDNF encodes multiple mRNAs with either short or long 3′ UTR, both hypothesized to harbor inducible dendritic targeting signals. However, the mechanisms of sorting of the two 3′ UTR isoforms are controversial. We found that dendritic localization of BDNF mRNAs with short 3′ UTR was induced by depolarization and NT3 in vitro or by seizures in vivo and required CPEB-1, -2 and ELAV-2, -4. Dendritic targeting of long 3′ UTR was induced by activity or BDNF and required CPEB-1 and the relief of soma-retention signals mediated by ELAV-1, -3, -4, and FXR proteins. Thus, long and short 3′ UTRs, by using different sets of RNA-binding proteins provide a mechanism of selective targeting in response to different stimuli which may underlay distinct roles of BDNF variants in neuronal development and plasticity. PMID:26578876

  16. Authentication Without Secrets

    SciTech Connect

    Pierson, Lyndon G.; Robertson, Perry J.

    2015-11-01

    This work examines a new approach to authentication, which is the most fundamental security primitive that underpins all cyber security protections. Current Internet authentication techniques require the protection of one or more secret keys along with the integrity protection of the algorithms/computations designed to prove possession of the secret without actually revealing it. Protecting a secret requires physical barriers or encryption with yet another secret key. The reason to strive for "Authentication without Secret Keys" is that protecting secrets (even small ones only kept in a small corner of a component or device) is much harder than protecting the integrity of information that is not secret. Promising methods are examined for authentication of components, data, programs, network transactions, and/or individuals. The successful development of authentication without secret keys will enable far more tractable system security engineering for high exposure, high consequence systems by eliminating the need for brittle protection mechanisms to protect secret keys (such as are now protected in smart cards, etc.). This paper is a re-release of SAND2009-7032 with new figures numerous edits.

  17. Chronic Unpredictable Stress Decreases Expression of Brain-Derived Neurotrophic Factor (BDNF) in Mouse Ovaries: Relationship to Oocytes Developmental Potential

    PubMed Central

    Tong, Xian-Hong; Han, Hui; Shen, Ni; Jin, Ren-Tao; Wang, Wei; Zhou, Gui-Xiang; He, Guo-Ping; Liu, Yu-Sheng

    2012-01-01

    Background Brain-derived neurotropic factor (BDNF) was originally described in the nervous system but has been shown to be expressed in ovary tissues recently, acting as a paracrine/autocrine regulator required for developments of follicles and oocytes. Although it is generally accepted that chronic stress impairs female reproduction and decreases the expression of BDNF in limbic structures of central nervous system, which contributes to mood disorder. However, it is not known whether chronic stress affects oocytes developments, nor whether it affects expression of BDNF in ovary. Methods Mice were randomly assigned into control group, stressed group, BDNF-treated group and BDNF-treated stressed group. The chronic unpredictable mild stress model was used to produce psychosocial stress in mice, and the model was verified by open field test and hypothalamic-pituitary-adrenal (HPA) axis activity. The methods of immunohistochemistry and western blotting were used to detect BDNF protein level and distribution. The number of retrieved oocytes, oocyte maturation, embryo cleavage and the rates of blastocyst formation after parthenogenetic activation were evaluated. Results Chronic unpredictable stress decreased the BDNF expression in antral follicles, but didn’t affect the BDNF expression in primordial, primary and secondary follicles. Chronic unpredictable stress also decreased the number of retrieved oocytes and the rate of blastocyst formation, which was rescued by exogenous BDNF treatment. Conclusion BDNF in mouse ovaries may be related to the decreased number of retrieved oocytes and impaired oocytes developmental potential induced by chronic unpredictable stress. PMID:23284991

  18. Pharmacological Profile of Brain-derived Neurotrophic Factor (BDNF) Splice Variant Translation Using a Novel Drug Screening Assay

    PubMed Central

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

    2014-01-01

    The neurotrophin brain-derived neurotrophic factor (BDNF) is a key regulator of neuronal development and plasticity. BDNF is a major pharmaceutical target in neurodevelopmental and psychiatric disorders. However, pharmacological modulation of this neurotrophin is challenging because BDNF is generated by multiple, alternatively spliced transcripts with different 5′- and 3′UTRs. Each BDNF mRNA variant is transcribed independently, but translation regulation is unknown. To evaluate the translatability of BDNF transcripts, we developed an in vitro luciferase assay in human neuroblastoma cells. In unstimulated cells, each BDNF 5′- and 3′UTR determined a different basal translation level of the luciferase reporter gene. However, constructs with either a 5′UTR or a 3′UTR alone showed poor translation modulation by BDNF, KCl, dihydroxyphenylglycine, AMPA, NMDA, dopamine, acetylcholine, norepinephrine, or serotonin. Constructs consisting of the luciferase reporter gene flanked by the 5′UTR of one of the most abundant BDNF transcripts in the brain (exons 1, 2c, 4, and 6) and the long 3′UTR responded selectively to stimulation with the different receptor agonists, and only transcripts 2c and 6 were increased by the antidepressants desipramine and mirtazapine. We propose that BDNF mRNA variants represent “a quantitative code” for regulated expression of the protein. Thus, to discriminate the efficacy of drugs in stimulating BDNF synthesis, it is appropriate to use variant-specific in vitro screening tests. PMID:25074925

  19. 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

  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.

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

    PubMed

    Giampà, Carmela; Montagna, Elena; Dato, Clemente; Melone, Mariarosa A B; Bernardi, Giorgio; Fusco, Francesca Romana

    2013-01-01

    Loss of huntingtin-mediated BDNF gene transcription has been shown to occur in HD and thus contribute to the degeneration of the striatum. Several studies have indicated that an increase in BDNF levels is associated with neuroprotection and amelioration of neurological signs in animal models of HD. In a recent study, an increase in BDNF mRNA and protein levels was recorded in mice administered recombinant BDNF peripherally. Chronic, indwelling osmotic mini-pumps containing either recombinant BDNF or saline were surgically placed in R6/2 or wild-type mice from 4 weeks of age until euthanasia. Neurological evaluation (paw clasping, rotarod performance, locomotor activity in an open field) was performed. After transcardial perfusion, histological and immunohistochemical studies were performed. We found that BDNF- treated R6/2 mice survived longer and displayed less severe signs of neurological dysfunction than the vehicle treated ones. Primary outcome measures such as brain volume, striatal atrophy, size and morphology of striatal neurons, neuronal intranuclear inclusions and microglial reaction confirmed a neuroprotective effect of the compound. BDNF was effective in increasing significantly the levels of activated CREB and of BDNF the striatal spiny neurons. Moreover, systemically administered BDNF increased the synthesis of BDNF as demonstrated by RT-PCR, and this might account for the beneficial effects observed in this model.

  2. Highly penetrant alterations of a critical region including BDNF contribute to human psychopathology

    PubMed Central

    Ernst, Carl; Marshall, Christian R.; Shen, Yiping; Metcalfe, Kay; Rosenfeld, Jill; Hodge, Jennelle C.; Torres, Alcy; Blumenthal, Ian; Chiang, Colby; Pillalamarri, Vamsee; Crapper, Liam; Diallo, Alpha B.; Ruderfer, Douglas; Pereira, Shahrin; Sklar, Pamela; Purcell, Shaun; Wildin, Robert S.; Spencer, Anne C.; Quade, Bradley F.; Harris, David J.; Lemyre, Emanuelle; Wu, Bailin; Stavropoulos, Dimitri J.; Geraghty, Michael T.; Shaffer, Lisa G.; Morton, Cynthia C; Scherer, Stephen W.; Gusella, James F.; Talkowski, Michael E.

    2013-01-01

    CONTEXT Brain-derived neurotrophic factor (BDNF) is suspected of being a causative factor in psychiatric disorders based on case reports or studies involving large structural anomalies. OBJECTIVE To determine the involvement of BDNF in human psychopathology DESIGN Case- Control study SETTING Microarray-based comparative genomic hybridization (aCGH) data from seven molecular diagnostic centers including 38, 550 affected subjects and 28, 705 unaffected subjects. PATIENTS Subjects referred to diagnostic screening centers for aCGH for physical or cognitive impairment. MAIN OUTCOME MEASURE Genomic copy number gains and losses RESULTS We report five individuals with psychopathology and genomic deletion of a critical region including BDNF. The defined critical region was never disrupted in control subjects or diagnostic cases without developmental abnormalities. CONCLUSION Hemizygosity of the BDNF region contributes to variable psychiatric phenotypes including anxiety, behavioral, and mood disorders. PMID:23044507

  3. The Neuroprotective Role of Acupuncture and Activation of the BDNF Signaling Pathway

    PubMed Central

    Lin, Dong; De La Pena, Ike; Lin, Lili; Zhou, Shu-Feng; Borlongan, Cesar V.; Cao, Chuanhai

    2014-01-01

    Recent studies have been conducted to examine the neuroprotective effects of acupuncture in many neurological disorders. Although the neuroprotective effects of acupuncture has been linked to changes in signaling pathways, accumulating evidence suggest the participation of endogenous biological mediators, such as the neurotrophin (NT) family of proteins, specifically, the brain derived neurotrophic factor (BDNF). Accordingly, acupuncture can inhibit neurodegeneration via expression and activation of BDNF. Moreover, recent studies have reported that acupuncture can increase ATP levels at local stimulated points. We have also demonstrated that acupuncture could activate monocytes and increase the expression of BDNF via the stimulation of ATP. The purpose of this article is to review the recent findings and ongoing studies on the neuroprotective roles of acupuncture and therapeutic implications of acupuncture-induced activation of BDNF and its signaling pathway. PMID:24566146

  4. BDNF and its receptors in human myasthenic thymus: implications for cell fate in thymic pathology.

    PubMed

    Berzi, Angela; Ayata, C Korcan; Cavalcante, Paola; Falcone, Chiara; Candiago, Elisabetta; Motta, Teresio; Bernasconi, Pia; Hohlfeld, Reinhard; Mantegazza, Renato; Meinl, Edgar; Farina, Cinthia

    2008-07-15

    Here we show that in myasthenic thymus several cell types, including thymic epithelial cells (TEC) and immune cells, were the source and the target of the neurotrophic factor brain-derived growth factor (BDNF). Interestingly, many actively proliferating medullary thymocytes expressed the receptor TrkB in vivo in involuted thymus, while this population was lost in hyperplastic or neoplastic thymuses. Furthermore, in hyperplastic thymuses the robust coordinated expression of BDNF in the germinal centers together with the receptor p75NTR on all proliferating B cells strongly suggests that this factor regulates germinal center reaction. Finally, all TEC dying of apoptosis expressed BDNF receptors, indicating that this neurotrophin is involved in TEC turnover. In thymomas both BDNF production and receptor expression in TEC were strongly hindered. This may represent an attempt of tumour escape from cell death.

  5. The requirement of BDNF for hippocampal synaptic plasticity is experience‐dependent

    PubMed Central

    Aarse, Janna; Herlitze, Stefan

    2016-01-01

    ABSTRACT 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

  6. BDNF deficiency and young-adult methamphetamine induce sex-specific effects on prepulse inhibition regulation

    PubMed Central

    Manning, Elizabeth E.; van den Buuse, Maarten

    2013-01-01

    Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of schizophrenia, yet its role in the development of specific symptoms is unclear. Methamphetamine (METH) users have an increased risk of psychosis and schizophrenia, and METH-treated animals have been used extensively as a model to study the positive symptoms of schizophrenia. We investigated whether METH treatment in BDNF heterozygous (HET) mutant mice has cumulative effects on sensorimotor gating, including the disruptive effects of psychotropic drugs. BDNF HETs and wildtype (WT) littermates were treated during young adulthood with METH and, following a 2-week break, prepulse inhibition (PPI) was examined. At baseline, BDNF HETs showed reduced PPI compared to WT mice irrespective of METH pre-treatment. An acute challenge with amphetamine (AMPH) disrupted PPI but male BDNF HETs were more sensitive to this effect, irrespective of METH pre-treatment. In contrast, female mice treated with METH were less sensitive to the disruptive effects of AMPH, and there were no effects of BDNF genotype. Similar changes were not observed in the response to an acute apomorphine (APO) or MK-801 challenge. These results show that genetically-induced reduction of BDNF caused changes in a behavioral endophenotype relevant to the positive symptoms of schizophrenia. However, major sex differences were observed in the effects of a psychotropic drug challenge on this behavior. These findings suggest sex differences in the effects of BDNF depletion and METH treatment on the monoamine signaling pathways that regulate PPI. Given that these same pathways are thought to contribute to the expression of positive symptoms in schizophrenia, this work suggests that there may be significant sex differences in the pathophysiology underlying these symptoms. Elucidating these sex differences may be important for our understanding of the neurobiology of schizophrenia and developing better treatments strategies for the

  7. Endogenous BDNF regulates inhibitory synaptic transmission in the ventromedial nucleus of the hypothalamus.

    PubMed

    Jo, Young-Hwan

    2012-01-01

    Output from steroidogenic factor-1 (SF-1) neurons in the ventromedial nucleus of the hypothalamus (VMH) is anorexigenic. SF-1 neurons express brain-derived neurotrophic factor (BDNF) that contributes to the regulation of food intake and body weight. Here I show that regulation of GABAergic inputs onto SF-1 neurons by endogenous BDNF determines the anorexigenic outcome from the VMH. Single-cell RT-PCR analysis reveals that one-third of SF-1 neurons express BDNF and that only a subset of BDNF-expressing SF-1 neurons coexpresses the melanocortin receptor type 4. Whole cell patch-clamp analysis of SF-1 neurons in the VMH shows that exogenous BDNF significantly increases the frequency of spontaneous GABAergic inhibitory postsynaptic currents (sIPSCs). This enhancement of GABA drive readily decreases the excitability of SF-1 neurons. However, treatment with BDNF has no significant effect on the frequency of TTX-independent GABAergic IPSCs. Moreover, TrkB receptors are not localized at the postsynaptic sites of GABAergic synapses on SF-1 neurons as there is no change in the amplitude of miniature IPSCs in the presence of BDNF. Dual patch-clamp recordings in mouse hypothalamic slices reveal that stimulation of one SF-1 neuron induces an increase in sIPSC frequency onto the neighboring SF-1 neuron. More importantly, this effect is blocked by a tyrosine kinase inhibitor. Hence, this increased GABA drive onto SF-1 neurons may, in part, explain the cellular mechanisms that mediate the anorexigenic effects of BDNF.

  8. Prenatal stress differentially alters BDNF expression and signaling across rat strains

    PubMed Central

    Neeley, Eric W.; Berger, Ralph; Koenig, James I.; Leonard, Sherry

    2011-01-01

    Background Psychiatric illness and anxiety disorders have strong neurodevelopmental components. Environmental insults such as prenatal exposure to stress and genetic differences in stress responses may affect brain development. Methods A rat model of random variable prenatal stress was used to study the expression and processing of hippocampal brain-derived neurotrophic factor (BDNF) in the offspring of the stressed rat dams. To account for unknown genetic influences that may play a role in the outcome of this prenatal stress paradigm, three different rat strains with known differences in stress responsivity were studied: Fischer, Sprague-Dawley, and Lewis rats (n=132). Results Multiple disparities in mRNA expression levels of BDNF, and transcripts related to its processing and signaling were found in the three strains. Of the numerous splice variants transcribed from the BDNF gene, the transcript containing BDNF exon VI was most aberrant in the prenatally stressed animals. Protein levels of both uncleaved proBDNF and mature BDNF were also altered, as was intra-cellular signaling by phosphorylation of the TrkB receptor and Erk 1/2. Changes were not only dependent on prenatal stress, but were also strain dependent, demonstrating the importance of genetic background. Conclusions BDNF signaling provides both positive neurotrophic support for neurons and negative apoptotic effects, both of which may contribute to behavioral or neurochemical outcomes after prenatal exposure to stress. Differential processing of BDNF after prenatal stress in the three rat strains has implications for human subjects where genetic differences may protect or exacerbate the effects of an environmental stressor during fetal development. PMID:21497180

  9. Secrets to success.

    PubMed

    Sorrel, Amy Lynn

    2014-02-01

    A new national study reveals what it takes for physician practices to stay financially viable. Several Texas practices, among those rated as "better performers," share their secrets to success. One of those secrets, a physician says, is "hiring good people and getting out of their way." PMID:24500918

  10. Secrets in "The Day of Ahmed's Secret."

    ERIC Educational Resources Information Center

    Duckett, Peter; Knox, Marjorie

    2001-01-01

    Examines images and the written text in the picture book, "The Day of Ahmed's Secret," by Florence Parry Heide and Judith Heide Gilliland. Examines the book in greater detail by looking for issues of authenticity as well as social issues within the book's pictures and written texts. (SG)

  11. 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

  12. Effect of exercise on the plasma BDNF levels in elderly women with knee osteoarthritis.

    PubMed

    Gomes, Wellington F; Lacerda, Ana Cristina R; Mendonça, Vanessa A; Arrieiro, Arthur N; Fonseca, Sueli F; Amorim, Mateus R; Teixeira, Antônio L; Teixeira, Mauro M; Miranda, Aline S; Coimbra, Cândido C; Brito-Melo, Gustavo E A

    2014-06-01

    Knee osteoarthritis is a common disease in the elderly population worldwide. The alleviation of the symptoms associated with this disease can be achieved with physical exercise that induces a cascade of molecular and cellular processes. Of the neurotrophins, brain-derived neurotrophic factor (BDNF) appears to be the most affected by physical activity. Moreover, BDNF seems to have a negative modulatory role in inflammation, and its production by skeletal muscle cells or by cells of the immune system drives the immunoprotective role of physical activity in situations of chronic inflammation. Therefore, the aim of this study was to evaluate plasma BDNF concentrations in elderly individuals presenting with knee osteoarthritis. To accomplish this, sixteen volunteers (mean age 67 ± 4.41 years) presenting with clinically and radiographically diagnosed knee osteoarthritis were evaluated during acute exercise (1 session of 20 min on a treadmill) and after chronic exercise (12 weeks of aerobic training, consisting of a 50-min walk 3 times per week). Additionally, both a functional assessment (during a 6-min walk) and a pain perception assessment were performed at the start and at the end of physical exercises (training). The plasma BDNF concentrations were measured by ELISA. For the population studied, acute exercise increased the levels of BDNF only before the 12-week training period (p < 0.001). Moreover, the training augmented the plasma concentrations of BDNF (p < 0.0001) and improved clinical parameters (functional p < 0.001; pain perception p < 0.01).

  13. Serum cortisol and BDNF in patients with major depression-effect of yoga.

    PubMed

    Naveen, G H; Varambally, Shivarama; Thirthalli, Jagadisha; Rao, Mukund; Christopher, Rita; Gangadhar, B N

    2016-06-01

    Depression is associated with low serum Brain Derived Neurotrophic Factor (BDNF) and elevated levels of serum cortisol. Yoga practices have been associated with antidepressant effects, increase in serum BDNF, and reduction in serum cortisol. This study examined the association between serum BDNF and cortisol levels in drug-naïve patients with depression treated with antidepressants, yoga therapy, and both. Fifty-four drug-naïve consenting adult outpatients with Major Depression (32 males) received antidepressants only (n = 16), yoga therapy only (n = 19), or yoga with antidepressants (n = 19). Serum BDNF andcortisol levels were obtained before and after 3 months using a sandwich ELISA method. One-way ANOVA, Chi-square test, and Pearson's correlation tests were used for analysis. The groups were comparable at baseline on most parameters. Significant improvement in depression scores and serum BDNF levels, and reduction in serum cortisol in the yoga groups, have been described in previous reports. A significant negative correlation was observed between change in BDNF (pre-post) and cortisol (pre-post) levels in the yoga-only group (r = -0.59, p = 0.008). In conclusion, yoga may facilitate neuroplasticity through stress reduction in depressed patients. Further studies are needed to confirm the findings and delineate the pathways for these effects. PMID:27174729

  14. Aerobic exercise improves hippocampal function and increases BDNF in the serum of young adult males.

    PubMed

    Griffin, Éadaoin W; Mullally, Sinéad; Foley, Carole; Warmington, Stuart A; O'Mara, Shane M; Kelly, Aine M

    2011-10-24

    Physical activity has been reported to improve cognitive function in humans and rodents, possibly via a brain-derived neurotrophic factor (BDNF)-regulated mechanism. In this study of human subjects, we have assessed the effects of acute and chronic exercise on performance of a face-name matching task, which recruits the hippocampus and associated structures of the medial temporal lobe, and the Stroop word-colour task, which does not, and have assessed circulating concentrations of BDNF and IGF-1 in parallel. The results show that a short period of high-intensity cycling results in enhancements in performance of the face-name matching, but not the Stroop, task. These changes in cognitive function were paralleled by increased concentration of BDNF, but not IGF-1, in the serum of exercising subjects. 3 weeks of cycling training had no effect on cardiovascular fitness, as assessed by VO2 scores, cognitive function, or serum BDNF concentration. Increases in fitness, cognitive function and serum BDNF response to acute exercise were observed following 5 weeks of aerobic training. These data indicate that both acute and chronic exercise improve medial temporal lobe function concomitant with increased concentrations of BDNF in the serum, suggesting a possible functional role for this neurotrophic factor in exercise-induced cognitive enhancement in humans. PMID:21722657

  15. ProBDNF inhibits collective migration and chemotaxis of rat Schwann cells.

    PubMed

    Ding, You-Quan; Li, Xuan-Yang; Xia, Guan-Nan; Ren, Hong-Yi; Zhou, Xin-Fu; Su, Bing-Yin; Qi, Jian-Guo

    2016-10-01

    Schwann cell migration, including collective migration and chemotaxis, is essential for the formation of coordinate interactions between Schwann cells and axons during peripheral nerve development and regeneration. Moreover, limited migration of Schwann cells imposed a serious obstacle on Schwann cell-astrocytes intermingling and spinal cord repair after Schwann cell transplantation into injured spinal cords. Recent studies have shown that mature brain-derived neurotrophic factor, a member of the neurotrophin family, inhibits Schwann cell migration. The precursor form of brain-derived neurotrophic factor, proBDNF, was expressed in the developing or degenerating peripheral nerves and the injured spinal cords. Since "the yin and yang of neurotrophin action" has been established as a common sense, proBDNF would be expected to promote Schwann cell migration. However, we found, in the present study, that exogenous proBDNF also inhibited in vitro collective migration and chemotaxis of RSC 96 cells, a spontaneously immortalized rat Schwann cell line. Moreover, proBDNF suppressed adhesion and spreading of those cells. At molecular level, proBDNF inhibits F-actin polymerization and focal adhesion dynamics in cultured RSC 96 cells. Therefore, our results suggested a special case against the classical opinion of "the yin and yang of neurotrophin action" and implied that proBDNF might modulate peripheral nerve development or regeneration and spinal cord repair through perturbing native or transplanted Schwann cell migration.

  16. BDNF concentration and impulsiveness level in post-traumatic stress disorder.

    PubMed

    Martinotti, Giovanni; Sepede, Gianna; Brunetti, Marcella; Ricci, Valerio; Gambi, Francesco; Chillemi, Eleonora; Vellante, Federica; Signorelli, Maria; Pettorruso, Mauro; De Risio, Luisa; Aguglia, Eugenio; Angelucci, Francesco; Caltagirone, Carlo; Di Giannantonio, Massimo

    2015-10-30

    Among the symptoms of post-traumatic stress disorder (PTSD), impulsiveness has been observed in patients with high levels of hyperarousal. Recent literature reveals the importance of investigating the role of neurotrophins, such as brain-derived neurotrophic factor (BDNF), in several psychiatric disorders. Specifically, contrasting findings have been reported on the levels of serum BDNF in subjects with PTSD. The aim of the present study was to investigate the correlation between BDNF serum levels and impulsiveness in PTSD. To this end, we measured BDNF serum levels in 23 PTSD patients and a control group of 19 trauma-exposed non-PTSD subjects. Results indicate a positive correlation in the PTSD group; that is, the higher the BDNF levels the higher the impulsiveness score, as measured by the Barratt Impulsiveness Scale (BIS-11), suggesting that impulsiveness could be associated with greater BDNF production. Alternatively, it is also possible that high impulsiveness acts as a psychological mechanism that counteracts the negative effects exerted by the traumatic experience and the associated obsessive thoughts. The present paper discusses both hypotheses.

  17. TrkB/BDNF Signaling Regulates Photoreceptor Progenitor Cell Fate Decisions

    PubMed Central

    Turner, Brian A.; Sparrow, Janet; Cai, Bolin; Monroe, Julie; Mikawa, Takashi; Hempstead, Barbara L.

    2008-01-01

    Neurotrophins, via activation of Trk receptor tyrosine kinases, serve as mitogens, survival factors and regulators of arborization during retinal development. Brain-derived neurotrophic factor (BDNF) and TrkB regulate neuronal arborization and survival in late retinal development. However, TrkB is expressed during early retinal developmet where its functions are unclear. To assess TrkB/BDNF actions in the early chick retina, replication-incompetent retroviruses were utilized to over-express a dominant negative truncated form of TrkB (trunc TrkB), or BDNF and effects were assessed at E15. Clones expressing trunc TrkB were smaller than controls, and proliferation and apoptosis assays suggest that decreased clone size correlated with increased cell death when BDNF/TrkB signaling was impaired. Analysis of clonal composition revealed that trunc TrkB over-expression decreased photoreceptor numbers (41%) and increased cell numbers in the middle third of the inner nuclear layer (INL) (23%). Conversely, BDNF over-expression increased photoreceptor numbers (25%) and decreased INL numbers (17%). Photoreceptors over-expressing trunc TrkB demonstrated no increase in apoptosis nor abnormalities in lamination suggesting that TrkB activation is not required for photoreceptor cell survival or migration. These studies suggest that TrkB signaling regulates commitment to and/or differentiation of photoreceptor cells from retinal progenitor cells, identifying a novel role for TrkB/BDNF in regulating cell fate decisions. PMID:17005175

  18. Computer Simulations Support a Morphological Contribution to BDNF Enhancement of Action Potential Generation

    PubMed Central

    Hiester, Brian G.; Jones, Kevin R.

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) regulates both action potential (AP) generation and neuron morphology. However, whether BDNF-induced changes in neuron morphology directly impact AP generation is unclear. We quantified BDNF’s effect on cultured cortical neuron morphological parameters and found that BDNF stimulates dendrite growth and addition of dendrites while increasing both excitatory and inhibitory presynaptic inputs in a spatially restricted manner. To gain insight into how these combined changes in neuron structure and synaptic input impact AP generation, we used the morphological parameters we gathered to generate computational models. Simulations suggest that BDNF-induced neuron morphologies generate more APs under a wide variety of conditions. Synapse and dendrite addition have the greatest impact on AP generation. However, subtle alterations in excitatory/inhibitory synapse ratio and strength have a significant impact on AP generation when synaptic activity is low. Consistent with these simulations, BDNF rapidly enhances spontaneous activity in cortical cultures. We propose that BDNF promotes neuron morphologies that are intrinsically more efficient at translating barrages of synaptic activity into APs, which is a previously unexplored aspect of BDNF’s function. PMID:27683544

  19. proBDNF Attenuates Hippocampal Neurogenesis and Induces Learning and Memory Deficits in Aged Mice.

    PubMed

    Chen, Jia; Li, Cheng-Ren; Yang, Heng; Liu, Juan; Zhang, Tao; Jiao, Shu-Sheng; Wang, Yan-Jiang; Xu, Zhi-Qiang

    2016-01-01

    Mature brain-derived neurotrophic factor has shown promotive effect on neural cells in rodents, including neural proliferation, differentiation, survival, and synaptic formation. Conversely, the precursor of brain-derived neurotrophic factor (proBDNF) has been emerging as a differing protein against its mature form, for its critical role in aging process and neurodegenerative diseases. In the present study, we investigated the role of proBDNF in neurogenesis in the hippocampal dentate gyrus of aged mice and examined the changes in mice learning and memory functions. The results showed that the newborn cells in the hippocampus revealed a significant decline in proBDNF-treated group compared with bovine serum albumin group, but an elevated level in anti-proBDNF group. During the maturation period, no significant change was observed in the proportions of phenotype of the newborn cells among the three groups. In water maze, proBDNF-treated mice had poorer scores in place navigation test and probe test, compared with those from any other group. Thus, we conclude that proBDNF attenuates neurogenesis in the hippocampus and induces the deficits in learning and memory functions of aged mice.

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

    PubMed

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

    2015-03-01

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

  1. Aerobic exercise improves hippocampal function and increases BDNF in the serum of young adult males.

    PubMed

    Griffin, Éadaoin W; Mullally, Sinéad; Foley, Carole; Warmington, Stuart A; O'Mara, Shane M; Kelly, Aine M

    2011-10-24

    Physical activity has been reported to improve cognitive function in humans and rodents, possibly via a brain-derived neurotrophic factor (BDNF)-regulated mechanism. In this study of human subjects, we have assessed the effects of acute and chronic exercise on performance of a face-name matching task, which recruits the hippocampus and associated structures of the medial temporal lobe, and the Stroop word-colour task, which does not, and have assessed circulating concentrations of BDNF and IGF-1 in parallel. The results show that a short period of high-intensity cycling results in enhancements in performance of the face-name matching, but not the Stroop, task. These changes in cognitive function were paralleled by increased concentration of BDNF, but not IGF-1, in the serum of exercising subjects. 3 weeks of cycling training had no effect on cardiovascular fitness, as assessed by VO2 scores, cognitive function, or serum BDNF concentration. Increases in fitness, cognitive function and serum BDNF response to acute exercise were observed following 5 weeks of aerobic training. These data indicate that both acute and chronic exercise improve medial temporal lobe function concomitant with increased concentrations of BDNF in the serum, suggesting a possible functional role for this neurotrophic factor in exercise-induced cognitive enhancement in humans.

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

    PubMed

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

    2010-05-01

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

  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. Computer Simulations Support a Morphological Contribution to BDNF Enhancement of Action Potential Generation

    PubMed Central

    Hiester, Brian G.; Jones, Kevin R.

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) regulates both action potential (AP) generation and neuron morphology. However, whether BDNF-induced changes in neuron morphology directly impact AP generation is unclear. We quantified BDNF’s effect on cultured cortical neuron morphological parameters and found that BDNF stimulates dendrite growth and addition of dendrites while increasing both excitatory and inhibitory presynaptic inputs in a spatially restricted manner. To gain insight into how these combined changes in neuron structure and synaptic input impact AP generation, we used the morphological parameters we gathered to generate computational models. Simulations suggest that BDNF-induced neuron morphologies generate more APs under a wide variety of conditions. Synapse and dendrite addition have the greatest impact on AP generation. However, subtle alterations in excitatory/inhibitory synapse ratio and strength have a significant impact on AP generation when synaptic activity is low. Consistent with these simulations, BDNF rapidly enhances spontaneous activity in cortical cultures. We propose that BDNF promotes neuron morphologies that are intrinsically more efficient at translating barrages of synaptic activity into APs, which is a previously unexplored aspect of BDNF’s function.

  5. BDNF/TRKB/P75NTR polymorphisms and their consequences on antidepressant efficacy in depressed patients.

    PubMed

    Colle, Romain; Deflesselle, Eric; Martin, Séverine; David, Denis J; Hardy, Patrick; Taranu, Adéla; Falissard, Bruno; Verstuyft, Céline; Corruble, Emmanuelle

    2015-01-01

    We propose an extensive review of the literature about BDNF/TRKB/P75NTR polymorphisms and their consequences on antidepressant efficacy in depressed patients. Five genome-wide association studies and 30 association studies were included. Twenty seven studies focused on the Val66Met polymorphism (rs6265), the Met allele being associated with a higher antidepressant efficacy only in Asian patients. Other BDNF/TRKB/P75NTR polymorphisms (BDNF: rs7103411, rs7124442, rs908867, rs2049046, rs61888800, rs10501087, rs1491850; TRKB: rs10868223, rs11140778, rs1565445, rs1659412; P75NTR: rs2072446) were reported to be associated with antidepressant efficacy but these results were not replicated. Finally, there are 15 positive studies among 30 studies regarding BDNF/TRKB/P75NTR polymorphisms. The only SNP which benefits of at least three positive studies is the BDNF Val66Met polymorphism (rs6265). Consequently, with a lack of good and consistent studies, the clinical utility of BDNF in treatment selection is far from clear. We propose several recommendations for further studies.

  6. Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity.

    PubMed

    Pang, Petti T; Teng, Henry K; Zaitsev, Eugene; Woo, Newton T; Sakata, Kazuko; Zhen, Shushuang; Teng, Kenneth K; Yung, Wing-Ho; Hempstead, Barbara L; Lu, Bai

    2004-10-15

    Long-term memory is thought to be mediated by protein synthesis-dependent, late-phase long-term potentiation (L-LTP). Two secretory proteins, tissue plasminogen activator (tPA) and brain-derived neurotrophic factor (BDNF), have been implicated in this process, but their relationship is unclear. Here we report that tPA, by activating the extracellular protease plasmin, converts the precursor proBDNF to the mature BDNF (mBDNF), and that such conversion is critical for L-LTP expression in mouse hippocampus. Moreover, application of mBDNF is sufficient to rescue L-LTP when protein synthesis is inhibited, which suggests that mBDNF is a key protein synthesis product for L-LTP expression.

  7. Respective pharmacological features of neuropathic-like pain evoked by intrathecal BDNF versus sciatic nerve ligation in rats.

    PubMed

    M'Dahoma, Saïd; Barthélemy, Sandrine; Tromilin, Claire; Jeanson, Tiffany; Viguier, Florent; Michot, Benoit; Pezet, Sophie; Hamon, Michel; Bourgoin, Sylvie

    2015-11-01

    Numerous reported data support the idea that Brain Derived Neurotrophic Factor (BDNF) is critically involved in both depression and comorbid pain. The possible direct effect of BDNF on pain mechanisms was assessed here and compared with behavioral/neurobiological features of neuropathic pain caused by chronic constriction injury to the sciatic nerve (CCI-SN). Sprague-Dawley male rats were either injected intrathecally with BDNF (3.0 ng i.t.) or subjected to unilateral CCI-SN. Their respective responses to anti-hyperalgesic drugs were assessed using the Randall-Selitto test and both immunohistochemical and RT-qPCR approaches were used to investigate molecular/cellular mechanisms underlying hyperalgesia in both models. Long lasting hyperalgesia and allodynia were induced by i.t. BDNF in intact healthy rats like those found after CCI-SN. Acute treatment with the BDNF-TrkB receptor antagonist cyclotraxin B completely prevented i.t. BDNF-induced hyperalgesia and partially reversed this symptom in both BDNF-pretreated and CCI-SN lesioned rats. Acute administration of the anticonvulsant pregabalin, the NMDA receptor antagonist ketamine, the opioid analgesics morphine and tapentadol or the antidepressant agomelatine also transiently reversed hyperalgesia in both i.t. BDNF injected- and CCI-SN lesioned-rats. Marked induction of microglia activation markers (OX42, Iba1, P-p38), proinflammatory cytokine IL-6, NMDA receptor subunit NR2B and BDNF was found in spinal cord and/or dorsal root ganglia of CCI-SN rats. A long lasting spinal BDNF overexpression was also observed in BDNF i.t. rats, indicating an autocrine self-induction, with downstream long lasting TrkB-mediated neuropathic-like pain. Accordingly, TrkB blockade appeared as a relevant approach to alleviate not only i.t. BDNF- but also nerve lesion-evoked neuropathic pain. PMID:26343858

  8. 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

  9. BDNF-mediated regulation of ethanol consumption requires the activation of the MAP kinase pathway and protein synthesis.

    PubMed

    Jeanblanc, Jerome; Logrip, Marian L; Janak, Patricia H; Ron, Dorit

    2013-02-01

    We previously found that the brain-derived neurotrophic factor (BDNF) in the dorsolateral striatum (DLS) is part of a homeostatic pathway that gates ethanol self-administration [Jeanblanc et al. (2009). J Neurosci, 29, 13494-13502)]. Specifically, we showed that moderate levels (10%) of ethanol consumption increase BDNF expression within the DLS, and that direct infusion of BDNF into the DLS decreases operant self-administration of a 10% ethanol solution. BDNF binding to its receptor, TrkB, activates the mitogen-activated protein kinase (MAPK), phospholipase C-γ (PLC-γ) and phosphatidylinositol 3-kinase (PI3K) pathways. Thus, here, we set out to identify which of these intracellular pathway(s) plays a role in the regulation of ethanol consumption by BDNF. We found that inhibition of the MAPK, but not PLC-γ or PI3K, activity blocks the BDNF-mediated reduction of ethanol consumption. As activation of the MAPK pathway leads to the initiation of transcription and/or translation events, we tested whether the BDNF-mediated reduction of ethanol self-administration requires de novo protein synthesis. We found that the inhibitory effect of BDNF on ethanol intake is blocked by the protein synthesis inhibitor cycloheximide. Together, our results show that BDNF attenuates ethanol drinking via activation of the MAPK pathway in a protein synthesis-dependent manner within the DLS.

  10. BDNF-mediated regulation of ethanol consumption requires the activation of the MAP kinase pathway and protein synthesis

    PubMed Central

    Jeanblanc, Jerome; Logrip, Marian L.; Janak, Patricia H.; Ron, Dorit

    2013-01-01

    We previously found that the brain-derived neurotrophic factor (BDNF) in the dorsolateral striatum (DLS) is part of a homeostatic pathway that gates ethanol self-administration [Jeanblanc et al. (2009). J Neurosci, 29, 13494–13502)]. Specifically, we showed that moderate levels (10%) of ethanol consumption increase BDNF expression within the DLS, and that direct infusion of BDNF into the DLS decreases operant self-administration of a 10% ethanol solution. BDNF binding to its receptor, TrkB, activates the mitogen-activated protein kinase (MAPK), phospholipase C-γ (PLC-γ) and phosphatidylinositol 3-kinase (PI3K) pathways. Thus, here, we set out to identify which of these intracellular pathway(s) plays a role in the regulation of ethanol consumption by BDNF. We found that inhibition of the MAPK, but not PLC-γ or PI3K, activity blocks the BDNF-mediated reduction of ethanol consumption. As activation of the MAPK pathway leads to the initiation of transcription and/or translation events, we tested whether the BDNF-mediated reduction of ethanol self-administration requires de novo protein synthesis. We found that the inhibitory effect of BDNF on ethanol intake is blocked by the protein synthesis inhibitor cycloheximide. Together, our results show that BDNF attenuates ethanol drinking via activation of the MAPK pathway in a protein synthesis-dependent manner within the DLS. PMID:23189980

  11. 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.

  12. A Large, Cross-Sectional Observational Study of Serum BDNF, Cognitive Function, and Mild Cognitive Impairment in the Elderly

    PubMed Central

    Shimada, Hiroyuki; Makizako, Hyuma; Doi, Takehiko; Yoshida, Daisuke; Tsutsumimoto, Kota; Anan, Yuya; Uemura, Kazuki; Lee, Sangyoon; Park, Hyuntae; Suzuki, Takao

    2014-01-01

    Objective: The clinical relationship between brain-derived neurotrophic factor (BDNF) and cognitive function or mild cognitive impairment (MCI) is not well-understood. The purpose of this study was to identify the relationship between serum BDNF and cognitive function and MCI, and determine whether serum BDNF level might be a useful biomarker for assessing risk for MCI in older people. Materials and Methods: A total of 4463 individuals aged 65 years or older (mean age 72 years) participating in the study. We measured performance in a battery of neuropsychological and cognitive function tests; serum BDNF concentration. Results: Eight hundred twenty-seven participants (18.8%) had MCI. After adjustment for sex, age, education level, diabetes, and current smoking, serum BDNF was associated with poorer performance in the story memory, and digit symbol substitution task scores. Serum BDNF was marginally associated with the presence of MCI (odds ratio, 95% confidence interval: 1.41, 1.00–1.99) when BDNF was 1.5 SD lower than the mean value standardized for sex and age, education level, diabetes, and current smoking. Conclusion: Low serum BDNF was associated with lower cognitive test scores and MCI. Future prospective studies should establish the discriminative value of serum BDNF for the risk of MCI. PMID:24782766

  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. BDNF-stimulated intracellular signalling mechanisms underlie exercise-induced improvement in spatial memory in the male Wistar rat.

    PubMed

    Bechara, Ranya G; Lyne, Ronan; Kelly, Áine M

    2014-12-15

    Exercise-induced improvements in learning are associated with neurotrophic and neurogenic changes in the dentate gyrus, but the intracellular signalling mechanisms that may mediate these improvements remain unknown. In the current study we investigate the effects of one week of forced exercise on spatial memory and analyse in parallel BDNF-stimulated signalling pathways in cells of the dentate gyrus. Additionally, we test whether a single intracerebroventricular (i.c.v.) injection of BDNF can mimic the observed cognitive and signalling changes. Male Wistar rats were assigned to exercised and sedentary groups and tested in a spatial task post-exercise. Tissue from the dentate gyrus was assessed for expression and release of BDNF, and for changes in expression and activation of TrkB, ERK and synapsin-1. In a separate set of experiments, male Wistar rats received a single i.c.v. injection of BDNF and were then tested in the same spatial learning task. Exercised and BDNF-treated (but not control) rats could successfully complete an object displacement task that tests spatial learning. Exercised rats and BDNF-treated rats displayed increases BDNF expression and ERK1 activation, while exercised rats showed increases in cell division, stimulated BDNF release, TrkB activation, and synapsin-1 expression in the dentate gyrus. We conclude that exercise-induced increases in BDNF in the dentate gyrus are sufficient to cause improvements in spatial memory by activating signalling cascades that enhance synaptic transmission in the hippocampus.

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

    PubMed

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

    2015-02-02

    BDNF and its gene polymorphism may be important in synaptic plasticity and neuron survival, and may become a key target in the physiopathology of long-term heroin use. Thus, we investigated the relationships between brain-derived neurotrophic factor (BDNF) plasma concentrations and the BDNF Val66Met nucleotide polymorphism (SNP) in heroin-dependent patients. The pretreatment expression levels of plasma BDNF and the BDNF Val66Met SNP in 172 heroin-dependent patients and 102 healthy controls were checked. BDNF levels were significantly lower in patients (F = 52.28, p < 0.0001), but the distribution of the SNP was not significantly different. Nor were plasma BDNF levels significantly different between Met/Met, Met/Val, and Val/Val carriers in each group, which indicated that the BDNF Val66Met SNP did not affect plasma BDNF levels in our participants. In heroin-dependent patients, plasma BDNF levels were negatively correlated with the length of heroin dependency. Long-term (>15 years) users had significantly lower plasma BDNF levels than did short-term (<5 years) users. We conclude that plasma BDNF concentration in habitual heroin users are not affected by BDNF Val66Met gene variants, but by the length of the heroin dependency.

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

    PubMed Central

    Shojaei, Shahla; Ghavami, Saeid; Panjehshahin, Mohammad Reza; Owji, Ali Akbar

    2015-01-01

    We aimed to compare the effects of oral ethanol (Eth) alone or combined with the phytoestrogen resveratrol (Rsv) on the expression of various brain-derived neurotrophic factor (BDNF) transcripts and the encoded protein pro-BDNF in the hippocampus of pregnant and embryonic rats. A low (0.25 g/kg body weight (BW)/day) dose of Eth produced an increase in the expression of BDNF exons I, III and IV and a decrease in that of the exon IX in embryos, but failed to affect BDNF transcript and pro-BDNF protein expression in adults. However, co-administration of Eth 0.25 g/kg·BW/day and Rsv led to increased expression of BDNF exons I, III and IV and to a small but significant increase in the level of pro-BDNF protein in maternal rats. A high (2.5 g/kg·BW/day) dose of Eth increased the expression of BDNF exons III and IV in embryos, but it decreased the expression of exon IX containing BDNF mRNAs in the maternal rats. While the high dose of Eth alone reduced the level of pro-BDNF in adults, it failed to change the levels of pro-BDNF in embryos. Eth differentially affects the expression pattern of BDNF transcripts and levels of pro-BDNF in the hippocampus of both adult and embryonic rats. PMID:26703578

  17. Activity-Dependent Dendritic Spine Shrinkage and Growth Involve Downregulation of Cofilin via Distinct Mechanisms

    PubMed Central

    Calabrese, Barbara; Saffin, Jean-Michel; Halpain, Shelley

    2014-01-01

    A current model posits that cofilin-dependent actin severing negatively impacts dendritic spine volume. Studies suggested that increased cofilin activity underlies activity-dependent spine shrinkage, and that reduced cofilin activity induces activity-dependent spine growth. We suggest instead that both types of structural plasticity correlate with decreased cofilin activity. However, the mechanism of inhibition determines the outcome for spine morphology. RNAi in rat hippocampal cultures demonstrates that cofilin is essential for normal spine maintenance. Cofilin-F-actin binding and filament barbed-end production decrease during the early phase of activity-dependent spine shrinkage; cofilin concentration also decreases. Inhibition of the cathepsin B/L family of proteases prevents both cofilin loss and spine shrinkage. Conversely, during activity-dependent spine growth, LIM kinase stimulates cofilin phosphorylation, which activates phospholipase D-1 to promote actin polymerization. These results implicate novel molecular mechanisms and prompt a revision of the current model for how cofilin functions in activity-dependent structural plasticity. PMID:24740405

  18. Activity-dependent FMRP requirements in development of the neural circuitry of learning and memory

    PubMed Central

    Doll, Caleb A.; Broadie, Kendal

    2015-01-01

    The activity-dependent refinement of neural circuit connectivity during critical periods of brain development is essential for optimized behavioral performance. We hypothesize that this mechanism is defective in fragile X syndrome (FXS), the leading heritable cause of intellectual disability and autism spectrum disorders. Here, we use optogenetic tools in the Drosophila FXS disease model to test activity-dependent dendritogenesis in two extrinsic neurons of the mushroom body (MB) learning and memory brain center: (1) the input projection neuron (PN) innervating Kenyon cells (KCs) in the MB calyx microglomeruli and (2) the output MVP2 neuron innervated by KCs in the MB peduncle. Both input and output neuron classes exhibit distinctive activity-dependent critical period dendritic remodeling. MVP2 arbors expand in Drosophila mutants null for fragile X mental retardation 1 (dfmr1), as well as following channelrhodopsin-driven depolarization during critical period development, but are reduced by halorhodopsin-driven hyperpolarization. Optogenetic manipulation of PNs causes the opposite outcome – reduced dendritic arbors following channelrhodopsin depolarization and expanded arbors following halorhodopsin hyperpolarization during development. Importantly, activity-dependent dendritogenesis in both neuron classes absolutely requires dfmr1 during one developmental window. These results show that dfmr1 acts in a neuron type-specific activity-dependent manner for sculpting dendritic arbors during early-use, critical period development of learning and memory circuitry in the Drosophila brain. PMID:25804740

  19. Down-regulation of BDNF in cell and animal models increases striatal-enriched protein tyrosine phosphatase 61 (STEP61 ) levels.

    PubMed

    Xu, Jian; Kurup, Pradeep; Azkona, Garikoitz; Baguley, Tyler D; Saavedra, Ana; Nairn, Angus C; Ellman, Jonathan A; Pérez-Navarro, Esther; Lombroso, Paul J

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) regulates synaptic strengthening and memory consolidation, and altered BDNF expression is implicated in a number of neuropsychiatric and neurodegenerative disorders. BDNF potentiates N-methyl-D-aspartate receptor function through activation of Fyn and ERK1/2. STriatal-Enriched protein tyrosine Phosphatase (STEP) is also implicated in many of the same disorders as BDNF but, in contrast to BDNF, STEP opposes the development of synaptic strengthening. STEP-mediated dephosphorylation of the NMDA receptor subunit GluN2B promotes internalization of GluN2B-containing NMDA receptors, while dephosphorylation of the kinases Fyn, Pyk2, and ERK1/2 leads to their inactivation. Thus, STEP and BDNF have opposing functions. In this study, we demonstrate that manipulation of BDNF expression has a reciprocal effect on STEP61 levels. Reduced BDNF signaling leads to elevation of STEP61 both in BDNF(+/-) mice and after acute BDNF knockdown in cortical cultures. Moreover, a newly identified STEP inhibitor reverses the biochemical and motor abnormalities in BDNF(+/-) mice. In contrast, increased BDNF signaling upon treatment with a tropomyosin receptor kinase B agonist results in degradation of STEP61 and a subsequent increase in the tyrosine phosphorylation of STEP substrates in cultured neurons and in mouse frontal cortex. These findings indicate that BDNF-tropomyosin receptor kinase B signaling leads to degradation of STEP61 , while decreased BDNF expression results in increased STEP61 activity. A better understanding of the opposing interaction between STEP and BDNF in normal cognitive functions and in neuropsychiatric disorders will hopefully lead to better therapeutic strategies. Altered expression of BDNF and STEP61 has been implicated in several neurological disorders. BDNF and STEP61 are known to regulate synaptic strengthening, but in opposite directions. Here, we report that reduced BDNF signaling leads to elevation of STEP61 both in

  20. Long term habitual exercise is associated with lower resting level of serum BDNF.

    PubMed

    Babaei, Parvin; Damirchi, Arsalan; Mehdipoor, Mohammad; Tehrani, Bahram Soltani

    2014-04-30

    This experiment has been designed to evaluate the basal serum BDNF level and memory performance, and also the change in BDNF in response to acute aerobic and anaerobic training in athletes and sedentary groups. Nineteen middle aged elite athletes (45-65 years) who used to be competing at domestic championship for more than 10 years and 20 sedentary subjects participated in this study. Blood samples and cognitive function were assessed at rest and also after performing a single bout of acute aerobic and anaerobic exercise. Basal serum BDNF significantly was lower in the athletes group compared to the control one (475.18±45.32, 1089.30±94.92, P=0.001). Serum BDNF was inversely correlated with Vo2 max (r=-0.5, P=0.013), but positively with BMI (r=0.2, p=0.4). Pictures recall memory was better in the athlete group (9.25±1.61) compared with the control ones (8±1.15, p=0.04). Basal platelets did not show any significant differences between athletes and controls (p>0.05). Both acute aerobic and anaerobic activity elevated serum BDNF and platelets in athletes and sedentary groups compared with rest (P<0.001). This study suggests that long-term habitual exercise is associated with lower peripheral BDNF and better intermediate memory. However acute form of intensive activity either aerobic or anaerobic are capable to elevate serum BDNF level in both sedentary and athletes.

  1. BDNF Interacts with Endocannabinoids to Regulate Cocaine-Induced Synaptic Plasticity in Mouse Midbrain Dopamine Neurons

    PubMed Central

    Zhong, Peng; Liu, Yong; Hu, Ying; Wang, Tong; Zhao, Yong-ping

    2015-01-01

    Brain-derived neurotrophic factor (BDNF) and endocannabinoids (eCBs) have been individually implicated in behavioral effects of cocaine. The present study examined how BDNF-eCB interaction regulates cocaine-induced synaptic plasticity in the ventral tegmental area and behavioral effects. We report that BDNF and selective tyrosine kinase receptor B (TrkB) agonist 7,8-dihydroxyflavone (DHF) activated the TrkB receptor to facilitate two forms of eCB-mediated synaptic depression, depolarization-induced suppression of inhibition (DSI), and long-term depression (I-LTD) of IPSCs in ventral tegmental area dopamine neurons in mouse midbrain slices. The facilitation appears to be mediated by an increase in eCB production via phospholipase Cγ pathway, but not by an increase in CB1 receptor responsiveness or a decrease in eCB hydrolysis. Using Cre-loxP technology to specifically delete BDNF in dopamine neurons, we showed that eCB-mediated I-LTD, cocaine-induced reduction of GABAergic inhibition, and potentiation of glutamatergic excitation remained intact in wild-type control mice, but were impaired in BDNF conditional knock-out mice. We also showed that cocaine-induced conditioned place preference was attenuated in BDNF conditional knock-out mice, in vivo pretreatments with DHF before place conditioning restored cocaine conditioned place preference in these mice, and the behavioral effect of DHF was blocked by a CB1 receptor antagonist. Together, these results suggest that BDNF in dopamine neurons regulates eCB responses, cocaine-induced synaptic plasticity, and associative learning. PMID:25762688

  2. BDNF interacts with endocannabinoids to regulate cocaine-induced synaptic plasticity in mouse midbrain dopamine neurons.

    PubMed

    Zhong, Peng; Liu, Yong; Hu, Ying; Wang, Tong; Zhao, Yong-ping; Liu, Qing-song

    2015-03-11

    Brain-derived neurotrophic factor (BDNF) and endocannabinoids (eCBs) have been individually implicated in behavioral effects of cocaine. The present study examined how BDNF-eCB interaction regulates cocaine-induced synaptic plasticity in the ventral tegmental area and behavioral effects. We report that BDNF and selective tyrosine kinase receptor B (TrkB) agonist 7,8-dihydroxyflavone (DHF) activated the TrkB receptor to facilitate two forms of eCB-mediated synaptic depression, depolarization-induced suppression of inhibition (DSI), and long-term depression (I-LTD) of IPSCs in ventral tegmental area dopamine neurons in mouse midbrain slices. The facilitation appears to be mediated by an increase in eCB production via phospholipase Cγ pathway, but not by an increase in CB1 receptor responsiveness or a decrease in eCB hydrolysis. Using Cre-loxP technology to specifically delete BDNF in dopamine neurons, we showed that eCB-mediated I-LTD, cocaine-induced reduction of GABAergic inhibition, and potentiation of glutamatergic excitation remained intact in wild-type control mice, but were impaired in BDNF conditional knock-out mice. We also showed that cocaine-induced conditioned place preference was attenuated in BDNF conditional knock-out mice, in vivo pretreatments with DHF before place conditioning restored cocaine conditioned place preference in these mice, and the behavioral effect of DHF was blocked by a CB₁ receptor antagonist. Together, these results suggest that BDNF in dopamine neurons regulates eCB responses, cocaine-induced synaptic plasticity, and associative learning. PMID:25762688

  3. Analyzing the influence of BDNF heterozygosity on spatial memory response to 17β-estradiol.

    PubMed

    Wu, Y W C; Du, X; van den Buuse, M; Hill, R A

    2015-01-20

    The recent use of estrogen-based therapies as adjunctive treatments for the cognitive impairments of schizophrenia has produced promising results; however the mechanism behind estrogen-based cognitive enhancement is relatively unknown. Brain-derived neurotrophic factor (BDNF) regulates learning and memory and its expression is highly responsive to estradiol. We recently found that estradiol modulates the expression of hippocampal parvalbumin-positive GABAergic interneurons, known to regulate neuronal synchrony and cognitive function. What is unknown is whether disruptions to the aforementioned estradiol-parvalbumin pathway alter learning and memory, and whether BDNF may mediate these events. Wild-type (WT) and BDNF heterozygous (+/-) mice were ovariectomized (OVX) at 5 weeks of age and simultaneously received empty, estradiol- or progesterone-filled implants for 7 weeks. At young adulthood, mice were tested for spatial and recognition memory in the Y-maze and novel-object recognition test, respectively. Hippocampal protein expression of BDNF and GABAergic interneuron markers, including parvalbumin, were assessed. WT OVX mice show impaired performance on Y-maze and novel-object recognition test. Estradiol replacement in OVX mice prevented the Y-maze impairment, a Behavioral abnormality of dorsal hippocampal origin. BDNF and parvalbumin protein expression in the dorsal hippocampus and parvalbumin-positive cell number in the dorsal CA1 were significantly reduced by OVX in WT mice, while E2 replacement prevented these deficits. In contrast, BDNF(+/-) mice showed either no response or an opposite response to hormone manipulation in both behavioral and molecular indices. Our data suggest that BDNF status is an important biomarker for predicting responsiveness to estrogenic compounds which have emerged as promising adjunctive therapeutics for schizophrenia patients.

  4. BDNF contributes to the facilitation of hippocampal synaptic plasticity and learning enabled by environmental enrichment.

    PubMed

    Novkovic, Tanja; Mittmann, Thomas; Manahan-Vaughan, Denise

    2015-01-01

    Sensory, motor, and cognitive stimuli, resulting from interactions with the environment, play a key role in optimizing and modifying the neuronal circuitry required for normal brain function. An experimental animal model for this phenomenon comprises environmental enrichment (EE) in rodents. EE causes profound changes in neuronal and signaling levels of excitation and plasticity throughout the entire central nervous system and the hippocampus is particularly affected. The mechanisms underlying these changes are not yet fully understood. As brain-derived neurotrophic factor (BDNF) supports hippocampal long-term potentiation (LTP), we explored whether it participates in the facilitation of synaptic plasticity and hippocampus-dependent learning that occurs following EE. In the absence of EE, LTP elicited by high-frequency stimulation was equivalent in wildtype mice and heterozygous BDNF(+/-) siblings. LTP elicited by theta-burst stimulation in BDNF(+/-) mice was less than in wildtypes. Long-term depression (LTD) was also impaired. EE for three weeks, beginning after weaning, improved hippocampal LTP in both wildtype and transgenic animals, with LTP in transgenics achieving levels seen in wildtypes in the absence of EE. Object recognition memory was evident in wildtypes 24 h and 7 days after initial object exposure. EE improved memory performance in wildtypes 24 h but not 7 days after initial exposure. BDNF(+/-) mice in the absence of EE showed impaired memory 7 days after initial object exposure that was restored by EE. Western blotting revealed increased levels of BDNF, but not proBDNF, among both EE cohorts. These data support that BDNF plays an intrinsic role in improvements of synaptic plasticity and cognition that occur in EE.

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

    PubMed Central

    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

  6. Gestational IV nicotine produces elevated BDNF in the mesocorticolimbic dopamine system of adolescent rat offspring

    PubMed Central

    Harrod, Steven B.; Lacy, Ryan T.; Zhu, Jun; Hughes, Benjamin A.; Perna, Marla K.; Brown, Russell W.

    2015-01-01

    Maternal smoking during pregnancy is associated with enduring psychopathology, such as increased likelihood of substance use, in offspring. Various animal models demonstrate that continuous nicotine exposure produces teratogenic effects in offspring, as well. In the present experiment, a novel intravenous (IV) exposure model was utilized to determine if gestational nicotine (GN) treatment produced alterations in methamphetamine-induced sensitization and the expression of brain derived neurotrophic factor (BDNF) in the mesocorticolimbic dopamine system of adolescent offspring. Dams were injected with IV saline or nicotine (0.05 mg/kg/injection) 3x/day on gestational days 8–21. Habituation was measured on postnatal day (PND) 25–27 and baseline activity on PND 28. On PND 29–35, offspring were injected with saline or methamphetamine (0.3 mg/kg) and locomotor activity was measured after the first and seventh injections. On PND 36, brains were removed, flash frozen, and BDNF protein levels in the nucleus accumbens (NAcc), dorsal striatum (Str), frontal cortex (FC), and hippocampus (Hipp) were analyzed. GN did not affect habituation or the induction of methamphetamine-induced sensitization. Interestingly, GN, but not adolescent methamphetamine treatment, elevated levels of BDNF in the NAcc and Str; however, the GN-induced increase in BDNF in the FC was attenuated by adolescent methamphetamine treatment. Both GN and adolescent methamphetamine treatment increased BDNF in the Hipp. These findings indicate that GN exposure will result in increased levels of BDNF protein throughout the mesocorticolimbic dopamine system during adolescent development, and suggests that methamphetamine abuse will modulate the expression of BDNF in motivational circuitries of adolescent offspring exposed to GN. PMID:21990022

  7. BDNF regulates atypical PKC at spinal synapses to initiate and maintain a centralized chronic pain state

    PubMed Central

    2013-01-01

    Background Chronic pain is an important medical problem affecting hundreds of millions of people worldwide. Mechanisms underlying the maintenance of chronic pain states are poorly understood but the elucidation of such mechanisms have the potential to reveal novel therapeutics capable of reversing a chronic pain state. We have recently shown that the maintenance of a chronic pain state is dependent on an atypical PKC, PKMζ, but the mechanisms involved in controlling PKMζ in chronic pain are completely unknown. Here we have tested the hypothesis that brain derived neurotrophic factor (BDNF) regulates PKMζ, and possibly other aPKCs, to maintain a centralized chronic pain state. Results We first demonstrate that although other kinases play a role in the initiation of persistent nociceptive sensitization, they are not involved in the maintenance of this chronic pain state indicating that a ZIP-reversible process is responsible for the maintenance of persistent sensitization. We further show that BDNF plays a critical role in initiating and maintaining persistent nociceptive sensitization and that this occurs via a ZIP-reversible process. Moreover, at spinal synapses, BDNF controls PKMζ and PKCλ nascent synthesis via mTORC1 and BDNF enhances PKMζ phosphorylaton. Finally, we show that BDNF signaling to PKMζ and PKCλ is conserved across CNS synapses demonstrating molecular links between pain and memory mechanisms. Conclusions Hence, BDNF is a key regulator of aPKC synthesis and phosphorylation and an essential mediator of the maintenance of a centralized chronic pain state. These findings point to BDNF regulation of aPKC as a potential therapeutic target for the permanent reversal of a chronic pain state. PMID:23510079

  8. Long term habitual exercise is associated with lower resting level of serum BDNF.

    PubMed

    Babaei, Parvin; Damirchi, Arsalan; Mehdipoor, Mohammad; Tehrani, Bahram Soltani

    2014-04-30

    This experiment has been designed to evaluate the basal serum BDNF level and memory performance, and also the change in BDNF in response to acute aerobic and anaerobic training in athletes and sedentary groups. Nineteen middle aged elite athletes (45-65 years) who used to be competing at domestic championship for more than 10 years and 20 sedentary subjects participated in this study. Blood samples and cognitive function were assessed at rest and also after performing a single bout of acute aerobic and anaerobic exercise. Basal serum BDNF significantly was lower in the athletes group compared to the control one (475.18±45.32, 1089.30±94.92, P=0.001). Serum BDNF was inversely correlated with Vo2 max (r=-0.5, P=0.013), but positively with BMI (r=0.2, p=0.4). Pictures recall memory was better in the athlete group (9.25±1.61) compared with the control ones (8±1.15, p=0.04). Basal platelets did not show any significant differences between athletes and controls (p>0.05). Both acute aerobic and anaerobic activity elevated serum BDNF and platelets in athletes and sedentary groups compared with rest (P<0.001). This study suggests that long-term habitual exercise is associated with lower peripheral BDNF and better intermediate memory. However acute form of intensive activity either aerobic or anaerobic are capable to elevate serum BDNF level in both sedentary and athletes. PMID:24572590

  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. Six secrets of champagne

    NASA Astrophysics Data System (ADS)

    Liger-Belair, Gérard

    2015-12-01

    Popping open a bottle of champagne is one of life's great delights, but how much do you really know about the science behind this greatest of wines? Gérard Liger-Belair reveals his six favourite champagne secrets.

  11. Secret quality of love.

    PubMed

    Strachan-Hall, Elaine

    2016-09-01

    Many of us can recite three Donabedian dimensions of the quality of care of structure, process and outcome. Recently, I was introduced to another of Avedis Donabedian's quotes about the 'secret quality of love'. PMID:27581908

  12. Efficient quantum secret sharing

    NASA Astrophysics Data System (ADS)

    Qin, Huawang; Dai, Yuewei

    2016-05-01

    An efficient quantum secret sharing scheme is proposed, in which the dealer generates some single particles and then uses the operations of quantum-controlled-not and Hadamard gate to encode a determinate secret into these particles. The participants get their shadows by performing the single-particle measurements on their particles, and even the dealer cannot know their shadows. Compared to the existing schemes, our scheme is more practical within the present technologies.

  13. Phosphorylation of Complexin by PKA Regulates Activity-Dependent Spontaneous Neurotransmitter Release and Structural Synaptic Plasticity.

    PubMed

    Cho, Richard W; Buhl, Lauren K; Volfson, Dina; Tran, Adrienne; Li, Feng; Akbergenova, Yulia; Littleton, J Troy

    2015-11-18

    Synaptic plasticity is a fundamental feature of the nervous system that allows adaptation to changing behavioral environments. Most studies of synaptic plasticity have examined the regulated trafficking of postsynaptic glutamate receptors that generates alterations in synaptic transmission. Whether and how changes in the presynaptic release machinery contribute to neuronal plasticity is less clear. The SNARE complex mediates neurotransmitter release in response to presynaptic Ca(2+) entry. Here we show that the SNARE fusion clamp Complexin undergoes activity-dependent phosphorylation that alters the basic properties of neurotransmission in Drosophila. Retrograde signaling following stimulation activates PKA-dependent phosphorylation of the Complexin C terminus that selectively and transiently enhances spontaneous release. Enhanced spontaneous release is required for activity-dependent synaptic growth. These data indicate that SNARE-dependent fusion mechanisms can be regulated in an activity-dependent manner and highlight the key role of spontaneous neurotransmitter release as a mediator of functional and structural plasticity.

  14. 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

  15. Elevated BDNF after cocaine withdrawal facilitates LTP in medial prefrontal cortex by suppressing GABA inhibition.

    PubMed

    Lu, Hui; Cheng, Pei-Lin; Lim, Byung Kook; Khoshnevisrad, Nina; Poo, Mu-Ming

    2010-09-01

    Medial prefrontal cortex (mPFC) is known to be involved in relapse after cocaine withdrawal, but the underlying cellular mechanism remains largely unknown. Here, we report that after terminating repeated cocaine exposure in rats, a gradual increase in the expression of brain-derived neurotrophic factor (BDNF) in the mPFC facilitates activity-induced long-term potentiation (LTP) of excitatory synapses on layer V pyramidal neurons. This enhanced synaptic plasticity could be attributed to BDNF-induced suppression of GABAergic inhibition in the mPFC by reducing the surface expression of GABA(A) receptors. The BDNF effect was mediated by BDNF-TrkB-phosphatase 2A signaling pathway. Downregulating TrkB expression bilaterally in the mPFC reduced the locomotor hypersensitivity to cocaine 8 days after cocaine withdrawal. Thus, elevated BDNF expression after cocaine withdrawal sensitizes the excitatory synapses in the mPFC to undergo activity-induced persistent potentiation that may contribute to cue-induced drug craving and drug-seeking behavior.

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

    PubMed

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

    2014-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  18. BDNF mediates neuroprotection against oxygen-glucose deprivation by the cardiac glycoside oleandrin.

    PubMed

    Van Kanegan, Michael J; He, Dong Ning; Dunn, Denise E; Yang, Peiying; Newman, Robert A; West, Anne E; Lo, Donald C

    2014-01-15

    We have previously shown that the botanical drug candidate PBI-05204, a supercritical CO2 extract of Nerium oleander, provides neuroprotection in both in vitro and in vivo brain slice-based models for focal ischemia (Dunn et al., 2011). Intriguingly, plasma levels of the neurotrophin BDNF were increased in patients treated with PBI-05204 in a phase I clinical trial (Bidyasar et al., 2009). We thus tested the hypothesis that neuroprotection provided by PBI-05204 to rat brain slices damaged by oxygen-glucose deprivation (OGD) is mediated by BDNF. We found, in fact, that exogenous BDNF protein itself is sufficient to protect brain slices against OGD, whereas downstream activation of TrkB receptors for BDNF is necessary for neuroprotection provided by PBI-05204, using three independent methods. Finally, we provide evidence that oleandrin, the principal cardiac glycoside component of PBI-05204, can quantitatively account for regulation of BDNF at both the protein and transcriptional levels. Together, these findings support further investigation of cardiac glycosides in providing neuroprotection in the context of ischemic stroke. PMID:24431454

  19. BDNF-dependent consolidation of fear memories in the perirhinal cortex

    PubMed Central

    Schulz-Klaus, Brigitte; Lessmann, Volkmar; Endres, Thomas

    2013-01-01

    In the recent years the perirhinal cortex (PRh) has been identified as a crucial brain area in fear learning. Since the neurotrophin brain-derived neurotrophic factor (BDNF) is an important mediator of synaptic plasticity and also crucially involved in memory consolidation of several learning paradigms, we analyzed now whether fear conditioning influences the expression of BDNF protein in the PRh. Here we observed a specific increase of BDNF protein 120 min after fear conditioning training. In order to test whether this increase of BDNF protein level is also required for the consolidation of the fear memory, we locally applied the Trk receptor inhibitor k252a into the PRh during this time window in a second series of experiments. By interfering with Trk-signaling during this critical time window, the formation of a long-term fear memory was completely blocked, indicated by a complete lack of fear potentiated startle 1 day later. In conclusion the present study further emphasizes the important role of the PRh in cued fear learning and identified BDNF as an important mediator for fear memory consolidation in the PRh. PMID:24381548

  20. 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

  1. Evaluation of nigrostriatal dopaminergic function in adult +/+ and +/- BDNF mutant mice.

    PubMed

    Dluzen, D E; Gao, X; Story, G M; Anderson, L I; Kucera, J; Walro, J M

    2001-07-01

    Deletion of a single copy of the BDNF gene has been shown to affect the nigrostriatal dopaminergic system of young adult BDNF mice. In the present report we evaluated various indices of nigrostriatal dopaminergic function between 9-month-old wild-type (+/+) and heterozygous (+/-) BDNF mutant mice. Performance in a sensorimotor beam walking task was significantly decreased in +/- mice as indicated by increased times required to traverse both a wide (21 mm) and narrow (6 mm) beam. No differences in spontaneous locomotor behavior were observed between the +/+ and +/- mice. Amphetamine-stimulated (5 mg/kg) locomotor behavior was increased to a greater degree in the +/- mice, with the number of movements performed by these mice being significantly greater than their +/+ controls. Corpus striatal dopamine concentrations were significantly greater in the +/- BDNF mice. The absence of any significant differences for dopamine concentrations within the hypothalamus and olfactory bulb of these mice, as well as an absence of any difference in striatal norepinephrine concentrations, suggested a relative specificity of these effects to the corpus striatum. Both the +/- and +/+ mice showed similar reductions in striatal dopamine concentrations in response to a neurotoxic regimen of methamphetamine (20 mg/kg). Collectively these data show increased levels of striatal dopamine concentrations associated with altered behavioral responses involving the nigrostriatal dopaminergic system within the heterozygous BDNF mutant mice. PMID:11421589

  2. BDNF, IGF-I, Glucose and Insulin during Continuous and Interval Exercise in Type 1 Diabetes.

    PubMed

    Tonoli, C; Heyman, E; Roelands, B; Buyse, L; Piacentini, F; Berthoin, S; Bailey, S; Pattyn, N; Meeusen, R

    2015-11-01

    Type 1 diabetes (T1D) can have a significant impact on brain function, mostly ascribed to episodes of hypoglycemia and chronic hyperglycemia. Exercise has positive effects on acute and chronic glycemic control in T1D, and has beneficial effects on cognitive function by increasing neurotrophins such as BDNF and IGF-I in non-diabetic humans. The present study examines the effects of different types of exercise intensities on neurotrophins in T1D. 10 participants with type 1 diabetes were evaluated in 3 sessions: high-intensity exercise (10×[60 s 90%Wmax, 60 s 50 W]), continuous exercise (22 min, 70% VO2 max) and a control session. Blood glucose, serum free insulin, serum BDNF and IGF-I were assessed pre/post all the trials and after recovery. Blood glucose significantly decreased after both exercise intensities and BDNF levels increased, with a dose-response effect for exercise intensity on BDNF. IGF-I changed over time, but without a difference between the different exercise protocols. Both exercise intensities change neurotrophins in T1D, but also exhibit a dose response effect for BDNF. The intensity-dependent findings may aid in designing exercise prescriptions for maintaining or improving neurological health in T1D, but both types of exercise can be implemented.

  3. 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.

  4. Elevated BDNF after cocaine withdrawal facilitates LTP in medial prefrontal cortex by suppressing GABA inhibition.

    PubMed

    Lu, Hui; Cheng, Pei-Lin; Lim, Byung Kook; Khoshnevisrad, Nina; Poo, Mu-Ming

    2010-09-01

    Medial prefrontal cortex (mPFC) is known to be involved in relapse after cocaine withdrawal, but the underlying cellular mechanism remains largely unknown. Here, we report that after terminating repeated cocaine exposure in rats, a gradual increase in the expression of brain-derived neurotrophic factor (BDNF) in the mPFC facilitates activity-induced long-term potentiation (LTP) of excitatory synapses on layer V pyramidal neurons. This enhanced synaptic plasticity could be attributed to BDNF-induced suppression of GABAergic inhibition in the mPFC by reducing the surface expression of GABA(A) receptors. The BDNF effect was mediated by BDNF-TrkB-phosphatase 2A signaling pathway. Downregulating TrkB expression bilaterally in the mPFC reduced the locomotor hypersensitivity to cocaine 8 days after cocaine withdrawal. Thus, elevated BDNF expression after cocaine withdrawal sensitizes the excitatory synapses in the mPFC to undergo activity-induced persistent potentiation that may contribute to cue-induced drug craving and drug-seeking behavior. PMID:20826313

  5. Tetramethylpyrazine Produces Antidepressant-Like Effects in Mice Through Promotion of BDNF Signaling Pathway

    PubMed Central

    Jiang, Bo; Huang, Chao; Chen, Xiang-Fan; Tong, Li-Juan

    2015-01-01

    Background: Current antidepressants are clinically effective only after several weeks of administration. Tetramethylpyrazine (TMP) is an identified component of Ligusticum wallichii with neuroprotective effects. Here, we investigated the antidepressant effects of TMP in mice models of depression. Methods: Antidepressant effects of TMP were first detected in the forced swim test (FST) and tail suspension test (TST), and further assessed in the chronic social defeat stress (CSDS) model. Changes in the brain-derived neurotrophic factor (BDNF) signaling pathway and in hippocampal neurogenesis after CSDS and TMP treatment were then investigated. A tryptophan hydroxylase inhibitor and BDNF signaling inhibitors were also used to determine the mechanisms of TMP. Results: TMP exhibited potent antidepressant effects in the FST and TST without affecting locomotor activity. TMP also prevented the CSDS-induced symptoms. Moreover, TMP completely restored the CSDS-induced decrease of BDNF signaling pathway and hippocampal neurogenesis. Furthermore, a blockade of the BDNF signaling pathway prevented the antidepressant effects of TMP, while TMP produced no influence on the monoaminergic system. Conclusions: In conclusion, these data provide the first evidence that TMP has antidepressant effects, and this was mediated by promoting the BDNF signaling pathway. PMID:25618406

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

    PubMed Central

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

    2013-01-01

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

  7. BDNF-induced synaptic delivery of AMPAR subunits is differentially dependent on NMDA receptors and requires ERK.

    PubMed

    Li, Wei; Keifer, Joyce

    2009-03-01

    Previous studies using an in vitro model of eyeblink classical conditioning in turtles suggest that increased numbers of synaptic AMPARs supports the acquisition and expression of conditioned responses (CRs). Brain-derived neurotrophic factor (BDNF) and its associated receptor tyrosine kinase, TrkB, is also required for acquisition of CRs. Bath application of BDNF alone induces synaptic delivery of GluR1- and GluR4-containing AMPARs that is blocked by coapplication of the receptor tyrosine kinase inhibitor K252a. The molecular mechanisms involved in BDNF-induced AMPAR trafficking remain largely unknown. The aim of this study was to determine whether BDNF-induced synaptic AMPAR incorporation utilizes similar cellular mechanisms as AMPAR trafficking that occurs during in vitro classical conditioning. Using pharmacological blockade and confocal imaging, the results show that synaptic delivery of GluR1 subunits during conditioning or BDNF application does not require activity of NMDARs but is mediated by extracellular signal-regulated kinase (ERK). In contrast, synaptic delivery of GluR4-containing AMPARs during both conditioning and BDNF application is NMDAR- as well as ERK-dependent. These findings indicate that BDNF application mimics AMPAR trafficking observed during conditioning by activation of some of the same intracellular signaling pathways and suggest that BDNF is a key signal transduction element in postsynaptic events that mediate conditioning.

  8. Disruption of the expression of the proprotein convertase PC7 reduces BDNF production and affects learning and memory in mice.

    PubMed

    Wetsel, William C; Rodriguiz, Ramona M; Guillemot, Johann; Rousselet, Estelle; Essalmani, Rachid; Kim, Il Hwan; Bryant, Jesse C; Marcinkiewicz, Jadwiga; Desjardins, Roxane; Day, Robert; Constam, Daniel B; Prat, Annik; Seidah, Nabil G

    2013-10-22

    PC7 belongs to the proprotein convertase family, whose members are implicated in the cleavage of secretory precursors. The in vivo function of PC7 is unknown. Herein, we find that the precursor proBDNF is processed into mature BDNF in COS-1 cells coexpressing proBDNF with either PC7 or Furin. Conversely, the processing of proBDNF into BDNF is markedly reduced in the absence of either Furin or PC7 in mouse primary hepatocytes. In vivo we observe that BDNF and PC7 mRNAs are colocalized in mouse hippocampus and amygdala and that mature BDNF protein levels are reduced in these brain areas in PC7 KO mice but not in the hippocampus of PC1/3 KO mice. Various behavioral tests reveal that in PC7 KO mice spatial memory is intact and plasticity of responding is mildly abnormal. Episodic and emotional memories are severely impaired, but both are rescued with the tyrosine receptor kinase B agonist 7,8-dihydroxyflavone. Altogether, these results support an in vivo role for PC7 in the regulation of certain types of cognitive performance, in part via proBDNF processing. Because polymorphic variants of human PC7 are being characterized, it will be important in future studies to determine their effects on additional physiological and behavioral processes. PMID:24101515

  9. Chronic fluoxetine treatment induces brain region-specific upregulation of genes associated with BDNF-induced long-term potentiation.

    PubMed

    Alme, Maria Nordheim; Wibrand, Karin; Dagestad, Grethe; Bramham, Clive R

    2007-01-01

    Several lines of evidence implicate BDNF in the pathogenesis of stress-induced depression and the delayed efficacy of antidepressant drugs. Antidepressant-induced upregulation of BDNF signaling is thought to promote adaptive neuronal plasticity through effects on gene expression, but the effector genes downstream of BDNF has not been identified. Local infusion of BDNF into the dentate gyrus induces a long-term potentiation (BDNF-LTP) of synaptic transmission that requires upregulation of the immediate early gene Arc. Recently, we identified five genes (neuritin, Narp, TIEG1, Carp, and Arl4d) that are coupregulated with Arc during BDNF-LTP. Here, we examined the expression of these genes in the dentate gyrus, hippocampus proper, and prefrontal cortex after antidepressant treatment. We show that chronic, but not acute, fluoxetine administration leads to upregulation of these BDNF-LTP-associated genes in a brain region-specific pattern. These findings link chronic effects of antidepressant treatment to molecular mechanisms underlying BDNF-induced synaptic plasticity. PMID:18301726

  10. Taste Bud-Derived BDNF Is Required to Maintain Normal Amounts of Innervation to Adult Taste Buds.

    PubMed

    Meng, Lingbin; Ohman-Gault, Lisa; Ma, Liqun; Krimm, Robin F

    2015-01-01

    Gustatory neurons transmit chemical information from taste receptor cells, which reside in taste buds in the oral cavity, to the brain. As adult taste receptor cells are renewed at a constant rate, nerve fibers must reconnect with new taste receptor cells as they arise. Therefore, the maintenance of gustatory innervation to the taste bud is an active process. Understanding how this process is regulated is a fundamental concern of gustatory system biology. We speculated that because brain-derived neurotrophic factor (BDNF) is required for taste bud innervation during development, it might function to maintain innervation during adulthood. If so, taste buds should lose innervation when Bdnf is deleted in adult mice. To test this idea, we first removed Bdnf from all cells in adulthood using transgenic mice with inducible CreERT2 under the control of the Ubiquitin promoter. When Bdnf was removed, approximately one-half of the innervation to taste buds was lost, and taste buds became smaller because of the loss of taste bud cells. Individual taste buds varied in the amount of innervation each lost, and those that lost the most innervation also lost the most taste bud cells. We then tested the idea that that the taste bud was the source of this BDNF by reducing Bdnf levels specifically in the lingual epithelium and taste buds. Taste buds were confirmed as the source of BDNF regulating innervation. We conclude that BDNF expressed in taste receptor cells is required to maintain normal levels of innervation in adulthood.

  11. Disruption of the expression of the proprotein convertase PC7 reduces BDNF production and affects learning and memory in mice.

    PubMed

    Wetsel, William C; Rodriguiz, Ramona M; Guillemot, Johann; Rousselet, Estelle; Essalmani, Rachid; Kim, Il Hwan; Bryant, Jesse C; Marcinkiewicz, Jadwiga; Desjardins, Roxane; Day, Robert; Constam, Daniel B; Prat, Annik; Seidah, Nabil G

    2013-10-22

    PC7 belongs to the proprotein convertase family, whose members are implicated in the cleavage of secretory precursors. The in vivo function of PC7 is unknown. Herein, we find that the precursor proBDNF is processed into mature BDNF in COS-1 cells coexpressing proBDNF with either PC7 or Furin. Conversely, the processing of proBDNF into BDNF is markedly reduced in the absence of either Furin or PC7 in mouse primary hepatocytes. In vivo we observe that BDNF and PC7 mRNAs are colocalized in mouse hippocampus and amygdala and that mature BDNF protein levels are reduced in these brain areas in PC7 KO mice but not in the hippocampus of PC1/3 KO mice. Various behavioral tests reveal that in PC7 KO mice spatial memory is intact and plasticity of responding is mildly abnormal. Episodic and emotional memories are severely impaired, but both are rescued with the tyrosine receptor kinase B agonist 7,8-dihydroxyflavone. Altogether, these results support an in vivo role for PC7 in the regulation of certain types of cognitive performance, in part via proBDNF processing. Because polymorphic variants of human PC7 are being characterized, it will be important in future studies to determine their effects on additional physiological and behavioral processes.

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

    PubMed Central

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

    2015-01-01

    Ischemic preconditioning (IPC) via protein kinase C epsilon (PKCɛ) activation induces neuroprotection against lethal ischemia. Brain-derived neurotrophic factor (BDNF) is a pro-survival signaling molecule that modulates synaptic plasticity and neurogenesis. Interestingly, BDNF mRNA expression increases after IPC. In this study, we investigated whether IPC or pharmacological preconditioning (PKCɛ activation) promoted BDNF-induced neuroprotection, if neuroprotection by IPC or PKCɛ activation altered neuronal excitability, and whether these changes were BDNF-mediated. We used both in vitro (hippocampal organotypic cultures and cortical neuronal-glial cocultures) and in vivo (acute hippocampal slices 48 hours after preconditioning) models of IPC or PKCɛ activation. BDNF protein expression increased 24 to 48 hours after preconditioning, where inhibition of the BDNF Trk receptors abolished neuroprotection against oxygen and glucose deprivation (OGD) in vitro. In addition, there was a significant decrease in neuronal firing frequency and increase in threshold potential 48 hours after preconditioning in vivo, where this threshold modulation was dependent on BDNF activation of Trk receptors in excitatory cortical neurons. In addition, 48 hours after PKCɛ activation in vivo, the onset of anoxic depolarization during OGD was significantly delayed in hippocampal slices. Overall, these results suggest that after IPC or PKCɛ activation, there are BDNF-dependent electrophysiologic modifications that lead to neuroprotection. PMID:25370861

  13. Adaptation of Slow Myofibers: The Effect of Sustained BDNF Treatment of Extraocular Muscles in Infant Nonhuman Primates

    PubMed Central

    Willoughby, Christy L.; Fleuriet, Jérome; Walton, Mark M.; Mustari, Michael J.; McLoon, Linda K.

    2015-01-01

    Purpose. We evaluated promising new treatment options for strabismus. Neurotrophic factors have emerged as a potential treatment for oculomotor disorders because of diverse roles in signaling to muscles and motor neurons. Unilateral treatment with sustained release brain-derived neurotrophic factor (BDNF) to a single lateral rectus muscle in infant monkeys was performed to test the hypothesis that strabismus would develop in correlation with extraocular muscle (EOM) changes during the critical period for development of binocularity. Methods. The lateral rectus muscles of one eye in two infant macaques were treated with sustained delivery of BDNF for 3 months. Eye alignment was assessed using standard photographic methods. Muscle specimens were analyzed to examine the effects of BDNF on the density, morphology, and size of neuromuscular junctions, as well as myofiber size. Counts were compared to age-matched controls. Results. No change in eye alignment occurred with BDNF treatment. Compared to control muscle, neuromuscular junctions on myofibers expressing slow myosins had a larger area. Myofibers expressing slow myosin had larger diameters, and the percentage of myofibers expressing slow myosins increased in the proximal end of the muscle. Expression of BDNF was examined in control EOM, and observed to have strongest immunoreactivity outside the endplate zone. Conclusions. We hypothesize that the oculomotor system adapted to sustained BDNF treatment to preserve normal alignment. Our results suggest that BDNF treatment preferentially altered myofibers expressing slow myosins. This implicates BDNF signaling as influencing the slow twitch properties of EOM. PMID:26030102

  14. Taste Bud-Derived BDNF Is Required to Maintain Normal Amounts of Innervation to Adult Taste Buds123

    PubMed Central

    Meng, Lingbin; Ohman-Gault, Lisa; Ma, Liqun

    2015-01-01

    Abstract Gustatory neurons transmit chemical information from taste receptor cells, which reside in taste buds in the oral cavity, to the brain. As adult taste receptor cells are renewed at a constant rate, nerve fibers must reconnect with new taste receptor cells as they arise. Therefore, the maintenance of gustatory innervation to the taste bud is an active process. Understanding how this process is regulated is a fundamental concern of gustatory system biology. We speculated that because brain-derived neurotrophic factor (BDNF) is required for taste bud innervation during development, it might function to maintain innervation during adulthood. If so, taste buds should lose innervation when Bdnf is deleted in adult mice. To test this idea, we first removed Bdnf from all cells in adulthood using transgenic mice with inducible CreERT2 under the control of the Ubiquitin promoter. When Bdnf was removed, approximately one-half of the innervation to taste buds was lost, and taste buds became smaller because of the loss of taste bud cells. Individual taste buds varied in the amount of innervation each lost, and those that lost the most innervation also lost the most taste bud cells. We then tested the idea that that the taste bud was the source of this BDNF by reducing Bdnf levels specifically in the lingual epithelium and taste buds. Taste buds were confirmed as the source of BDNF regulating innervation. We conclude that BDNF expressed in taste receptor cells is required to maintain normal levels of innervation in adulthood. PMID:26730405

  15. Taste Bud-Derived BDNF Is Required to Maintain Normal Amounts of Innervation to Adult Taste Buds.

    PubMed

    Meng, Lingbin; Ohman-Gault, Lisa; Ma, Liqun; Krimm, Robin F

    2015-01-01

    Gustatory neurons transmit chemical information from taste receptor cells, which reside in taste buds in the oral cavity, to the brain. As adult taste receptor cells are renewed at a constant rate, nerve fibers must reconnect with new taste receptor cells as they arise. Therefore, the maintenance of gustatory innervation to the taste bud is an active process. Understanding how this process is regulated is a fundamental concern of gustatory system biology. We speculated that because brain-derived neurotrophic factor (BDNF) is required for taste bud innervation during development, it might function to maintain innervation during adulthood. If so, taste buds should lose innervation when Bdnf is deleted in adult mice. To test this idea, we first removed Bdnf from all cells in adulthood using transgenic mice with inducible CreERT2 under the control of the Ubiquitin promoter. When Bdnf was removed, approximately one-half of the innervation to taste buds was lost, and taste buds became smaller because of the loss of taste bud cells. Individual taste buds varied in the amount of innervation each lost, and those that lost the most innervation also lost the most taste bud cells. We then tested the idea that that the taste bud was the source of this BDNF by reducing Bdnf levels specifically in the lingual epithelium and taste buds. Taste buds were confirmed as the source of BDNF regulating innervation. We conclude that BDNF expressed in taste receptor cells is required to maintain normal levels of innervation in adulthood. PMID:26730405

  16. Plasma BDNF Is Reduced among Middle-Aged and Elderly Women with Impaired Insulin Function: Evidence of a Compensatory Mechanism

    ERIC Educational Resources Information Center

    Arentoft, Alyssa; Sweat, Victoria; Starr, Vanessa; Oliver, Stephen; Hassenstab, Jason; Bruehl, Hannah; Tirsi, Aziz; Javier, Elizabeth; McHugh, Pauline F.; Convit, Antonio

    2009-01-01

    Brain-derived neurotrophic factor (BDNF) plays a regulatory role in neuronal differentiation and synaptic plasticity and has been linked to glucose regulation and cognition. Associations among plasma BDNF, cognition, and insulin function were explored. Forty-one participants with impaired insulin function (IIF), ranging from insulin resistance to…

  17. Disruption of the expression of the proprotein convertase PC7 reduces BDNF production and affects learning and memory in mice

    PubMed Central

    Wetsel, William C.; Rodriguiz, Ramona M.; Guillemot, Johann; Rousselet, Estelle; Essalmani, Rachid; Kim, Il Hwan; Bryant, Jesse C.; Marcinkiewicz, Jadwiga; Desjardins, Roxane; Day, Robert; Constam, Daniel B.; Prat, Annik; Seidah, Nabil G.

    2013-01-01

    PC7 belongs to the proprotein convertase family, whose members are implicated in the cleavage of secretory precursors. The in vivo function of PC7 is unknown. Herein, we find that the precursor proBDNF is processed into mature BDNF in COS-1 cells coexpressing proBDNF with either PC7 or Furin. Conversely, the processing of proBDNF into BDNF is markedly reduced in the absence of either Furin or PC7 in mouse primary hepatocytes. In vivo we observe that BDNF and PC7 mRNAs are colocalized in mouse hippocampus and amygdala and that mature BDNF protein levels are reduced in these brain areas in PC7 KO mice but not in the hippocampus of PC1/3 KO mice. Various behavioral tests reveal that in PC7 KO mice spatial memory is intact and plasticity of responding is mildly abnormal. Episodic and emotional memories are severely impaired, but both are rescued with the tyrosine receptor kinase B agonist 7,8-dihydroxyflavone. Altogether, these results support an in vivo role for PC7 in the regulation of certain types of cognitive performance, in part via proBDNF processing. Because polymorphic variants of human PC7 are being characterized, it will be important in future studies to determine their effects on additional physiological and behavioral processes. PMID:24101515

  18. ERK1/2 Activation Is Necessary for BDNF to Increase Dendritic Spine Density in Hippocampal CA1 Pyramidal Neurons

    ERIC Educational Resources Information Center

    Alonso, Mariana; Medina, Jorge H.; Pozzo-Miller, Lucas

    2004-01-01

    Brain-derived neurotrophic factor (BDNF) is a potent modulator of synaptic transmission and plasticity in the CNS, acting both pre- and postsynaptically. We demonstrated recently that BDNF/TrkB signaling increases dendritic spine density in hippocampal CA1 pyramidal neurons. Here, we tested whether activation of the prominent ERK (MAPK) signaling…

  19. Activity-dependent fluorescent labeling of bacterial cells expressing the TOL pathway

    SciTech Connect

    William K. Keener; Mary E. Watwood

    2005-01-01

    3-Ethynylbenzoate functions as an activity-dependent, fluorogenic and chromogenic probe for Pseudomonas putida mt-2, which is known to degrade toluene via conversion to benzoate, followed by meta ring fission of the intermediate, catechol. This direct physiological analysis allows the fluorescent labeling of cells whose toluene-degrading enzymes have been induced by an aromatic substrate.

  20. Effects of the BDNF Val66Met polymorphism on white matter microstructure in healthy adults.

    PubMed

    Tost, Heike; Alam, Tajvar; Geramita, Matthew; Rebsch, Christine; Kolachana, Bhaskar; Dickinson, Dwight; Verchinski, Beth A; Lemaitre, Herve; Barnett, Alan S; Trampush, Joey W; Weinberger, Daniel R; Marenco, Stefano

    2013-02-01

    The BDNF Val(66)Met polymorphism, a possible risk variant for mental disorders, is a potent modulator of neural plasticity in humans and has been linked to deficits in gray matter structure, function, and cognition. The impact of the variant on brain white matter structure, however, is controversial and remains poorly understood. Here, we used diffusion tensor imaging to examine the effects of BDNF Val(66)Met genotype on white matter microstructure in a sample of 85 healthy Caucasian adults. We demonstrate decreases of fractional anisotropy and widespread increases in radial diffusivity in Val/Val homozygotes compared with Met-allele carriers, particularly in prefrontal and occipital pathways. These data provide an independent confirmation of prior imaging genetics work, are consistent with complex effects of the BDNF Val(66)Met polymorphism on human brain structure, and may serve to generate hypotheses about variation in white matter microstructure in mental disorders associated with this variant. PMID:23132269

  1. Effects of the BDNF Val66Met Polymorphism on White Matter Microstructure in Healthy Adults

    PubMed Central

    Tost, Heike; Alam, Tajvar; Geramita, Matthew; Rebsch, Christine; Kolachana, Bhaskar; Dickinson, Dwight; Verchinski, Beth A; Lemaitre, Herve; Barnett, Alan S; Trampush, Joey W; Weinberger, Daniel R; Marenco, Stefano

    2013-01-01

    The BDNF Val66Met polymorphism, a possible risk variant for mental disorders, is a potent modulator of neural plasticity in humans and has been linked to deficits in gray matter structure, function, and cognition. The impact of the variant on brain white matter structure, however, is controversial and remains poorly understood. Here, we used diffusion tensor imaging to examine the effects of BDNF Val66Met genotype on white matter microstructure in a sample of 85 healthy Caucasian adults. We demonstrate decreases of fractional anisotropy and widespread increases in radial diffusivity in Val/Val homozygotes compared with Met-allele carriers, particularly in prefrontal and occipital pathways. These data provide an independent confirmation of prior imaging genetics work, are consistent with complex effects of the BDNF Val66Met polymorphism on human brain structure, and may serve to generate hypotheses about variation in white matter microstructure in mental disorders associated with this variant. PMID:23132269

  2. Val66Met BDNF polymorphism is associated with Parkinson's disease cognitive impairment.

    PubMed

    Altmann, Vivian; Schumacher-Schuh, Artur F; Rieck, Mariana; Callegari-Jacques, Sidia M; Rieder, Carlos R M; Hutz, Mara H

    2016-02-26

    Parkinson's disease (PD) is one of the most common neurodegenerative diseases worldwide. Besides characteristic PD motor features, the disease has important non-motor characteristics such as cognitive impairment. The role of genetic factors in cognitive impairment associated with PD is still unclear. In this study, we examined whether BDNF Val66Met was associated with impaired cognition in Parkinson's disease. One hundred and seventy five patients with a clinical diagnosis of Parkinson's disease were included. Global cognitive abilities of the patients were measured by the Mini-Mental State Examination (MMSE). Poisson Regression models were used to test for association between 66Met carriers and cognitive impairment controlling for covariates. Carriers of at least one BDNF 66Met allele presented a higher prevalence of cognitive impairment (p=0.005 RR=1.45 IC=95% [1.1-1.8]). These results suggest a role for BDNF Val66Met polymorphism on cognitive impairment in PD. PMID:26806863

  3. Pathophysiology of insulin secretion.

    PubMed

    Scheen, A J

    2004-02-01

    Defects in pancreatic islet beta-cell function play a major role in the development of diabetes mellitus. Type 1 diabetes is caused by a more or less rapid destruction of pancreatic beta cells, and the autoimmune process begins years before the beta-cell destruction becomes complete, thereby providing a window of opportunity for intervention. During the preclinical period and early after diagnosis, much of the insulin deficiency may be the result of functional inhibition of insulin secretion that may be at least partially and transiently reversible. Type 2 diabetes is characterized by a progressive loss of beta-cell function throughout the course of the disease. The pattern of loss is an initial (probably of genetic origin) defect in acute or first-phase insulin secretion, followed by a decreasing maximal capacity of insulin secretion. Last, a defective steady-state and basal insulin secretion develops, leading to almost complete beta-cell failure requiring insulin treatment. Because of the reciprocal relation between insulin secretion and insulin sensitivity, valid representation of beta-cell function requires interpretation of insulin responses in the context of the prevailing degree of insulin sensitivity. This appropriate approach highlights defects in insulin secretion at the various stages of the natural history of type 2 diabetes and already present in individuals at risk to develop the disease. To date none of the available therapies can stop the progressive beta-cell defect and the progression of the metabolic disorder. The better understanding of the pathophysiology of the disease should lead to the development of new strategies to preserve beta-cell function in both type 1 and type 2 diabetes mellitus.

  4. 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

  5. Late Protein Synthesis-Dependent Phases in CTA Long-Term Memory: BDNF Requirement.

    PubMed

    Martínez-Moreno, Araceli; Rodríguez-Durán, Luis F; Escobar, Martha L

    2011-01-01

    It has been proposed that long-term memory (LTM) persistence requires a late protein synthesis-dependent phase, even many hours after memory acquisition. Brain-derived neurotrophic factor (BDNF) is an essential protein synthesis product that has emerged as one of the most potent molecular mediators for long-term synaptic plasticity. Studies in the rat hippocampus have been shown that BDNF is capable to rescue the late-phase of long-term potentiation as well as the hippocampus-related LTM when protein synthesis was inhibited. Our previous studies on the insular cortex (IC), a region of the temporal cortex implicated in the acquisition and storage of conditioned taste aversion (CTA), have demonstrated that intracortical delivery of BDNF reverses the deficit in CTA memory caused by the inhibition of IC protein synthesis due to anisomycin administration during early acquisition. In this work, we first analyze whether CTA memory storage is protein synthesis-dependent in different time windows. We observed that CTA memory become sensible to protein synthesis inhibition 5 and 7 h after acquisition. Then, we explore the effect of BDNF delivery (2 μg/2 μl per side) in the IC during those late protein synthesis-dependent phases. Our results show that BDNF reverses the CTA memory deficit produced by protein synthesis inhibition in both phases. These findings support the notion that recurrent rounds of consolidation-like events take place in the neocortex for maintenance of CTA memory trace and that BDNF is an essential component of these processes.

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

    PubMed Central

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

    2014-01-01

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

  7. Intensive Rehabilitation Enhances Lymphocyte BDNF-TrkB Signaling in Patients With Parkinson's Disease.

    PubMed

    Fontanesi, Cecilia; Kvint, Svetlana; Frazzitta, Giuseppe; Bera, Rossana; Ferrazzoli, Davide; Di Rocco, Alessandro; Rebholz, Heike; Friedman, Eitan; Pezzoli, Gianni; Quartarone, Angelo; Wang, Hoau-Yan; Ghilardi, M Felice

    2016-06-01

    Background In a combined animal and human study, we have previously found that a 5-day treatment that enhances cortical plasticity also facilitates brain-derived neurotrophic factor (BDNF)-tyrosine receptor kinase B (TrkB) signaling and increases activated TrkB and N-methyl-d-aspartate receptor (NMDAR) association in both the cortex and the peripheral lymphocytes. Patients with Parkinson's disease (PD), in general, show decreased cortical plasticity, as demonstrated by electrophysiological and behavioral studies. Here, we test the hypothesis that an exercise program that improves motor function and seems to slow down symptom progression can enhance BDNF-TrkB signaling in lymphocytes. Methods A total of 16 patients with PD underwent a 4-week multidisciplinary intensive rehabilitation treatment (MIRT), which included aerobic training and physical and occupational therapy. Blood was collected before and after 2 and 4 weeks of MIRT. Lymphocytes were isolated to examine BDNF-TrkB signaling induced by incubation with recombinant human BDNF. TrkB signaling complexes, extracellular-signal-regulated kinase-2 and protein-kinase-B were immunoprecipitated; the content of immunocomplexes was determined by Western blotting. Results After MIRT, all patients showed improvement in motor function. TrkB interaction with NMDAR and BDNF-TrkB signaling increased in peripheral lymphocytes at receptor, intracellular mediator, and downstream levels. The decrements in Unified Parkinson's Disease Rating Scale II (UPDRSII) and total scores were significantly correlated with the increases in TrkB signaling at receptor, intracellular mediator, and NMDAR interaction levels. Conclusions The significant correlation between reduced UPDRS scores and the changes in lymphocyte activity suggest that enhanced BDNF-TrkB signaling in lymphocyte and reduced severity of PD symptoms may be related. PMID:26253177

  8. Fetal iron deficiency induces chromatin remodeling at the Bdnf locus in adult rat hippocampus.

    PubMed

    Tran, Phu V; Kennedy, Bruce C; Lien, Yu-Chin; Simmons, Rebecca A; Georgieff, Michael K

    2015-02-15

    Fetal and subsequent early postnatal iron deficiency causes persistent impairments in cognitive and affective behaviors despite prompt postnatal iron repletion. The long-term cognitive impacts are accompanied by persistent downregulation of brain-derived neurotrophic factor (BDNF), a factor critical for hippocampal plasticity across the life span. This study determined whether early-life iron deficiency epigenetically modifies the Bdnf locus and whether dietary choline supplementation during late gestation reverses these modifications. DNA methylation and histone modifications were assessed at the Bdnf-IV promoter in the hippocampus of rats [at postnatal day (PND) 65] that were iron-deficient (ID) during the fetal-neonatal period. Iron deficiency was induced in rat pups by providing pregnant and nursing dams an ID diet (4 mg/kg Fe) from gestational day (G) 2 through PND7, after which iron deficiency was treated with an iron-sufficient (IS) diet (200 mg/kg Fe). This paradigm resulted in about 60% hippocampal iron loss on PND15 with complete recovery by PND65. For choline supplementation, pregnant rat dams were given dietary choline (5 g/kg) from G11 through G18. DNA methylation was determined by quantitative sequencing of bisulfite-treated DNA, revealing a small alteration at the Bdnf-IV promoter. Chromatin immunoprecipitation analysis showed increased HDAC1 binding accompanied by reduced binding of RNA polymerase II and USF1 at the Bdnf-IV promoter in formerly ID rats. These changes were correlated with altered histone methylations. Prenatal choline supplementation reverses these epigenetic modifications. Collectively, the findings identify epigenetic modifications as a potential mechanism to explicate the long-term repression of Bdnf following fetal and early postnatal iron deficiency.

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

    PubMed

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

    2016-01-01

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

  10. Late Protein Synthesis-Dependent Phases in CTA Long-Term Memory: BDNF Requirement

    PubMed Central

    Martínez-Moreno, Araceli; Rodríguez-Durán, Luis F.; Escobar, Martha L.

    2011-01-01

    It has been proposed that long-term memory (LTM) persistence requires a late protein synthesis-dependent phase, even many hours after memory acquisition. Brain-derived neurotrophic factor (BDNF) is an essential protein synthesis product that has emerged as one of the most potent molecular mediators for long-term synaptic plasticity. Studies in the rat hippocampus have been shown that BDNF is capable to rescue the late-phase of long-term potentiation as well as the hippocampus-related LTM when protein synthesis was inhibited. Our previous studies on the insular cortex (IC), a region of the temporal cortex implicated in the acquisition and storage of conditioned taste aversion (CTA), have demonstrated that intracortical delivery of BDNF reverses the deficit in CTA memory caused by the inhibition of IC protein synthesis due to anisomycin administration during early acquisition. In this work, we first analyze whether CTA memory storage is protein synthesis-dependent in different time windows. We observed that CTA memory become sensible to protein synthesis inhibition 5 and 7 h after acquisition. Then, we explore the effect of BDNF delivery (2 μg/2 μl per side) in the IC during those late protein synthesis-dependent phases. Our results show that BDNF reverses the CTA memory deficit produced by protein synthesis inhibition in both phases. These findings support the notion that recurrent rounds of consolidation-like events take place in the neocortex for maintenance of CTA memory trace and that BDNF is an essential component of these processes. PMID:21960964

  11. BDNF Expression in Perirhinal Cortex is Associated with Exercise-Induced Improvement in Object Recognition Memory

    PubMed Central

    Hopkins, Michael E.; Bucci, David J.

    2010-01-01

    Physical exercise induces widespread neurobiological adaptations and improves learning and memory. Most research in this field has focused on hippocampus-based spatial tasks and changes in brain-derived neurotrophic factor (BDNF) as a putative substrate underlying exercise-induced cognitive improvements. Chronic exercise can also be anxiolytic and causes adaptive changes in stress reactivity. The present study employed a perirhinal cortex-dependent object recognition task as well as the elevated plus maze to directly test for interactions between the cognitive and anxiolytic effects of exercise in male Long Evans rats. Hippocampal and perirhinal cortex tissue was collected to determine whether the relationship between BDNF and cognitive performance extends to this non-spatial and non-hippocampal-dependent task. We also examined whether the cognitive improvements persisted once the exercise regimen was terminated. Our data indicate that 4 weeks of voluntary exercise every-other-day improved object recognition memory. Importantly, BDNF expression in the perirhinal cortex of exercising rats was strongly correlated with object recognition memory. Exercise also decreased anxiety-like behavior, however there was no evidence to support a relationship between anxiety-like behavior and performance on the novel object recognition task. There was a trend for a negative relationship between anxiety-like behavior and hippocampal BDNF. Neither the cognitive improvements nor the relationship between cognitive function and perirhinal BDNF levels persisted after 2 weeks of inactivity. These are the first data demonstrating that region-specific changes in BDNF protein levels are correlated with exercise-induced improvements in non-spatial memory, mediated by structures outside the hippocampus and are consistent with the theory that, with regard to object recognition, the anxiolytic and cognitive effects of exercise may be mediated through separable mechanisms. PMID:20601027

  12. Late Protein Synthesis-Dependent Phases in CTA Long-Term Memory: BDNF Requirement.

    PubMed

    Martínez-Moreno, Araceli; Rodríguez-Durán, Luis F; Escobar, Martha L

    2011-01-01

    It has been proposed that long-term memory (LTM) persistence requires a late protein synthesis-dependent phase, even many hours after memory acquisition. Brain-derived neurotrophic factor (BDNF) is an essential protein synthesis product that has emerged as one of the most potent molecular mediators for long-term synaptic plasticity. Studies in the rat hippocampus have been shown that BDNF is capable to rescue the late-phase of long-term potentiation as well as the hippocampus-related LTM when protein synthesis was inhibited. Our previous studies on the insular cortex (IC), a region of the temporal cortex implicated in the acquisition and storage of conditioned taste aversion (CTA), have demonstrated that intracortical delivery of BDNF reverses the deficit in CTA memory caused by the inhibition of IC protein synthesis due to anisomycin administration during early acquisition. In this work, we first analyze whether CTA memory storage is protein synthesis-dependent in different time windows. We observed that CTA memory become sensible to protein synthesis inhibition 5 and 7 h after acquisition. Then, we explore the effect of BDNF delivery (2 μg/2 μl per side) in the IC during those late protein synthesis-dependent phases. Our results show that BDNF reverses the CTA memory deficit produced by protein synthesis inhibition in both phases. These findings support the notion that recurrent rounds of consolidation-like events take place in the neocortex for maintenance of CTA memory trace and that BDNF is an essential component of these processes. PMID:21960964

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

    PubMed

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

    2016-01-01

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

  14. 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

  15. BDNF expression in perirhinal cortex is associated with exercise-induced improvement in object recognition memory.

    PubMed

    Hopkins, Michael E; Bucci, David J

    2010-09-01

    Physical exercise induces widespread neurobiological adaptations and improves learning and memory. Most research in this field has focused on hippocampus-based spatial tasks and changes in brain-derived neurotrophic factor (BDNF) as a putative substrate underlying exercise-induced cognitive improvements. Chronic exercise can also be anxiolytic and causes adaptive changes in stress-reactivity. The present study employed a perirhinal cortex-dependent object recognition task as well as the elevated plus maze to directly test for interactions between the cognitive and anxiolytic effects of exercise in male Long Evans rats. Hippocampal and perirhinal cortex tissue was collected to determine whether the relationship between BDNF and cognitive performance extends to this non-spatial and non-hippocampal-dependent task. We also examined whether the cognitive improvements persisted once the exercise regimen was terminated. Our data indicate that 4weeks of voluntary exercise every-other-day improved object recognition memory. Importantly, BDNF expression in the perirhinal cortex of exercising rats was strongly correlated with object recognition memory. Exercise also decreased anxiety-like behavior, however there was no evidence to support a relationship between anxiety-like behavior and performance on the novel object recognition task. There was a trend for a negative relationship between anxiety-like behavior and hippocampal BDNF. Neither the cognitive improvements nor the relationship between cognitive function and perirhinal BDNF levels persisted after 2weeks of inactivity. These are the first data demonstrating that region-specific changes in BDNF protein levels are correlated with exercise-induced improvements in non-spatial memory, mediated by structures outside the hippocampus and are consistent with the theory that, with regard to object recognition, the anxiolytic and cognitive effects of exercise may be mediated through separable mechanisms.

  16. Deltamethrin, a type II pyrethroid insecticide, has neurotrophic effects on neurons with continuous activation of the Bdnf promoter.

    PubMed

    Ihara, Daisuke; Fukuchi, Mamoru; Honma, Daisuke; Takasaki, Ichiro; Ishikawa, Mitsuru; Tabuchi, Akiko; Tsuda, Masaaki

    2012-02-01

    Pyrethroids, widely used insecticides with low acute toxicity in mammals, affect sodium channels in neurons. In a primary culture of rat cortical neurons, deltamethrin (DM), a type II pyrethroid, markedly enhanced the expression of brain-derived neurotrophic factor (BDNF) exon IV-IX (Bdnf eIV-IX) mRNA. In this study, we found that DM has a neurotrophic effect on cultured neurons and investigated the mechanisms responsible for it. One μM DM increased cell survival, neurite complexity and length. Neurite complexity and length were reduced not only by a blockade of cellular excitation with GABA or Ca(2+) influx via L-type voltage-dependent calcium channels with nicardipine, but also by a blockade of TrkB, a specific receptor for BDNF, with TrkB/Fc. These data indicate DM has neurotrophic actions. DM-induced Bdnf eIV-IX mRNA expression through the calcineurin and ERK/MAPK pathways, the increase of which was reduced by GABA(A) receptor activation. Using a promoter assay, we found that Ca(2+)-responsive elements including a CRE are involved in the DM-induced activation of the Bdnf promoter IV (Bdnf-pIV). The intracellular concentration of Ca(2+) and activation of Bdnf-pIV remained elevated for, at least, 1 and 24 h, respectively. Moreover, GABA(A) receptor activation or a blockade of Ca(2+) influx even after starting the incubation with DM reduced the elevated activity of Bdnf-pIV. These data demonstrated that the prolonged activation of Bdnf-pIV occurred because of this continuous increase in the intracellular Ca(2+) concentration. Thus, DM has neurotrophic effects on neurons, likely due to prolonged activation of Bdnf promoter in neurons. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

  17. BDNF Promotes Axon Branching of Retinal Ganglion Cells via miRNA-132 and p250GAP

    PubMed Central

    Marler, Katharine J.; Suetterlin, Philipp; Dopplapudi, Asha; Rubikaite, Aine; Adnan, Jihad; Maiorano, Nicola A.; Lowe, Andrew S.; Thompson, Ian D.; Pathania, Manav; Bordey, Angelique; Fulga, Tudor; Van Vactor, David L.; Hindges, Robert

    2014-01-01

    A crucial step in the development of the vertebrate visual system is the branching of retinal ganglion cell (RGC) axons within their target, the superior colliculus/tectum. A major player in this process is the neurotrophin brain-derived neurotrophic factor (BDNF). However, the molecular basis for the signaling pathways mediating BDNF action is less well understood. As BDNF exerts some of its functions by controlling the expression of microRNAs (miRNAs), we investigated whether miRNAs are also involved in BDNF-mediated retinal axon branching. Here, we demonstrate that the expression pattern of miRNA-132 in the retina is consistent with its involvement in this process, and that BDNF induces the upregulation of miRNA-132 in retinal cultures. Furthermore, in vitro gain-of-function and loss-of-function approaches in retinal cultures reveal that miRNA-132 mediates axon branching downstream of BDNF. A known target of miRNA-132 is the Rho family GTPase-activating protein, p250GAP. We find that p250GAP is expressed in RGC axons and mediates the effects of miRNA-132 in BDNF-induced branching. BDNF treatment or overexpression of miRNA-132 leads to a reduction in p250GAP protein levels in retinal cultures, whereas the overexpression of p250GAP abolishes BDNF-induced branching. Finally, we used a loss-of-function approach to show that miRNA-132 affects the maturation of RGC termination zones in the mouse superior colliculus in vivo, while their topographic targeting remains intact. Together, our data indicate that BDNF promotes RGC axon branching during retinocollicular/tectal map formation via upregulation of miRNA-132, which in turn downregulates p250GAP. PMID:24431455

  18. Corticosterone effects on BDNF mRNA expression in the rat hippocampus during morris water maze training.

    PubMed

    Schaaf, M J; Sibug, R M; Duurland, R; Fluttert, M F; Oitzl, M S; De Kloet, E R; Vreugdenhil, E

    1999-12-01

    Corticosterone and Brain-Derived Neurotrophic Factor (BDNF) have both been shown to be involved in spatial memory formation in rats. In the present study we have investigated the effect of corticosterone on hippocampal BDNF mRNA expression after training in the Morris water maze in young adult Wistar rats. Therefore, we first studied BDNF mRNA levels in the hippocampus in relation to corticosterone levels at several time points after 4 training trials in the Morris water maze. Corticosterone levels were significantly increased after this procedure, and hippocampal BDNF mRNA levels only displayed a minor change: an increase in CA1 at 1 hr after training. However, in a previous study we observed dramatically decreased hippocampal BDNF mRNA levels in dentate gyrus and CA1 at 3 hr after injection of corticosterone. In order to analyze this discrepancy, we subsequently investigated if hippocampal BDNF mRNA expression is affected by corticosterone at 3 hr after water maze training. Therefore, we incorporated ADX animals and ADX animals which were injected with corticosterone in our study. ADX animals which were subjected to water maze training displayed similar hippocampal BDNF mRNA levels 3 hr after training compared to control ADX animals. Furthermore, ADX animals which were injected with corticosterone showed decreased BDNF mRNA levels in all hippocampal regions compared to control ADX animals. Water maze training did not alter this effect. Thus, the increased corticosterone levels during water maze training do not affect hippocampal BDNF mRNA expression, although exogenous corticosterone is effective under these conditions. Hence, our results suggest that in this situation BDNF is resistant to regulation by endogenous corticosterone, which may be important for learning and memory processes.

  19. BDNF contributes to both rapid and homeostatic alterations in AMPA receptor surface expression in nucleus accumbens medium spiny neurons

    PubMed Central

    Reimers, Jeremy M.; Loweth, Jessica A.; Wolf, Marina E.

    2015-01-01

    Brain-derived neurotrophic factor (BDNF) plays a critical role in plasticity at glutamate synapses and the effects of repeated cocaine exposure. We recently showed that intracranial injection of BDNF into the rat nucleus accumbens (NAc), a key region for cocaine addiction, rapidly increases AMPA receptor (AMPAR) surface expression. To further characterize BDNF’s role in both rapid AMPAR trafficking and slower, homeostatic changes in AMPAR surface expression, we investigated the effects of acute (30 min) and long-term (24 h) treatment with BDNF on AMPAR distribution in NAc medium spiny neurons from postnatal rats co-cultured with mouse prefrontal cortex (PFC) neurons to restore excitatory inputs. Immunocytochemical studies showed that acute BDNF treatment increased cell surface GluA1 and GluA2 levels, as well as their co-localization, on NAc neurons. This effect of BDNF, confirmed using a protein crosslinking assay, was dependent on ERK but not AKT signaling. In contrast, long-term BDNF treatment decreased AMPAR surface expression on NAc neurons. Based on this latter result, we tested the hypothesis that BDNF plays a role in AMPAR “scaling down” in response to a prolonged increase in neuronal activity produced by bicuculline (24 h). Supporting this hypothesis, decreasing BDNF signaling with the extracellular BDNF scavenger TrkB-Fc prevented the scaling down of GluA1 and GluA2 surface levels in NAc neurons normally produced by bicuculline. In conclusion, BDNF exerts bidirectional effects on NAc AMPAR surface expression, depending on duration of exposure. Furthermore, BDNF’s involvement in synaptic scaling in the NAc differs from its previously described role in the visual cortex. PMID:24712995

  20. BDNF in Lower Brain Parts Modifies Auditory Fiber Activity to Gain Fidelity but Increases the Risk for Generation of Central Noise After Injury.

    PubMed

    Chumak, Tetyana; Rüttiger, Lukas; Lee, Sze Chim; Campanelli, Dario; Zuccotti, Annalisa; Singer, Wibke; Popelář, Jiří; Gutsche, Katja; Geisler, Hyun-Soon; Schraven, Sebastian Philipp; Jaumann, Mirko; Panford-Walsh, Rama; Hu, Jing; Schimmang, Thomas; Zimmermann, Ulrike; Syka, Josef; Knipper, Marlies

    2016-10-01

    For all sensory organs, the establishment of spatial and temporal cortical resolution is assumed to be initiated by the first sensory experience and a BDNF-dependent increase in intracortical inhibition. To address the potential of cortical BDNF for sound processing, we used mice with a conditional deletion of BDNF in which Cre expression was under the control of the Pax2 or TrkC promoter. BDNF deletion profiles between these mice differ in the organ of Corti (BDNF (Pax2) -KO) versus the auditory cortex and hippocampus (BDNF (TrkC) -KO). We demonstrate that BDNF (Pax2) -KO but not BDNF (TrkC) -KO mice exhibit reduced sound-evoked suprathreshold ABR waves at the level of the auditory nerve (wave I) and inferior colliculus (IC) (wave IV), indicating that BDNF in lower brain regions but not in the auditory cortex improves sound sensitivity during hearing onset. Extracellular recording of IC neurons of BDNF (Pax2) mutant mice revealed that the reduced sensitivity of auditory fibers in these mice went hand in hand with elevated thresholds, reduced dynamic range, prolonged latency, and increased inhibitory strength in IC neurons. Reduced parvalbumin-positive contacts were found in the ascending auditory circuit, including the auditory cortex and hippocampus of BDNF (Pax2) -KO, but not of BDNF (TrkC) -KO mice. Also, BDNF (Pax2) -WT but not BDNF (Pax2) -KO mice did lose basal inhibitory strength in IC neurons after acoustic trauma. These findings suggest that BDNF in the lower parts of the auditory system drives auditory fidelity along the entire ascending pathway up to the cortex by increasing inhibitory strength in behaviorally relevant frequency regions. Fidelity and inhibitory strength can be lost following auditory nerve injury leading to diminished sensory outcome and increased central noise.

  1. BDNF in Lower Brain Parts Modifies Auditory Fiber Activity to Gain Fidelity but Increases the Risk for Generation of Central Noise After Injury.

    PubMed

    Chumak, Tetyana; Rüttiger, Lukas; Lee, Sze Chim; Campanelli, Dario; Zuccotti, Annalisa; Singer, Wibke; Popelář, Jiří; Gutsche, Katja; Geisler, Hyun-Soon; Schraven, Sebastian Philipp; Jaumann, Mirko; Panford-Walsh, Rama; Hu, Jing; Schimmang, Thomas; Zimmermann, Ulrike; Syka, Josef; Knipper, Marlies

    2016-10-01

    For all sensory organs, the establishment of spatial and temporal cortical resolution is assumed to be initiated by the first sensory experience and a BDNF-dependent increase in intracortical inhibition. To address the potential of cortical BDNF for sound processing, we used mice with a conditional deletion of BDNF in which Cre expression was under the control of the Pax2 or TrkC promoter. BDNF deletion profiles between these mice differ in the organ of Corti (BDNF (Pax2) -KO) versus the auditory cortex and hippocampus (BDNF (TrkC) -KO). We demonstrate that BDNF (Pax2) -KO but not BDNF (TrkC) -KO mice exhibit reduced sound-evoked suprathreshold ABR waves at the level of the auditory nerve (wave I) and inferior colliculus (IC) (wave IV), indicating that BDNF in lower brain regions but not in the auditory cortex improves sound sensitivity during hearing onset. Extracellular recording of IC neurons of BDNF (Pax2) mutant mice revealed that the reduced sensitivity of auditory fibers in these mice went hand in hand with elevated thresholds, reduced dynamic range, prolonged latency, and increased inhibitory strength in IC neurons. Reduced parvalbumin-positive contacts were found in the ascending auditory circuit, including the auditory cortex and hippocampus of BDNF (Pax2) -KO, but not of BDNF (TrkC) -KO mice. Also, BDNF (Pax2) -WT but not BDNF (Pax2) -KO mice did lose basal inhibitory strength in IC neurons after acoustic trauma. These findings suggest that BDNF in the lower parts of the auditory system drives auditory fidelity along the entire ascending pathway up to the cortex by increasing inhibitory strength in behaviorally relevant frequency regions. Fidelity and inhibitory strength can be lost following auditory nerve injury leading to diminished sensory outcome and increased central noise. PMID:26476841

  2. Salivary Gland Secretion.

    ERIC Educational Resources Information Center

    Dorman, H. L.; And Others

    1981-01-01

    Describes materials and procedures for an experiment utilizing a live dog to demonstrate: (1) physiology of the salivary gland; (2) parasympathetic control of the salivary gland; (3) influence of varying salivary flow rates on sodium and potassium ions, osmolarity and pH; and (4) salivary secretion as an active process. (DS)

  3. Biliary lipid secretion.

    PubMed

    Hişmioğullari, Adnan Adil; Bozdayi, A Mithat; Rahman, Khalid

    2007-06-01

    The liver has many biochemical functions, of which one of the most important is bile formation. Bile is both a secretory and an excretory fluid and two of its most important functions are the delivery to the intestinal tract of: (i) bile acids to assist in fat digestion and absorption; and (ii) liver-derived metabolites of potentially toxic materials prior to their elimination from the body in the feces. Bile contains numerous solutes, including bile acids, phospholipids and cholesterol. Biliary lipids mainly consist of cholesterol and phospholipids and their secretion into bile is affected by the secretion of bile acids. Phospholipids and cholesterol are synthesized in the hepatocytes and are thought to be transferred via vesicle- and non-vesicle-mediated mechanisms into the bile canaliculus. Hepatocytes acquire biliary lipid by three pathways, which are biosynthesis, lipoproteins and existing molecules drawn from intracellular membranes, with the newly synthesized biliary lipid accounting for less than 20% of the total lipids. The hepatic determinants of biliary cholesterol elimination are not limited to total cholesterol homeostasis, but also concern biliary disease conditions, since excess biliary cholesterol secretion is involved in cholesterol gallstone formation, as well as being a major risk factor for gallbladder cancer. The purpose of this review was to highlight some of the major mechanisms involved in biliary lipid secretion.

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

    PubMed

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

    2016-09-23

    Patients with Parkinson's disease (PD) often have aggregated α-synuclein (aSyn) in enteric nervous system (ENS) neurons, which may be associated with the development of constipation. This occurs well before the onset of classic PD motor symptoms. We previously found that aging A53T transgenic (Tg) mice closely model PD-like ENS aSyn pathology, making them appropriate for testing potential PD therapies. Here we show that Tg mice overexpressing mutant human aSyn develop ENS pathology by 4 months. We then evaluated the responses of Tg mice and their WT littermates to the Food and Drug Administration-approved drug FTY720 (fingolimod, Gilenya) or vehicle control solution from 5 months of age. Long term oral FTY720 in Tg mice reduced ENS aSyn aggregation and constipation, enhanced gut motility, and increased levels of brain-derived neurotrophic factor (BDNF) but produced no significant change in WT littermates. A role for BDNF was directly assessed in a cohort of young A53T mice given vehicle, FTY720, the Trk-B receptor inhibitor ANA-12, or FTY720 + ANA-12 from 1 to 4 months of age. ANA-12-treated Tg mice developed more gut aSyn aggregation as well as constipation, whereas FTY720-treated Tg mice had reduced aSyn aggregation and less constipation, occurring in part by increasing both pro-BDNF and mature BDNF levels. The data from young and old Tg mice revealed FTY720-associated neuroprotection and reduced aSyn pathology, suggesting that FTY720 may also benefit PD patients and others with synucleinopathy. Another finding was a loss of tyrosine hydroxylase immunoreactivity in gut neurons with aggregated aSyn, comparable with our prior findings in the CNS. PMID:27528608

  5. Activity-dependent signal changes in neurons by fiber-coupled microscopy

    NASA Astrophysics Data System (ADS)

    Sakurai, Takashi; Koida, Kowa

    2014-03-01

    To study neuronal functions in brain, we developed a higher resolution type fiber-coupled microscope (FCM), and measured the activity-dependent fluorescence intensity of the excitable cells over time. FCM was constructed by combining a fluorescence microscope with the high density type of fiber bundle, which consisted of 1.5 x 104 unit fiber in the assemble less than 0.5 mm tip. The spatial resolution was calculated to be 2.4 mm with the 5 mm focal depth. The activity-dependent Ca signals were detectable in each cell of either the pancreatic spheroids or the brain slices. The present FCM is very promising for detailed studies with the live imaging of signal molecules in the body at a single cell level.

  6. Molecular mechanisms of activity-dependent changes in dendritic morphology: role of RGK proteins

    PubMed Central

    Ghiretti, Amy E.; Paradis, Suzanne

    2014-01-01

    The nervous system has the amazing capacity to transform sensory experience from the environment into changes in neuronal activity that, in turn, cause long-lasting alterations in neuronal morphology. Recent findings illustrate a somewhat surprising result: sensory experience concurrently activates molecular signaling pathways that both promote and inhibit dendritic complexity. Historically, a number of positive regulators of activity-dependent dendritic complexity have been described, while the list of identified negative regulators of this process is much shorter. In recent years, there has been an emerging appreciation of the importance of the Rad/Rem/Rem2/Gem/Kir (RGK) GTPases as mediators of activity-dependent structural plasticity. In the following review, we discuss the traditional view of RGK proteins, as well as our evolving understanding of the role of these proteins in instructing structural plasticity. PMID:24910262

  7. Modeling activity-dependent changes of axonal spike conduction in primary afferent C-nociceptors

    PubMed Central

    Tigerholm, Jenny; Petersson, Marcus E.; Obreja, Otilia; Lampert, Angelika; Carr, Richard; Schmelz, Martin

    2013-01-01

    Action potential initiation and conduction along peripheral axons is a dynamic process that displays pronounced activity dependence. In patients with neuropathic pain, differences in the modulation of axonal conduction velocity by activity suggest that this property may provide insight into some of the pathomechanisms. To date, direct recordings of axonal membrane potential have been hampered by the small diameter of the fibers. We have therefore adopted an alternative approach to examine the basis of activity-dependent changes in axonal conduction by constructing a comprehensive mathematical model of human cutaneous C-fibers. Our model reproduced axonal spike propagation at a velocity of 0.69 m/s commensurate with recordings from human C-nociceptors. Activity-dependent slowing (ADS) of axonal propagation velocity was adequately simulated by the model. Interestingly, the property most readily associated with ADS was an increase in the concentration of intra-axonal sodium. This affected the driving potential of sodium currents, thereby producing latency changes comparable to those observed for experimental ADS. The model also adequately reproduced post-action potential excitability changes (i.e., recovery cycles) observed in vivo. We performed a series of control experiments replicating blockade of particular ion channels as well as changing temperature and extracellular ion concentrations. In the absence of direct experimental approaches, the model allows specific hypotheses to be formulated regarding the mechanisms underlying activity-dependent changes in C-fiber conduction. Because ADS might functionally act as a negative feedback to limit trains of nociceptor activity, we envisage that identifying its mechanisms may also direct efforts aimed at alleviating neuronal hyperexcitability in pain patients. PMID:24371290

  8. Evidence for evolutionary divergence of activity-dependent gene expression in developing neurons

    PubMed Central

    Qiu, Jing; McQueen, Jamie; Bilican, Bilada; Dando, Owen; Magnani, Dario; Punovuori, Karolina; Selvaraj, Bhuvaneish T; Livesey, Matthew; Haghi, Ghazal; Heron, Samuel; Burr, Karen; Patani, Rickie; Rajan, Rinku; Sheppard, Olivia; Kind, Peter C; Simpson, T Ian; Tybulewicz, Victor LJ; Wyllie, David JA; Fisher, Elizabeth MC; Lowell, Sally; Chandran, Siddharthan; Hardingham, Giles E

    2016-01-01

    Evolutionary differences in gene regulation between humans and lower mammalian experimental systems are incompletely understood, a potential translational obstacle that is challenging to surmount in neurons, where primary tissue availability is poor. Rodent-based studies show that activity-dependent transcriptional programs mediate myriad functions in neuronal development, but the extent of their conservation in human neurons is unknown. We compared activity-dependent transcriptional responses in developing human stem cell-derived cortical neurons with those induced in developing primary- or stem cell-derived mouse cortical neurons. While activity-dependent gene-responsiveness showed little dependence on developmental stage or origin (primary tissue vs. stem cell), notable species-dependent differences were observed. Moreover, differential species-specific gene ortholog regulation was recapitulated in aneuploid mouse neurons carrying human chromosome-21, implicating promoter/enhancer sequence divergence as a factor, including human-specific activity-responsive AP-1 sites. These findings support the use of human neuronal systems for probing transcriptional responses to physiological stimuli or indeed pharmaceutical agents. DOI: http://dx.doi.org/10.7554/eLife.20337.001 PMID:27692071

  9. Histone methyltransferase Ash1L mediates activity-dependent repression of neurexin-1α.

    PubMed

    Zhu, Τao; Liang, Chen; Li, Dongdong; Tian, Miaomiao; Liu, Sanxiong; Gao, Guanjun; Guan, Ji-Song

    2016-05-27

    Activity-dependent transcription is critical for the regulation of long-term synaptic plasticity and plastic rewiring in the brain. Here, we report that the transcription of neurexin1α (nrxn1α), a presynaptic adhesion molecule for synaptic formation, is regulated by transient neuronal activation. We showed that 10 minutes of firing at 50 Hz in neurons repressed the expression of nrxn1α for 24 hours in a primary cortical neuron culture through a transcriptional repression mechanism. By performing a screening assay using a synthetic zinc finger protein (ZFP) to pull down the proteins enriched near the nrxn1α promoter region in vivo, we identified that Ash1L, a histone methyltransferase, is enriched in the nrxn1α promoter. Neuronal activity triggered binding of Ash1L to the promoter and enriched the histone marker H3K36me2 at the nrxn1α promoter region. Knockout of Ash1L in mice completely abolished the activity-dependent repression of nrxn1α. Taken together, our results reveal that a novel process of activity-dependent transcriptional repression exists in neurons and that Ash1L mediates the long-term repression of nrxn1α, thus implicating an important role for epigenetic modification in brain functioning.

  10. Histone methyltransferase Ash1L mediates activity-dependent repression of neurexin-1α

    PubMed Central

    Zhu, Τao; Liang, Chen; Li, Dongdong; Tian, Miaomiao; Liu, Sanxiong; Gao, Guanjun; Guan, Ji-Song

    2016-01-01

    Activity-dependent transcription is critical for the regulation of long-term synaptic plasticity and plastic rewiring in the brain. Here, we report that the transcription of neurexin1α (nrxn1α), a presynaptic adhesion molecule for synaptic formation, is regulated by transient neuronal activation. We showed that 10 minutes of firing at 50 Hz in neurons repressed the expression of nrxn1α for 24 hours in a primary cortical neuron culture through a transcriptional repression mechanism. By performing a screening assay using a synthetic zinc finger protein (ZFP) to pull down the proteins enriched near the nrxn1α promoter region in vivo, we identified that Ash1L, a histone methyltransferase, is enriched in the nrxn1α promoter. Neuronal activity triggered binding of Ash1L to the promoter and enriched the histone marker H3K36me2 at the nrxn1α promoter region. Knockout of Ash1L in mice completely abolished the activity-dependent repression of nrxn1α. Taken together, our results reveal that a novel process of activity-dependent transcriptional repression exists in neurons and that Ash1L mediates the long-term repression of nrxn1α, thus implicating an important role for epigenetic modification in brain functioning. PMID:27229316

  11. Activity-dependent plasticity of spinal circuits in the developing and mature spinal cord.

    PubMed

    Tahayori, Behdad; Koceja, David M

    2012-01-01

    Part of the development and maturation of the central nervous system (CNS) occurs through interactions with the environment. Through physical activities and interactions with the world, an animal receives considerable sensory information from various sources. These sources can be internally (proprioceptive) or externally (such as touch and pressure) generated senses. Ample evidence exists to demonstrate that the sensory information originating from large diameter afferents (Ia fibers) have an important role in inducing essential functional and morphological changes for the maturation of both the brain and the spinal cord. The Ia fibers transmit sensory information generated by muscle activity and movement. Such use or activity-dependent plastic changes occur throughout life and are one reason for the ability to acquire new skills and learn new movements. However, the extent and particularly the mechanisms of activity-dependent changes are markedly different between a developing nervous system and a mature nervous system. Understanding these mechanisms is an important step to develop strategies for regaining motor function after different injuries to the CNS. Plastic changes induced by activity occur both in the brain and spinal cord. This paper reviews the activity-dependent changes in the spinal cord neural circuits during both the developmental stages of the CNS and in adulthood. PMID:22900208

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

    SciTech Connect

    Phillips, H.S.; Hains, J.M.; Laramee, G.R.; Rosenthal, A.; Winslow, J.W. )

    1990-10-12

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

  13. 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

  14. Gastric Bypass Surgery Reverses Diabetic Phenotypes in Bdnf-Deficient Mice.

    PubMed

    Jiang, Shujun; Wang, Qinghua; Huang, Zan; Song, Anying; Peng, Yu; Hou, Siyuan; Guo, Shiying; Zhu, Weiyun; Yan, Sheng; Lin, Zhaoyu; Gao, Xiang

    2016-08-01

    Duodenum-jejunum gastric bypass (DJB) has been used to treat morbid diabetic patients. However, neither the suitability among patients nor the mechanisms of this surgical treatment is clear. Previously, we reported a new mouse strain named Timo as type 2 diabetes model caused by brain-derived neurotrophic factor (Bdnf) deficiency. In this study, we found that DJB on Timo mice reversed their metabolic abnormalities without altering the expression of Bdnf. Glucose tolerance and insulin sensitivity were improved greatly, along with reduction of fat accumulation in liver and white adipose tissue. The gut flora population was altered by DJB with increased proportion of Firmicutes and decreased Actinobacteria and Proteobacteria in the ileum after surgery. Systemic inflammation in Timo mice was greatly suppressed with less macrophage infiltration and lower tumor necrosis factor-α levels in liver and white adipose tissue after surgery. Interestingly, the alteration of gut microflora abundance and improved metabolism preceded the inflammation alleviation after DJB surgery. These results suggested that DJB can reverse Bdnf deficiency-associated metabolic abnormality. In addition, the reduced inflammation may not be the initial cause for the DJB-associated metabolic and microbiota alterations. The increased BDNF protein levels in hypothalamus and hippocampus may result from microbiota change after DJB surgery. PMID:27418549

  15. Action control is mediated by prefrontal BDNF and glucocorticoid receptor binding.

    PubMed

    Gourley, Shannon L; Swanson, Andrew M; Jacobs, Andrea M; Howell, Jessica L; Mo, Michelle; Dileone, Ralph J; Koleske, Anthony J; Taylor, Jane R

    2012-12-11

    Stressor exposure biases decision-making strategies from those based on the relationship between actions and their consequences to others restricted by stimulus-response associations. Chronic stressor exposure also desensitizes glucocorticoid receptors (GR) and diminishes motivation to acquire food reinforcement, although causal relationships are largely not established. We show that a history of chronic exposure to the GR ligand corticosterone or acute posttraining GR blockade with RU38486 makes rodents less able to perform actions based on their consequences. Thus, optimal GR binding is necessary for the consolidation of new response-outcome learning. In contrast, medial prefrontal (but not striatal) BDNF can account for stress-related amotivation, in that selective medial prefrontal cortical Bdnf knockdown decreases break-point ratios in a progressive-ratio task. Knockdown also increases vulnerability to RU38486. Despite the role of BDNF in dendritic spine reorganization, deep-layer spine remodeling does not obviously parallel progressive-ratio response patterns, but treatment with the Na(+)-channel inhibitor riluzole reverses corticosteroid-induced motivational deficits and restores prefrontal BDNF expression after corticosterone. We argue that when prefrontal neurotrophin systems are compromised, and GR-mediated hypothalamic-pituitary-adrenal axis feedback is desensitized (as in the case of chronic stress hormone exposure), amotivation and inflexible maladaptive response strategies that contribute to stress-related mood disorders result. PMID:23185000

  16. Altered social cognition in male BDNF heterozygous mice and following chronic methamphetamine exposure.

    PubMed

    Manning, Elizabeth E; van den Buuse, Maarten

    2016-05-15

    Growing clinical evidence suggests that persistent psychosis which occurs in methamphetamine users is closely related to schizophrenia. However, preclinical studies in animal models have focussed on psychosis-related behaviours following methamphetamine, and less work has been done to assess endophenotypes relevant to other deficits observed in schizophrenia. Altered social behaviour is a feature of both the negative symptoms and cognitive deficits in schizophrenia, and significantly impacts patient functioning. We recently found that brain-derived neurotrophic factor (BDNF) heterozygous mice show disrupted sensitization to methamphetamine, supporting other work suggesting an important role of this neurotrophin in the pathophysiology of psychosis and the neuronal response to stimulant drugs. In the current study, we assessed social and cognitive behaviours in methamphetamine-treated BDNF heterozygous mice and wildtype littermate controls. Following chronic methamphetamine exposure male wildtype mice showed a 50% reduction in social novelty preference. Vehicle-treated male BDNF heterozygous mice showed a similar impairment in social novelty preference, with a trend for no further disruption by methamphetamine exposure. Female mice were unaffected in this task, and no groups showed any changes in sociability or short-term spatial memory. These findings suggest that chronic methamphetamine alters behaviour relevant to disruption of social cognition in schizophrenia, supporting other studies which demonstrate a close resemblance between persistent methamphetamine psychosis and schizophrenia. Together these findings suggest that dynamic regulation of BDNF signalling is necessary to mediate the effects of methamphetamine on behaviours relevant to schizophrenia.

  17. Altered social cognition in male BDNF heterozygous mice and following chronic methamphetamine exposure.

    PubMed

    Manning, Elizabeth E; van den Buuse, Maarten

    2016-05-15

    Growing clinical evidence suggests that persistent psychosis which occurs in methamphetamine users is closely related to schizophrenia. However, preclinical studies in animal models have focussed on psychosis-related behaviours following methamphetamine, and less work has been done to assess endophenotypes relevant to other deficits observed in schizophrenia. Altered social behaviour is a feature of both the negative symptoms and cognitive deficits in schizophrenia, and significantly impacts patient functioning. We recently found that brain-derived neurotrophic factor (BDNF) heterozygous mice show disrupted sensitization to methamphetamine, supporting other work suggesting an important role of this neurotrophin in the pathophysiology of psychosis and the neuronal response to stimulant drugs. In the current study, we assessed social and cognitive behaviours in methamphetamine-treated BDNF heterozygous mice and wildtype littermate controls. Following chronic methamphetamine exposure male wildtype mice showed a 50% reduction in social novelty preference. Vehicle-treated male BDNF heterozygous mice showed a similar impairment in social novelty preference, with a trend for no further disruption by methamphetamine exposure. Female mice were unaffected in this task, and no groups showed any changes in sociability or short-term spatial memory. These findings suggest that chronic methamphetamine alters behaviour relevant to disruption of social cognition in schizophrenia, supporting other studies which demonstrate a close resemblance between persistent methamphetamine psychosis and schizophrenia. Together these findings suggest that dynamic regulation of BDNF signalling is necessary to mediate the effects of methamphetamine on behaviours relevant to schizophrenia. PMID:26965573

  18. Interaction between serum BDNF and aerobic fitness predicts recognition memory in healthy young adults.

    PubMed

    Whiteman, Andrew S; Young, Daniel E; He, Xuemei; Chen, Tai C; Wagenaar, Robert C; Stern, Chantal E; Schon, Karin

    2014-02-01

    Convergent evidence from human and non-human animal studies suggests aerobic exercise and increased aerobic capacity may be beneficial for brain health and cognition. It is thought growth factors may mediate this putative relationship, particularly by augmenting plasticity mechanisms in the hippocampus, a brain region critical for learning and memory. Among these factors, glucocorticoids, brain derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), and vascular endothelial growth factor (VEGF), hormones that have considerable and diverse physiological importance, are thought to effect normal and exercise-induced hippocampal plasticity. Despite these predictions, relatively few published human studies have tested hypotheses that relate exercise and fitness to the hippocampus, and none have considered the potential links to all of these hormonal components. Here we present cross-sectional data from a study of recognition memory; serum BDNF, cortisol, IGF-1, and VEGF levels; and aerobic capacity in healthy young adults. We measured circulating levels of these hormones together with performance on a recognition memory task, and a standard graded treadmill test of aerobic fitness. Regression analyses demonstrated BDNF and aerobic fitness predict recognition memory in an interactive manner. In addition, IGF-1 was positively associated with aerobic fitness, but not with recognition memory. Our results may suggest an exercise adaptation-related change in the BDNF dose-response curve that relates to hippocampal memory.

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

    PubMed

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

    2013-01-01

    Previous literature suggests that learning and memory formation can be influenced by diet and exercise. In the current study, we investigated the combined effects of forced swimming exercise (FSE) and every other day fasting (EODF) on spatial memory formation and on the levels of brain-derived neurotrophic factor (BDNF) in the hippocampus of Wistar male rats. The radial arm water maze (RAWM) paradigm was used to assess changes in learning and memory formation, whereas ELISA assay was used to measure BDNF protein levels. The FSE and/or EODF were simultaneously instituted for 6 weeks. Results show that FSE improved learning, short-term as well as long-term memory formation, and significantly increased BDNF protein in the hippocampus (p<0.05). However, EODF had no effect on either spatial learning and memory formation or the levels of hippocamapal BDNF protein (p>0.05). In addition, EODF did not modulate beneficial effect of swimming exercise on cognitive function (p>0.05). Thus exercise enhanced, while EODF did not affect spatial learning and memory formation.

  20. Genetic Variation in BDNF is Associated with Antipsychotic Treatment Resistance in Patients with Schizophrenia

    PubMed Central

    Zhang, Jian-Ping; Lencz, Todd; Geisler, Stephen; DeRosse, Pamela; Bromet, Evelyn J.; Malhotra, Anil K.

    2013-01-01

    Objective Antipsychotic drugs are the mainstay of treatment for schizophrenia. However, a substantial proportion of patients are poorly responsive or resistant to first-line treatments, and clozapine treatment is often indicated. Therefore, we and others have used clozapine treatment as a proxy phenotype for antipsychotic treatment resistance in pharmacogenetic studies. In the present study, we utilized this phenotype to test previously-identified candidate genes for antipsychotic treatment response. Method We assessed 89 Caucasian schizophrenia patients clinically assigned to clozapine treatment versus 190 Caucasian patients that were not selected for clozapine treatment. We conducted gene-based association tests on a set of 74 relevant candidate genes nominated in the CATIE pharmacogenetic study (Need et al, 2009), using the GATES procedure (Li et al, 2011). Results After correcting for multiple testing in the gene-based association test, the gene for brain derived neurotrophic factor (BDNF) was significantly associated with treatment resistance. The top single nucleotide polymorphisms (SNPs) in BDNF included rs11030104 (OR=2.57), rs10501087 (OR=2.19) and rs6265 (Val66Met) (OR=2.08). These SNPs appear to be in high linkage disequilibrium with each other. Conclusion BDNF appears to have a strong association with antipsychotic treatment resistance. Future studies are needed to replicate this finding and further elucidate the biological pathways underlying the association between BDNF and antipsychotic drug response. PMID:23433505

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

    PubMed

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

    2014-10-17

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

  2. The analysis of BDNF gene polymorphism haplotypes and impulsivity in methamphetamine abusers.

    PubMed

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

    2015-05-01

    An increasing number of evidence showed that genetic factors might contribute to drug abuse vulnerability. Data from genetic scans in humans suggest that brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, may be associated with substance abuse or dependence. To test the hypothesis that the BDNF gene polymorphism is involved in methamphetamine abuse, we compared three single nucleotide polymorphisms (SNPs, rs16917204, rs16917234, and rs2030324) of the BDNF gene in 200 methamphetamine abusers and 219 healthy individuals. We also considered the association of these polymorphisms with impulsivity in methamphetamine abusers using Barratt Impulsivity Scale-11(BIS-11) Chinese version. Individual SNP analysis showed no significant differences in genotype and allele distributions between the methamphetamine abusers and controls. Haplotype analysis of rs16917204-rs16917234-rs2030324 revealed that a major C-C-T haplotype was significantly associated a lower odds of methamphetamine abuse, even after Bonferroni correction. Within the methamphetamine-abuse group, subjects carrying the T allele of rs2030324 genotype had significantly higher motor impulsivity scores of BIS compared to those with the C/C genotype. Our findings suggest that the BDNF gene polymorphism may contribute to the impulsivity in methamphetamine abusers.

  3. Extracellular secretion of recombinant proteins

    SciTech Connect

    Linger, Jeffrey G.; Darzins, Aldis

    2014-07-22

    Nucleic acids encoding secretion signals, expression vectors containing the nucleic acids, and host cells containing the expression vectors are disclosed. Also disclosed are polypeptides that contain the secretion signals and methods of producing polypeptides, including methods of directing the extracellular secretion of the polypeptides. Exemplary embodiments include cellulase proteins fused to secretion signals, methods to produce and isolate these polypeptides, and methods to degrade lignocellulosic biomass.

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

    PubMed

    Dalle Molle, R; Portella, A K; Goldani, M Z; Kapczinski, F P; Leistner-Segal, S; 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.

  5. Prolonged abstinence from developmental cocaine exposure dysregulates BDNF and its signaling network in the medial prefrontal cortex of adult rats.

    PubMed

    Giannotti, Giuseppe; Caffino, Lucia; Calabrese, Francesca; Racagni, Giorgio; Riva, Marco A; Fumagalli, Fabio

    2014-04-01

    Although evidence exists that chronic cocaine exposure during adulthood is associated with changes in BDNF expression, whether and how cocaine exposure during adolescence modulates BDNF is still unknown. To address this issue, we exposed rats to repeated cocaine injections from post-natal day (PD) 28 to PD 42, a period that roughly approximates adolescence in humans, and we carried out a detailed analysis of the BDNF system in the medial prefrontal cortex (mPFC) of rats sacrificed 3 d (PD 45) and 48 d (PD 90) after the last cocaine treatment. We found that developmental exposure to cocaine altered transcriptional and translational mechanisms governing neurotrophin expression. Total BDNF mRNA levels, in fact, were enhanced in the mPFC of PD 90 rats exposed to cocaine in adolescence, an effect sustained by changes in BDNF exon IV through the transcription factors CaRF and NF-kB. While a profound reduction of specific BDNF-related miRNAs (let7d, miR124 and miR132) may contribute to explaining the increased proBDNF levels, the up-regulation of the extracellular proteases tPA is indicative of increased processing leading to higher levels of released mBDNF. These changes were associated with increased activation of the trkB-Akt pathway resulting in enhanced pmTOR and pS6 kinase, which ultimately produced an up-regulation of Arc and a consequent reduction of GluA1 expression in the mPFC of PD 90 cocaine-treated rats. These findings demonstrate that developmental exposure to cocaine dynamically dysregulates BDNF and its signaling network in the mPFC of adult rats, providing novel mechanisms that may contribute to cocaine-induced changes in synaptic plasticity. PMID:24345425

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

    PubMed

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

    2012-03-01

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

  7. Cisplatin regulates SH-SY5Y cell growth through downregulation of BDNF via miR-16.

    PubMed

    Sun, Yun-Xiao; Yang, Jian; Wang, Ping-Yu; Li, You-Jie; Xie, Shu-Yang; Sun, Ruo-Peng

    2013-11-01

    Brain-derived neurotropic factor (BDNF) is a member of the neurotropin family. High levels of BDNF are associated with more aggressive malignant behavior in human cancer. In the present study, we observed the effect of cisplatin on BDNF expression in SH-SY5Y cells and investigated the mechanism of cisplatin in inducing the apoptosis of SH-SY5Y cells. Our results revealed that the expression of BDNF was obviously decreased in cisplatin-treated SH-SY5Y cells. In addition, the 3'-untranslated region of BDNF was found to be targeted by miR-16 using microRNA analysis software. After miR-16 was synthesized chemically, SH-SY5Y cells were transfected with miR-16 to investigate the regulatory role of miR-16 in regards to BDNF. The results showed that the expression of BDNF was markedly decreased in the miR‑16-transfected cells when compared with that in the control cultures as determined by western blotting. Moreover, miR-16 expression was obviously upregulated in the cisplatin-treated cells when compared with the untreated controls. Furthermore, SH-SY5Y cells were xenografted subcutaneously in nude mice to study the effect of cisplatin on the growth of SH-SY5Y cells in vivo. The results further showed that cisplatin inhibited the proliferation of SH-SY5Y cells in the cisplatin-treated mice when compared with the saline-treated control. The expression of miR-16 was increased, while the expression of BDNF was decreased in the cisplatin-treated mice. Our results demonstrated that cisplatin downregulated the expression of BDNF through miR-16 to inhibit SH-SY5Y cell proliferation in vitro and in vivo. These findings provide the basis for new targets for drug design or cancer therapy.

  8. Prolonged abstinence from developmental cocaine exposure dysregulates BDNF and its signaling network in the medial prefrontal cortex of adult rats.

    PubMed

    Giannotti, Giuseppe; Caffino, Lucia; Calabrese, Francesca; Racagni, Giorgio; Riva, Marco A; Fumagalli, Fabio

    2014-04-01

    Although evidence exists that chronic cocaine exposure during adulthood is associated with changes in BDNF expression, whether and how cocaine exposure during adolescence modulates BDNF is still unknown. To address this issue, we exposed rats to repeated cocaine injections from post-natal day (PD) 28 to PD 42, a period that roughly approximates adolescence in humans, and we carried out a detailed analysis of the BDNF system in the medial prefrontal cortex (mPFC) of rats sacrificed 3 d (PD 45) and 48 d (PD 90) after the last cocaine treatment. We found that developmental exposure to cocaine altered transcriptional and translational mechanisms governing neurotrophin expression. Total BDNF mRNA levels, in fact, were enhanced in the mPFC of PD 90 rats exposed to cocaine in adolescence, an effect sustained by changes in BDNF exon IV through the transcription factors CaRF and NF-kB. While a profound reduction of specific BDNF-related miRNAs (let7d, miR124 and miR132) may contribute to explaining the increased proBDNF levels, the up-regulation of the extracellular proteases tPA is indicative of increased processing leading to higher levels of released mBDNF. These changes were associated with increased activation of the trkB-Akt pathway resulting in enhanced pmTOR and pS6 kinase, which ultimately produced an up-regulation of Arc and a consequent reduction of GluA1 expression in the mPFC of PD 90 cocaine-treated rats. These findings demonstrate that developmental exposure to cocaine dynamically dysregulates BDNF and its signaling network in the mPFC of adult rats, providing novel mechanisms that may contribute to cocaine-induced changes in synaptic plasticity.

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

    PubMed

    Dalle Molle, R; Portella, A K; Goldani, M Z; Kapczinski, F P; Leistner-Segal, S; 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

  10. 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

  11. Reduced Hippocampal Brain-Derived Neurotrophic Factor (BDNF) in Neonatal Rats after Prenatal Exposure to Propylthiouracil (PTU)

    PubMed Central

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

    2012-01-01

    Thyroid hormone is critical for central nervous system development. Fetal hypothyroidism leads to reduced cognitive performance in offspring as well as other effects on neural development in both humans and experimental animals. The nature of these impairments suggests that thyroid hormone may exert its effects via dysregulation of the neurotrophin brain-derived neurotrophic factor (BDNF), which is critical to normal development of the central nervous system and has been implicated in neurodevelopmental disorders. The only evidence of BDNF dysregulation in early development, however, comes from experimental models in which severe prenatal hypothyroidism occurred. By contrast, milder prenatal hypothyroidism has been shown to alter BDNF levels and BDNF-dependent functions only much later in life. We hypothesized that mild experimental prenatal hypothyroidism might lead to dysregulation of BDNF in the early postnatal period. BDNF levels were measured by ELISA at 3 or 7 d after birth in different regions of the brains of rats exposed to propylthiouracil (PTU) in the drinking water. The dose of PTU that was used induced mild maternal thyroid hormone insufficiency. Pups, but not the parents, exhibited alterations in tissue BDNF levels. Hippocampal BDNF levels were reduced at both d 3 and 7, but no significant reductions were observed in either the cerebellum or brain stem. Unexpectedly, more males than females were born to PTU-treated dams, suggesting an effect of PTU on sex determination. These results support the hypothesis that reduced hippocampal BDNF levels during early development may contribute to the adverse neurodevelopmental effects of mild thyroid hormone insufficiency during pregnancy. PMID:22253429

  12. Exercise-induced improvement in cognitive performance after traumatic brain-injury in rats is dependent on BDNF Activation

    PubMed Central

    Griesbach, Grace Sophia; Hovda, David Allen; Gomez-Pinilla, Fernando

    2009-01-01

    We have previously shown that voluntary exercise upregulates brain-derived neurotrophic factor (BDNF) within the hippocampus and is associated with an enhancement of cognitive recovery after a lateral fluid-percussion injury (FPI). In order to determine if BDNF is critical to this effect we used an immunoadhesin chimera (TrkB-IgG) that inactivates free BDNF. This BDNF inhibitor was administered to adult male rats two weeks after they had received a mild fluid percussion injury (FPI) or sham surgery. These animals were then housed with or without access to a running wheel (RW) from post-injury-day (PID) 14 to 20. On PID 21, rats were tested for spatial learning in a Morris Water Maze. Results showed that exercise counteracted the cognitive deficits associated with the injury. However this exercise-induced cognitive improvement was attenuated in the FPI-RW rats that were treated with TrkB-IgG. Molecules important for synaptic plasticity and learning were measured in a separate group of rats that were sacrificed immediately after exercise (PID 21). Western blot analyses showed that exercise increased the mature form of BDNF, synapsin I and cyclic-AMP response-element-binding protein (CREB) in the vehicle treated Sham-RW group. However, only the mature form of BDNF and CREB were increased in the vehicle treated FPI-RW group. Blocking BDNF (pre administration of TrkB-IgG) greatly reduced the molecular effects of exercise in that exercise-induced increases of BDNF, synapsin I and CREB were not observed. These studies provide evidence that BDNF has a major role in exercise's cognitive effects in traumatically injured brain. PMID:19555673

  13. Telling stories: keeping secrets.

    PubMed

    Jensen, Joan M

    2009-01-01

    This article addresses the reticence of some farm women to share their experiences with historians and how that desire to keep secrets collides with the desire by scholars to tell the stories of these women. It argues that scholars must continue to struggle with the issue of which stories to tell publicly and which to keep private. The author discusses her own experience telling stories about rural women in the 1970s and the need to give voice to the heritage of rural women, especially of groups that have feared revealing their experiences. She offers examples of historians of rural women who have successfully worked with formerly silenced populations and urges historians to continue to tell stories about these lives, to reevaluate what has been already learned, to ask new questions, and to discuss which secrets need to be shared.

  14. Cell secretion: an update.

    PubMed

    Jeremic, A

    2008-08-01

    This past decade has witnessed the publication of a flurry of scientific papers and reports on the subject of cell secretion, following discovery of a permanent plasma membrane structure termed 'porosome' and its determination as the universal secretory machinery in cells. This discovery has led to a paradigm shift in our understanding of the secretory process, demonstrating that membrane-bound secretory vesicles transiently dock and fuse at the porosome base to release their contents to the cell exterior. The regulated release of intravesicular contents during cell secretion is governed by dilation of the porosome opening to the outside, and the extent of vesicle swelling. In agreement, a great number of articles have been written and studies performed, which are briefly discussed in this article.

  15. Cell secretion: an update

    PubMed Central

    Jeremic, A

    2008-01-01

    This past decade has witnessed the publication of a flurry of scientific papers and reports on the subject of cell secretion, following discovery of a permanent plasma membrane structure termed ‘porosome’ and its determination as the universal secretory machinery in cells. This discovery has led to a paradigm shift in our understanding of the secretory process, demonstrating that membrane-bound secretory vesicles transiently dock and fuse at the porosome base to release their contents to the cell exterior. The regulated release of intravesicular contents during cell secretion is governed by dilation of the porosome opening to the outside, and the extent of vesicle swelling. In agreement, a great number of articles have been written and studies performed, which are briefly discussed in this article. PMID:18363838

  16. Bile Formation and Secretion

    PubMed Central

    Boyer, James L.

    2014-01-01

    Bile is a unique and vital aqueous secretion of the liver that is formed by the hepatocyte and modified down stream by absorptive and secretory properties of the bile duct epithelium. Approximately 5% of bile consists of organic and inorganic solutes of considerable complexity. The bile-secretory unit consists of a canalicular network which is formed by the apical membrane of adjacent hepatocytes and sealed by tight junctions. The bile canaliculi (~1 μm in diameter) conduct the flow of bile countercurrent to the direction of portal blood flow and connect with the canal of Hering and bile ducts which progressively increase in diameter and complexity prior to the entry of bile into the gallbladder, common bile duct, and intestine. Canalicular bile secretion is determined by both bile salt-dependent and independent transport systems which are localized at the apical membrane of the hepatocyte and largely consist of a series of adenosine triphosphate-binding cassette transport proteins that function as export pumps for bile salts and other organic solutes. These transporters create osmotic gradients within the bile canalicular lumen that provide the driving force for movement of fluid into the lumen via aquaporins. Species vary with respect to the relative amounts of bile salt-dependent and independent canalicular flow and cholangiocyte secretion which is highly regulated by hormones, second messengers, and signal transduction pathways. Most determinants of bile secretion are now characterized at the molecular level in animal models and in man. Genetic mutations serve to illuminate many of their functions. PMID:23897680

  17. Daily intermittent hypoxia augments spinal BDNF levels, ERK phosphorylation and respiratory long-term facilitation

    PubMed Central

    Wilkerson, Julia E.R.; Mitchell, Gordon S.

    2009-01-01

    Acute intermittent hypoxia (AIH) elicits a form of respiratory plasticity known as long-term facilitation (LTF). We hypothesized that: 1) daily AIH (dAIH) preconditioning enhances phrenic and hypoglossal (XII) LTF in a rat strain with low constitutive LTF expression; 2) dAIH induces brain-derived neurotrophic factor (BDNF), a critical protein for phrenic LTF (pLTF) in the cervical spinal cord; and 3) dAIH increases post-AIH extracellular regulated kinase (ERK) activation. Phrenic and XII motor output were monitored in anesthetized dAIH- or sham-treated Brown Norway rats with and without acute AIH. pLTF was observed in both sham (18 ± 9% baseline; 60 min post-hypoxia; p < 0.05; n = 18) and dAIH treated rats (37 ± 8%; p < 0.05; n = 14), but these values were not significantly different (p = 0.13). XII LTF was not observed in sham-treated rats (4 ± 5%), but was revealed in dAIH pretreated rats (48 ± 18%; p < 0.05). dAIH preconditioning increased basal ventral cervical BDNF protein levels (24 ± 8%; p < 0.05), but had no significant effect on ERK phosphorylation. AIH increased BDNF in sham (25 ± 8%; p < 0.05), but not dAIH-pretreated rats (−7 ± 4%), and had complex effects on ERK phosphorylation (ERK2 increased in shams whereas ERK1 increased in dAIH-treated rats). Thus, dAIH elicits metaplasticity in LTF, revealing XII LTF in a rat strain with no constitutive XII LTF expression. Increased BDNF synthesis may no longer be necessary for phrenic LTF following dAIH preconditioning since BDNF concentration is already elevated. PMID:19416672

  18. BDNF modulates GABAA receptors microtransplanted from the human epileptic brain to Xenopus oocytes

    PubMed Central

    Palma, E.; Torchia, G.; Limatola, C.; Trettel, F.; Arcella, A.; Cantore, G.; Di Gennaro, G.; Manfredi, M.; Esposito, V.; Quarato, P. P.; Miledi, R.; Eusebi, F.

    2005-01-01

    Cell membranes isolated from brain tissues, obtained surgically from six patients afflicted with drug-resistant temporal lobe epilepsy and from one nonepileptic patient afflicted with a cerebral oligodendroglioma, were injected into frog oocytes. By using this approach, the oocytes acquire human GABAA receptors, and we have shown previously that the “epileptic receptors” (receptors transplanted from epileptic brains) display a marked run-down during repetitive applications of GABA. It was found that exposure to the neurotrophin BDNF increased the amplitude of the “GABA currents” (currents elicited by GABA) generated by the epileptic receptors and decreased their run-down; both events being blocked by K252A, a neurotrophin tyrosine kinase receptor B inhibitor. These effects of BDNF were not mimicked by nerve growth factor. In contrast, the GABAA receptors transplanted from the nonepileptic human hippocampal uncus (obtained during surgical resection as part of the nontumoral tissue from the oligodendroglioma margins) or receptors expressed by injecting rat recombinant α1β2γ2 GABAA receptor subunit cDNAs generated GABA currents whose time-course and run-down were not altered by BDNF. Loading the oocytes with the Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetate-acetoxymethyl ester (BAPTA-AM), or treating them with Rp-8-Br-cAMP, an inhibitor of the cAMP-dependent PKA, did not alter the GABA currents. However, staurosporine (a broad spectrum PK inhibitor), bisindolylmaleimide I (a PKC inhibitor), and U73122 (a phospholipase C inhibitor) blocked the BDNF-induced effects on the epileptic GABA currents. Our results indicate that BDNF potentiates the epileptic GABAA currents and antagonizes their use-dependent run-down, thus strengthening GABAergic inhibition, probably by means of activation of tyrosine kinase receptor B receptors and of both PLC and PKC. PMID:15665077

  19. 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

  20. The Role of BDNF, Leptin, and Catecholamines in Reward Learning in Bulimia Nervosa

    PubMed Central

    Grob, Simona; Milos, Gabriella; Schnyder, Ulrich; Eckert, Anne; Lang, Undine; Hasler, Gregor

    2015-01-01

    Background: A relationship between bulimia nervosa and reward-related behavior is supported by several lines of evidence. The dopaminergic dysfunctions in the processing of reward-related stimuli have been shown to be modulated by the neurotrophin brain derived neurotrophic factor (BDNF) and the hormone leptin. Methods: Using a randomized, double-blind, placebo-controlled, crossover design, a reward learning task was applied to study the behavior of 20 female subjects with remitted bulimia nervosa and 27 female healthy controls under placebo and catecholamine depletion with alpha-methyl-para-tyrosine (AMPT). The plasma levels of BDNF and leptin were measured twice during the placebo and the AMPT condition, immediately before and 1 hour after a standardized breakfast. Results: AMPT–induced differences in plasma BDNF levels were positively correlated with the AMPT–induced differences in reward learning in the whole sample (P=.05). Across conditions, plasma brain derived neurotrophic factor levels were higher in remitted bulimia nervosa subjects compared with controls (diagnosis effect; P=.001). Plasma BDNF and leptin levels were higher in the morning before compared with after a standardized breakfast across groups and conditions (time effect; P<.0001). The plasma leptin levels were higher under catecholamine depletion compared with placebo in the whole sample (treatment effect; P=.0004). Conclusions: This study reports on preliminary findings that suggest a catecholamine-dependent association of plasma BDNF and reward learning in subjects with remitted bulimia nervosa and controls. A role of leptin in reward learning is not supported by this study. However, leptin levels were sensitive to a depletion of catecholamine stores in both remitted bulimia nervosa and controls. PMID:25522424

  1. Catechin secretion and phytotoxicity

    PubMed Central

    Kaushik, Shail

    2010-01-01

    Research indicates that the invasiveness of Centaurea stoebe is attributed to the stronger allelopathic effects on the native North American species than on the related European species, which is one of the unquestionable aspects of the “novel weapons hypothesis (NWH).” Studies originating from controlled to field conditions have shown that C. stoebe utilizes its biochemical potential to exert its invasiveness. The roots of C. stoebe secrete a potent phytotoxin, catechin, which has a detrimental effect on the surrounding plant species. Although, studies on catechin secretion and phytotoxicity represent one of the most well studied systems describing negative plant-plant interactions, it has also sparked controversies lately due to its phytotoxicity dosages and secretion effluxes. Previous reports negate the phytotoxic and pro-oxidant nature of catechin.1–3 In our recent study we have shown that catechin is highly phytotoxic against Arabidopsis thaliana and Festuca idahoensis. We also show that (±) catechin applied to roots of A. thaliana induces reactive oxygen species (ROS) confirming the pro-oxidant nature of catechin. In addition, activation of signature cell death genes such as acd2 and cad1 post catechin treatment in A. thaliana ascertains the phytotoxic nature of catechin. PMID:21057643

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

    PubMed

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

    2013-01-01

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

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

    PubMed

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

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) plays a critical role in cognitive processes including learning and memory. However, it has been difficult to detect BDNF in the brains of behaving animals because of its extremely low concentration, i.e., at the sub-nanogram/mL level. Here, we developed an interdigitated microelectrode (IME) biosensor coated with an anti-BDNF an anti-BDNF antibody in a polydimethylsiloxane (PDMS)-based microfluidic channel chip. This sensor could detect BDNF from microliter volumes of liquid samples even at femtogram/mL concentrations with high selectivity over other growth factors. Using this biosensor, we examined whether BDNF is detectable from periodical collection of cerebrospinal fluid microdialysate, sampled every 10 min from the hippocampus of mice during the context-dependent fear-conditioning test. We found that the IME biosensor could detect a significant increase in BDNF levels after the memory task. This increase in BDNF levels was prevented by gene silencing of BDNF, indicating that the IME biosensor reliably detected BDNF in vivo. We propose that the IME biosensor provides a general-purpose probe for ultrasensitive detection of biomolecules with low abundance in the brains of behaving animals. PMID:27640722

  4. Intranasal Delivery of Recombinant AAV Containing BDNF Fused with HA2TAT: a Potential Promising Therapy Strategy for Major Depressive Disorder.

    PubMed

    Ma, Xian-cang; Liu, Peng; Zhang, Xiao-ling; Jiang, Wen-hui; Jia, Min; Wang, Cai-xia; Dong, Ying-ying; Dang, Yong-hui; Gao, Cheng-ge

    2016-01-01

    Depression is a disturbing psychiatric disease with unsatisfied therapy. Not all patients are sensitive to anti-depressants currently in use, side-effects are unavoidable during therapy, and the cases with effectiveness are always accompanied with delayed onset of clinical efficacy. Delivering brain-derived neurotrophic factor (BDNF) to brain seems to be a promising therapy. However, a better approach to delivery is still rudimentary. The purpose of our present work is to look for a rapid-onset and long-lasting therapeutic strategy for major depressive disorder (MDD) by effectively delivering BDNF to brain. BDNF, fused with cell-penetrating peptides (TAT and HA2), was packaged in adenovirus associated virus (AAV) to construct the BDNF-HA2TAT/AAV for intranasally delivering BDNF to central nervous system (CNS) via nose-brain pathway. Intranasal administration of BDNF-HA2TAT/AAV to normal mice displayed anti-depression effect in forced swimming test when the delivery lasted relatively longer. The AAV applied to mice subjected to chronic mild stress (CMS) through intranasal administration for 10 days also alleviated depression-like behaviors. Western-blotting analysis revealed that BDNF-HA2TAT/AAV nasal administration enhanced hippocampal BDNF content. These results indicate intranasal administration of constructed BDNF-HA2TAT/AAV exerts anti-depression effect in CMS mice by increasing hippocampal BDNF, suggesting that this strategy holds a promising therapeutic potential for MDD. PMID:26935651

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

    PubMed Central

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

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) plays a critical role in cognitive processes including learning and memory. However, it has been difficult to detect BDNF in the brains of behaving animals because of its extremely low concentration, i.e., at the sub-nanogram/mL level. Here, we developed an interdigitated microelectrode (IME) biosensor coated with an anti-BDNF an anti-BDNF antibody in a polydimethylsiloxane (PDMS)-based microfluidic channel chip. This sensor could detect BDNF from microliter volumes of liquid samples even at femtogram/mL concentrations with high selectivity over other growth factors. Using this biosensor, we examined whether BDNF is detectable from periodical collection of cerebrospinal fluid microdialysate, sampled every 10 min from the hippocampus of mice during the context-dependent fear-conditioning test. We found that the IME biosensor could detect a significant increase in BDNF levels after the memory task. This increase in BDNF levels was prevented by gene silencing of BDNF, indicating that the IME biosensor reliably detected BDNF in vivo. We propose that the IME biosensor provides a general-purpose probe for ultrasensitive detection of biomolecules with low abundance in the brains of behaving animals. PMID:27640722

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

    PubMed

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

    2014-10-01

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

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

    PubMed

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

    2013-01-01

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

  8. Intranasal Delivery of Recombinant AAV Containing BDNF Fused with HA2TAT: a Potential Promising Therapy Strategy for Major Depressive Disorder

    PubMed Central

    Ma, Xian-cang; Liu, Peng; Zhang, Xiao-ling; Jiang, Wen-hui; Jia, Min; Wang, Cai-xia; Dong, Ying-ying; Dang, Yong-hui; Gao, Cheng-ge

    2016-01-01

    Depression is a disturbing psychiatric disease with unsatisfied therapy. Not all patients are sensitive to anti-depressants currently in use, side-effects are unavoidable during therapy, and the cases with effectiveness are always accompanied with delayed onset of clinical efficacy. Delivering brain-derived neurotrophic factor (BDNF) to brain seems to be a promising therapy. However, a better approach to delivery is still rudimentary. The purpose of our present work is to look for a rapid-onset and long-lasting therapeutic strategy for major depressive disorder (MDD) by effectively delivering BDNF to brain. BDNF, fused with cell-penetrating peptides (TAT and HA2), was packaged in adenovirus associated virus (AAV) to construct the BDNF-HA2TAT/AAV for intranasally delivering BDNF to central nervous system (CNS) via nose-brain pathway. Intranasal administration of BDNF-HA2TAT/AAV to normal mice displayed anti-depression effect in forced swimming test when the delivery lasted relatively longer. The AAV applied to mice subjected to chronic mild stress (CMS) through intranasal administration for 10 days also alleviated depression-like behaviors. Western-blotting analysis revealed that BDNF-HA2TAT/AAV nasal administration enhanced hippocampal BDNF content. These results indicate intranasal administration of constructed BDNF-HA2TAT/AAV exerts anti-depression effect in CMS mice by increasing hippocampal BDNF, suggesting that this strategy holds a promising therapeutic potential for MDD. PMID:26935651

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

    PubMed

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

    2015-12-01

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

  10. Relevance of Post-Stroke Circulating BDNF Levels as a Prognostic Biomarker of Stroke Outcome. Impact of rt-PA Treatment.

    PubMed

    Rodier, Marion; Quirié, Aurore; Prigent-Tessier, Anne; Béjot, Yannick; Jacquin, Agnès; Mossiat, Claude; Marie, Christine; Garnier, Philippe

    2015-01-01

    The recombinant form of tissue plasminogen activator (rt-PA) is the only curative treatment for ischemic stroke. Recently, t-PA has been linked to the metabolism of brain-derived neurotrophic factor (BDNF), a major neurotrophin involved in post-stroke neuroplasticity. Thus, the objective of our study was to investigate the impact of rt-PA treatment on post-stroke circulating BDNF levels in humans and in animals. Serum BDNF levels and t-PA/plasmin activity were measured at hospital admission and at up to 90 days in stroke patients receiving (n = 24) or not (n = 14) rt-PA perfusion. We investigated the relationships between serum BDNF with concurrent t-PA/plasmin activity, neurological outcomes and cardiovascular scores at admission. In parallel, serum BDNF levels and t-PA/plasmin activity were assessed before and after (1, 4 and 24h) the induction of ischemic stroke in rats. Our study revealed higher serum BDNF levels and better neurological outcome in rt-PA-treated than non-treated patients. However, serum BDNF levels did not predict stroke outcome when the whole cohort of stroke patients was analyzed. By contrast, serum BDNF levels when measured at admission and at day 90 correlated with cardiovascular scores, and those at day 1 correlated with serum t-PA/plasmin activity in the whole cohort of patients whereas no association could be found in the rt-PA-treated group. In rats devoid of cardiovascular risk, no difference in post-stroke serum BDNF levels was detected between rt-PA- and vehicle-treated animals and no correlation was found between serum BDNF levels and t-PA/plasmin activity. Overall, the data suggest that serum BDNF levels may not be useful as a prognostic biomarker of stroke outcome and that endothelial dysfunction could be a confounding factor when serum BDNF levels after stroke are used to reflect of brain BDNF levels.

  11. Relevance of Post-Stroke Circulating BDNF Levels as a Prognostic Biomarker of Stroke Outcome. Impact of rt-PA Treatment

    PubMed Central

    Rodier, Marion; Quirié, Aurore; Prigent-Tessier, Anne; Béjot, Yannick; Jacquin, Agnès; Mossiat, Claude; Marie, Christine; Garnier, Philippe

    2015-01-01

    The recombinant form of tissue plasminogen activator (rt-PA) is the only curative treatment for ischemic stroke. Recently, t-PA has been linked to the metabolism of brain-derived neurotrophic factor (BDNF), a major neurotrophin involved in post-stroke neuroplasticity. Thus, the objective of our study was to investigate the impact of rt-PA treatment on post-stroke circulating BDNF levels in humans and in animals. Serum BDNF levels and t-PA/plasmin activity were measured at hospital admission and at up to 90 days in stroke patients receiving (n = 24) or not (n = 14) rt-PA perfusion. We investigated the relationships between serum BDNF with concurrent t-PA/plasmin activity, neurological outcomes and cardiovascular scores at admission. In parallel, serum BDNF levels and t-PA/plasmin activity were assessed before and after (1, 4 and 24h) the induction of ischemic stroke in rats. Our study revealed higher serum BDNF levels and better neurological outcome in rt-PA-treated than non-treated patients. However, serum BDNF levels did not predict stroke outcome when the whole cohort of stroke patients was analyzed. By contrast, serum BDNF levels when measured at admission and at day 90 correlated with cardiovascular scores, and those at day 1 correlated with serum t-PA/plasmin activity in the whole cohort of patients whereas no association could be found in the rt-PA-treated group. In rats devoid of cardiovascular risk, no difference in post-stroke serum BDNF levels was detected between rt-PA- and vehicle-treated animals and no correlation was found between serum BDNF levels and t-PA/plasmin activity. Overall, the data suggest that serum BDNF levels may not be useful as a prognostic biomarker of stroke outcome and that endothelial dysfunction could be a confounding factor when serum BDNF levels after stroke are used to reflect of brain BDNF levels. PMID:26469350

  12. The Role of BDNF Genotype, Parental Depression, and Relationship Discord in Predicting Early-Emerging Negative Emotionality

    PubMed Central

    Hayden, Elizabeth P.; Klein, Daniel N.; Dougherty, Lea R.; Olino, Thomas M.; Dyson, Margaret W.; Durbin, C. Emily; Sheikh, Haroon I.; Singh, Shiva M.

    2012-01-01

    The brain-derived neurotrophic factor (BDNF) gene is a plausible candidate for early-emerging negative emotionality (NE), and evidence suggests that the effects of this gene may be especially salient in the context of familial risk for child maladjustment. We therefore examined whether the BDNF val66met polymorphism was associated with child NE in the context of parental depression and relationship discord. A sample of 413 three-year-old children was assessed for NE using standardized laboratory measures. Parents completed clinical interviews and a measure of marital satisfaction. Children with at least one BDNF met allele exhibited elevated NE when a parent had a history of depressive disorder, or when relationship discord was present. In contrast, this allele was associated with especially low NE when parent depression was absent, and when the parental relationship was not discordant. Findings suggest that the BDNF met allele confers increased child sensitivity to both positive and negative familial influences. PMID:20921572

  13. BDNF modulates heart contraction force and long-term homeostasis through truncated TrkB.T1 receptor activation

    PubMed Central

    Fulgenzi, Gianluca; Tomassoni-Ardori, Francesco; Babini, Lucia; Becker, Jodi; Barrick, Colleen; Puverel, Sandrine

    2015-01-01

    Brain-derived neurotrophic factor (BDNF) is critical for mammalian development and plasticity of neuronal circuitries affecting memory, mood, anxiety, pain sensitivity, and energy homeostasis. Here we report a novel unexpected role of BDNF in regulating the cardiac contraction force independent of the nervous system innervation. This function is mediated by the truncated TrkB.T1 receptor expressed in cardiomyocytes. Loss of TrkB.T1 in these cells impairs calcium signaling and causes cardiomyopathy. TrkB.T1 is activated by BDNF produced by cardiomyocytes, suggesting an autocrine/paracrine loop. These findings unveil a novel signaling mechanism in the heart that is activated by BDNF and provide evidence for a global role of this neurotrophin in the homeostasis of the organism by signaling through different TrkB receptor isoforms. PMID:26347138

  14. A Single Intra-PFC Infusion of BDNF Prevents Cocaine-Induced Alterations in Extracellular Glutamate within the Nucleus Accumbens

    PubMed Central

    Berglind, William J.; Whitfield, Timothy W.; LaLumiere, Ryan T.; Kalivas, Peter W.; McGinty, Jacqueline F.

    2009-01-01

    The glutamatergic pathway arising in the dorsomedial prefrontal cortex (dmPFC) and projecting to the nucleus accumbens (NAc) core is a critical component of the reward circuitry that underlies reinstatement to cocaine-seeking behavior. Brain derived neurotrophic factor (BDNF) is expressed by and modulates PFC-NAc neurons. BDNF infusion into the dmPFC attenuates reinstatement to cocaine-seeking behavior as well as some cocaine-induced molecular adaptations within the NAc. In the present study, it is demonstrated that a single intra-dmPFC infusion of BDNF prevents cocaine self administration-induced reduction in basal extracelluar glutamate, as well as cocaine prime-induced increases in extracellular glutamate levels within the NAc. These data suggest that intra-PFC BDNF attenuates reinstatement to cocaine-seeking behavior by normalizing cocaine-induced neuroadaptations that alter glutamate neurotransmission within the NAc. PMID:19321768

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

    PubMed

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

    2015-01-01

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

  16. MicroRNAs downregulated in neuropathic pain regulate MeCP2 and BDNF related to pain sensitivity.

    PubMed

    Manners, Melissa T; Tian, Yuzhen; Zhou, Zhaolan; Ajit, Seena K

    2015-01-01

    Nerve injury induces chronic pain and dysregulation of microRNAs in dorsal root ganglia (DRG). Several downregulated microRNAs are predicted to target Mecp2. MECP2 mutations cause Rett syndrome and these patients report decreased pain perception. We confirmed MeCP2 upregulation in DRG following nerve injury and repression of MeCP2 by miRNAs in vitro. MeCP2 regulates brain-derived neurotrophic factor (BDNF) and downregulation of MeCP2 by microRNAs decreased Bdnf in vitro. MeCP2 T158A mice exhibited reduced mechanical sensitivity and Mecp2-null and MeCP2 T158A mice have decreased Bdnf in DRG. MeCP2-mediated regulation of Bdnf in the DRG could contribute to altered pain sensitivity. PMID:26448907

  17. Blocking GSK3β-mediated dynamin1 phosphorylation enhances BDNF-dependent TrkB endocytosis and the protective effects of BDNF in neuronal and mouse models of Alzheimer's disease.

    PubMed

    Liu, Xiang-Hua; Geng, Zhao; Yan, Jing; Li, Ting; Chen, Qun; Zhang, Qun-Ye; Chen, Zhe-Yu

    2015-02-01

    Endocytosis of tropomyosin related kinase B (TrkB) receptors has critical roles in brain-derived neurotrophic factor (BDNF) mediated signal transduction and biological function, however the mechanism that is governing TrkB endocytosis is still not completely understood. In this study, we showed that GSK3β, a key kinase in neuronal development and survival, could regulate TrkB endocytosis through phosphorylating dynamin1 (Dyn1) but not dynamin2 (Dyn2). Moreover, we found that beta-amyloid (Aβ) oligomer exposure could impair BDNF-dependent TrkB endocytosis and Akt activation through enhancing GSK3β activity in cultured hippocampal neurons, which suggested that BDNF-induced TrkB endocytosis and the subsequent signaling were impaired in neuronal model of Alzheimer's disease (AD). Notably, we found that inhibiting GSK3β phosphorylating Dyn1 by using TAT-Dyn1SpS could rescue the impaired TrkB endocytosis and Akt activation upon BDNF stimuli under Aβ exposure. Finally, TAT-Dyn1SpS could facilitate BDNF-mediated neuronal survival and cognitive enhancement in mouse models of AD. These results clarified a role of GSK3β in BDNF-dependent TrkB endocytosis and the subsequent signaling, and provided a potential new strategy by inhibiting GSK3β-induced Dyn1 phosphorylation for AD treatment.

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

    PubMed Central

    Suliman, Sharain; Hemmings, Sian M. J.; Seedat, Soraya

    2013-01-01

    Background: Brain-Derived Neurotrophic Factor (BDNF) is a neurotrophin that is involved in the synaptic plasticity and survival of neurons. BDNF is believed to be involved in the pathogenesis of several neuropsychiatric disorders. As findings of BDNF levels in anxiety disorders have been inconsistent, we undertook to conduct a systematic review and meta-analysis of studies that assessed BDNF protein levels in these disorders. Methods: We conducted the review using electronic databases and searched reference lists of relevant articles for any further studies. Studies that measured BDNF protein levels in any anxiety disorder and compared these to a control group were included. Effect sizes of the differences in BDNF levels between anxiety disorder and control groups were calculated. Results: Eight studies with a total of 1179 participants were included. Initial findings suggested that BDNF levels were lower in individuals with any anxiety disorder compared to those without [Standard Mean Difference (SMD) = −0.94 (−1.75, −0.12), p ≤ 0.05]. This was, however, dependent on source of BDNF protein [plasma: SMD = −1.31 (−1.69, −0.92), p ≤ 0.01; serum: SMD = −1.06 (−2.27, 0.16), p ≥ 0.01] and type of anxiety disorder [PTSD: SMD = −0.05 (−1.66, 1.75), p ≥ 0.01; OCD: SMD = −2.33 (−4.21, −0.45), p ≤ 0.01]. Conclusion: Although BDNF levels appear to be reduced in individuals with an anxiety disorder, this is not consistent across the various anxiety disorders and may largely be explained by the significantly lowered BDNF levels found in OCD. Results further appear to be mediated by differences in sampling methods. Findings are, however, limited by the lack of research in this area, and given the potential for BDNF as a biomarker of anxiety disorders, it would be useful to clarify the relationship further. PMID:23908608

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

    PubMed

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

    2016-03-01

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

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

    PubMed

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

    2016-03-01

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

  1. Mood Disorders and BDNF Relationship with Alcohol Drinking Trajectories among PLWH Receiving Care

    PubMed Central

    Míguez-Burbano, María José; Espinoza, Luis; Vargas, Mayra; LaForest, Diana

    2015-01-01

    Background Despite the excessive rates of Hazardous Alcohol Use (HAU) among people living with HIV (PLWH), although largely speculated, psychological and physiological components associated with HAU, has not been actively measured. Therefore, the present study was geared toward determining: 1) the rates of mood disorders and its relationship with HAU, and 2) to assess the impact of Brain Derived Neurotrophic Factor (BDNF), a well-known regulator of alcohol and mood disorders. Methods For this study, participants of the longitudinal PADS Study n=400, were followed over time. Alcohol use (Alcohol Use Disorders Identification Test –AUDIT- and the Alcohol Dependence Scale –ADS) and moods (depression, anxiety, and stress) were assessed repeatedly. Results A cluster analyses shows three distinctive trajectories. The first one, revealed a group with increased drinking (Cluster 1: n=140), constant alcohol intake (Cluster 2: n = 60), and one with decreased consumption (Cluster 3: n =120). Analyses discovered higher AUDIT scores across the clusters with Cluster 1 being followed by Clusters 2 and 3 (1: 14.5 ± 8 vs. 2=8.7 ± 7.5 vs. 3= 6.6 ± 4.2, p = 0.001). Women in Clusters 1 and 2 had higher levels of stress (1:21 ± 7.5; 2:19.3 ± 7) and lower BDNF levels (7904 ± 1248 pg/ml and 10405 ± 909 pg/mL) than their counterparts in Cluster 3 (PSS: 3: 16.6 ±5, p = 0.02 BDNF: 10828 ± 1127 pg/mL, p = 0.08). Men in Cluster 1 differed in terms of stress (19.8 ± 7 vs. 21 ± 7.5 score) and BDNF levels (Cluster 1: 5204 ± 818 vs. Cluster 2: 7656 ± 843 pg/ml, p = 0.002) but not in the number of years living with HIV. The proportion of subjects with multiple mood comorbidities was disturbingly higher (26%), and all were members of Cluster 1. Multiple logistic regression analyses indicated that participants reporting high relative to low levels of perceived stress, dual mood comorbidity, altered BDNF levels and low income increased the likelihood of being a member of Cluster 1

  2. No exercise-induced increase in serum BDNF after cycling near a major traffic road.

    PubMed

    Bos, I; Jacobs, L; Nawrot, T S; de Geus, B; Torfs, R; Int Panis, L; Degraeuwe, B; Meeusen, R

    2011-08-15

    Commuting by bike has a clear health enhancing effect. Moreover, regular exercise is known to improve brain plasticity, which results in enhanced cognition and memory performance. Animal research has clearly shown that exercise upregulates brain-derived neurotrophic factor (BDNF - a neurotrophine) enhancing brain plasticity. Studies in humans found an increase in serum BDNF concentration in response to an acute exercise bout. Recently, more evidence is emerging suggesting that exposure to air pollution (such as particulate matter (PM)) is higher in commuter cyclists compared to car drivers. Furthermore, exposure to PM is linked to negative neurological effects, such as neuroinflammation and cognitive decline. We carried-out a cross-over experiment to examine the acute effect of exercise on serum BDNF, and the potential effect-modification by exposure to traffic-related air pollution. Thirty eight physically fit, non-asthmatic volunteers (mean age: 43, 26% women) performed two cycling trials, one near a major traffic road (Antwerp Ring, R1, up to 260,000 vehicles per day) and one in an air-filtered room. The air-filtered room was created by reducing fine particles as well as ultrafine particles (UFP). PM10, PM2.5 and UFP were measured. The duration (∼20min) and intensity of cycling were kept the same for each volunteer for both cycling trials. Serum BDNF concentrations were measured before and 30min after each cycling trial. Average concentrations of PM10 and PM2.5 were 64.9μg/m(3) and 24.6μg/m(3) in cycling near a major ring way, in contrast to 7.7μg/m(3) and 2.0μg/m(3) in the air-filtered room. Average concentrations of UFP were 28,180 particles/cm(3) along the road in contrast to 496 particles/cm(3) in the air-filtered room. As expected, exercise significantly increased serum BDNF concentration after cycling in the air-filtered room (+14.4%; p=0.02). In contrast, serum BDNF concentrations did not increase after cycling near the major traffic route (+0.5%; p

  3. MeCP2 regulates activity-dependent transcriptional responses in olfactory sensory neurons.

    PubMed

    Lee, Wooje; Yun, Jung-Mi; Woods, Rima; Dunaway, Keith; Yasui, Dag H; Lasalle, Janine M; Gong, Qizhi

    2014-12-01

    During postnatal development, neuronal activity controls the remodeling of initially imprecise neuronal connections through the regulation of gene expression. MeCP2 binds to methylated DNA and modulates gene expression during neuronal development and MECP2 mutation causes the autistic disorder Rett syndrome. To investigate a role for MeCP2 in neuronal circuit refinement and to identify activity-dependent MeCP2 transcription regulations, we leveraged the precise organization and accessibility of olfactory sensory axons to manipulation of neuronal activity through odorant exposure in vivo. We demonstrate that olfactory sensory axons failed to develop complete convergence when Mecp2 is deficient in olfactory sensory neurons (OSNs) in an otherwise wild-type animal. Furthermore, we demonstrate that expression of selected adhesion genes was elevated in Mecp2-deficient glomeruli, while acute odor stimulation in control mice resulted in significantly reduced MeCP2 binding to these gene loci, correlating with increased expression. Thus, MeCP2 is required for both circuitry refinement and activity-dependent transcriptional responses in OSNs.

  4. NRC-interacting factor directs neurite outgrowth in an activity-dependent manner.

    PubMed

    Zhao, X-S; Fu, W-Y; Hung, K-W; Chien, W W Y; Li, Z; Fu, A K; Ip, N Y

    2015-03-19

    Nuclear hormone receptor coregulator-interacting factor 1 (NIF-1) is a zinc finger nuclear protein that was initially identified to enhance nuclear hormone receptor transcription via its interaction with nuclear hormone receptor coregulator (NRC). NIF-1 may regulate gene transcription either by modulating general transcriptional machinery or remodeling chromatin structure through interactions with specific protein partners. We previously reported that the cytoplasmic/nuclear localization of NIF-1 is regulated by the neuronal Cdk5 activator p35, suggesting potential neuronal functions for NIF-1. The present study reveals that NIF-1 plays critical roles in regulating neuronal morphogenesis at early stages. NIF-1 was prominently expressed in the nuclei of developing rat cortical neurons. Knockdown of NIF-1 expression attenuated both neurite outgrowth in cultured cortical neurons and retinoic acid (RA)-treated Neuro-2a neuroblastoma cells. Furthermore, activity-induced Ca(2+) influx, which is critical for neuronal morphogenesis, stimulated the nuclear localization of NIF-1 in cortical neurons. Suppression of NIF-1 expression reduced the up-regulation of neuronal activity-dependent gene transcription. These findings collectively suggest that NIF-1 directs neuronal morphogenesis during early developmental stages through modulating activity-dependent gene transcription.

  5. Dense small molecule labeling enables activator-dependent STORM by proximity mapping.

    PubMed

    Chen, Ye; Gu, Min; Gunning, Peter W; Russell, Sarah M

    2016-09-01

    Stochastic optical reconstruction microscopy (STORM) enables high-resolution imaging, but multi-channel 3D imaging is problematic because of chromatic aberrations and alignment errors. The use of activator-dependent STORM in which spectrally distinct activators can be coupled with a single reporter can circumvent such issues. However, the standard approach of linking activators and reporters to a single antibody molecule is hampered by low labeling density and the large size of the antibody. We proposed that small molecule labels might enable activator-dependent STORM if the reporter or activator were linked to separate small molecules that bound within 3.5 nm of each other. This would greatly increase the labeling density and therefore improve resolution. We tested various mixtures of phalloidin- or mCling-conjugated fluorophore to demonstrate this feasibility. The specific activation was dependent on the choice of activator, its density, a matching activating laser and its power. In addition to providing an effective means of multi-channel 3D STORM imaging, this method also provides information about the local proximity between labels, potentially enabling super-resolved mapping of the conformation of the labeled structures. PMID:27246003

  6. Trim9 regulates activity-dependent fine-scale topography in Drosophila.

    PubMed

    Yang, Limin; Li, Ruonan; Kaneko, Takuya; Takle, Kendra; Morikawa, Rei K; Essex, Laura; Wang, Xin; Zhou, Jie; Emoto, Kazuo; Xiang, Yang; Ye, Bing

    2014-05-01

    Topographic projection of afferent terminals into 2D maps in the CNS is a general strategy used by the nervous system to encode the locations of sensory stimuli. In vertebrates, it is known that although guidance cues are critical for establishing a coarse topographic map, neural activity directs fine-scale topography between adjacent afferent terminals [1-4]. However, the molecular mechanism underlying activity-dependent regulation of fine-scale topography is poorly understood. Molecular analysis of the spatial relationship between adjacent afferent terminals requires reliable localization of the presynaptic terminals of single neurons as well as genetic manipulations with single-cell resolution in vivo. Although both requirements can potentially be met in Drosophila melanogaster [5, 6], no activity-dependent topographic system has been identified in flies [7]. Here we report a topographic system that is shaped by neuronal activity in Drosophila. With this system, we found that topographic separation of the presynaptic terminals of adjacent nociceptive neurons requires different levels of Trim9, an evolutionarily conserved signaling molecule [8-11]. Neural activity regulates Trim9 protein levels to direct fine-scale topography of sensory afferents. This study offers both a novel mechanism by which neural activity directs fine-scale topography of axon terminals and a new system to study this process at single-neuron resolution.

  7. Dense small molecule labeling enables activator-dependent STORM by proximity mapping.

    PubMed

    Chen, Ye; Gu, Min; Gunning, Peter W; Russell, Sarah M

    2016-09-01

    Stochastic optical reconstruction microscopy (STORM) enables high-resolution imaging, but multi-channel 3D imaging is problematic because of chromatic aberrations and alignment errors. The use of activator-dependent STORM in which spectrally distinct activators can be coupled with a single reporter can circumvent such issues. However, the standard approach of linking activators and reporters to a single antibody molecule is hampered by low labeling density and the large size of the antibody. We proposed that small molecule labels might enable activator-dependent STORM if the reporter or activator were linked to separate small molecules that bound within 3.5 nm of each other. This would greatly increase the labeling density and therefore improve resolution. We tested various mixtures of phalloidin- or mCling-conjugated fluorophore to demonstrate this feasibility. The specific activation was dependent on the choice of activator, its density, a matching activating laser and its power. In addition to providing an effective means of multi-channel 3D STORM imaging, this method also provides information about the local proximity between labels, potentially enabling super-resolved mapping of the conformation of the labeled structures.

  8. Trim9 regulates activity-dependent fine-scale topography in Drosophila.

    PubMed

    Yang, Limin; Li, Ruonan; Kaneko, Takuya; Takle, Kendra; Morikawa, Rei K; Essex, Laura; Wang, Xin; Zhou, Jie; Emoto, Kazuo; Xiang, Yang; Ye, Bing

    2014-05-01

    Topographic projection of afferent terminals into 2D maps in the CNS is a general strategy used by the nervous system to encode the locations of sensory stimuli. In vertebrates, it is known that although guidance cues are critical for establishing a coarse topographic map, neural activity directs fine-scale topography between adjacent afferent terminals [1-4]. However, the molecular mechanism underlying activity-dependent regulation of fine-scale topography is poorly understood. Molecular analysis of the spatial relationship between adjacent afferent terminals requires reliable localization of the presynaptic terminals of single neurons as well as genetic manipulations with single-cell resolution in vivo. Although both requirements can potentially be met in Drosophila melanogaster [5, 6], no activity-dependent topographic system has been identified in flies [7]. Here we report a topographic system that is shaped by neuronal activity in Drosophila. With this system, we found that topographic separation of the presynaptic terminals of adjacent nociceptive neurons requires different levels of Trim9, an evolutionarily conserved signaling molecule [8-11]. Neural activity regulates Trim9 protein levels to direct fine-scale topography of sensory afferents. This study offers both a novel mechanism by which neural activity directs fine-scale topography of axon terminals and a new system to study this process at single-neuron resolution. PMID:24746793

  9. Intense exercise increases circulating endocannabinoid and BDNF levels in humans--possible implications for reward and depression.

    PubMed

    Heyman, E; Gamelin, F-X; Goekint, M; Piscitelli, F; Roelands, B; Leclair, E; Di Marzo, V; Meeusen, R

    2012-06-01

    The endocannabinoid system is known to have positive effects on depression partly through its actions on neurotrophins, such as Brain-Derived Neurotrophic Factor (BDNF). As BDNF is also considered the major candidate molecule for exercise-induced brain plasticity, we hypothesized that the endocannabinoid system represents a crucial signaling system mediating the beneficial antidepressant effects of exercise. Here we investigated, in 11 healthy trained male cyclists, the effects of an intense exercise (60 min at 55% followed by 30 min at 75% W(max)) on plasma levels of endocannabinoids (anandamide, AEA and 2-arachidonoylglycerol, 2-AG) and their possible link with serum BDNF. AEA levels increased during exercise and the 15 min recovery (P<0.001), whereas 2-AG concentrations remained stable. BDNF levels increased significantly during exercise and then decreased during the 15 min of recovery (P<0.01). Noteworthy, AEA and BDNF concentrations were positively correlated at the end of exercise and after the 15 min recovery (r>0.66, P<0.05), suggesting that AEA increment during exercise might be one of the factors involved in exercise-induced increase in peripheral BDNF levels and that AEA high levels during recovery might delay the return of BDNF to basal levels. AEA production during exercise might be triggered by cortisol since we found positive correlations between these two compounds and because corticosteroids are known to stimulate endocannabinoid biosynthesis. These findings provide evidence in humans that acute exercise represents a physiological stressor able to increase peripheral levels of AEA and that BDNF might be a mechanism by which AEA influences the neuroplastic and antidepressant effects of exercise. PMID:22029953

  10. The release of glutamate from cortical neurons regulated by BDNF via the TrkB/Src/PLC-γ1 pathway.

    PubMed

    Zhang, Zitao; Fan, Jin; Ren, Yongxin; Zhou, Wei; Yin, Guoyong

    2013-01-01

    The brain-derived neurotrophic factor (BDNF) participates in the regulation of cortical neurons by influencing the release of glutamate. However, the specific mechanisms are unclear. Hence, we isolated and cultured the cortical neurons of Sprague Dawley rats. Specific inhibitors of TrkB, Src, PLC-γ1, Akt, and MEK1/2 (i.e., K252a, PP2, U73122, LY294002, and PD98059, respectively) were used to treat cortical neurons and to detect the glutamate release from cortical neurons stimulated with BDNF. BDNF significantly increased glutamate release, and simultaneously enhanced phosphorylation levels of TrkB, Src, PLC-γ, Akt, and Erk1/2. For BDNF-stimulated cortical neurons, K252a inhibited glutamate release and inhibited the phosphorylation levels of TrkB, Src, PLC-γ, Erk1/2, and Akt (P < 0.05). PP2 reduced the glutamate release from BDNF-stimulated cortical neurons (P < 0.05) and inhibited the phosphorylation levels of TrkB and PLC-γ1 (P < 0.05). However, PP2 had no effect on the phosphorylation levels of Erk1/2 or Akt (P > 0.05). U73122 inhibited the glutamate release from BDNF-stimulated cortical neurons, but had no influence on the phosphorylation levels of TrkB, Src, Erk1/2, or Akt (P > 0.05). LY294002 and PD98059 did not affect the BDNF-stimulated glutamate release and did not inhibit the phosphorylation levels of TrkB, Src, or PLC-γ1. In summary, BDNF stimulated the glutamate release from cortical neurons via the TrkB/Src/PLC-γ1 signaling pathway.

  11. Comparison of high-intensity vs. high-volume resistance training on the BDNF response to exercise.

    PubMed

    Church, David D; Hoffman, Jay R; Mangine, Gerald T; Jajtner, Adam R; Townsend, Jeremy R; Beyer, Kyle S; Wang, Ran; La Monica, Michael B; Fukuda, David H; Stout, Jeffrey R

    2016-07-01

    This study compared the acute and chronic response of circulating plasma brain-derived neurotrophic factor (BDNF) to high-intensity low-volume (HI) and low-intensity high volume (HV) resistance training. Twenty experienced resistance-trained men (23.5 ± 2.6 y, 1.79 ± 0.05 m, 75.7 ± 13.8 kg) volunteered for this study. Before the resistance training program (PRE), participants performed an acute bout of exercise using either the HI [3-5 reps; 90% of one repetition maximum (1RM)] or HV (10-12 reps; 70% 1RM) training paradigm. The acute exercise protocol was repeated after 7 wk of training (POST). Blood samples were obtained at rest (BL), immediately (IP), 30 min (30P), and 60 min (60P) post exercise at PRE and POST. A three-way repeated measure ANOVA was used to analyze acute changes in BDNF concentrations during HI and HV resistance exercise and the effect of 7 wk of training. No training × time × group interaction in BDNF was noted (P = 0.994). Significant main effects for training (P = 0.050) and time (P < 0.001) in BDNF were observed. Significant elevations in BDNF concentrations were seen from BL at IP (P = 0.001), 30P (P < 0.001), and 60P (P < 0.001) in both HI and HV combined during PRE and POST. BDNF concentrations were also observed to increase from PRE to POST when collapsed across groups and time. No significant group × training interaction (P = 0.342), training (P = 0.105), or group (P = 0.238) effect were noted in the BDNF area under the curve response. Results indicate that BDNF concentrations are increased after an acute bout of resistance exercise, regardless of training paradigm, and are further increased during a 7-wk training program in experienced lifters. PMID:27231312

  12. Increased serum brain-derived neurotrophic factor (BDNF) is predictive of cocaine relapse outcomes: A prospective study

    PubMed Central

    D’Sa, Carrol; Fox, Helen C.; Hong, Adam K.; Dileone, Ralph J.; Sinha, Rajita

    2011-01-01

    Background Cocaine dependence is associated with high relapse rates but few biological markers associated with relapse outcomes have been identified. Extending preclinical research showing a role for central Brain Derived Neurotrophic Factor (BDNF) in cocaine seeking, we examined whether serum BDNF is altered in abstinent, early recovering, cocaine-dependent individuals and if it is predictive of subsequent relapse risk. Methods Serum samples were collected across three consecutive mornings from 35 treatment-engaged, 3 week abstinent cocaine-dependent inpatients (17M/18F) and 34 demographically matched hospitalized healthy control participants (17M/17F). Cocaine dependent individuals were prospectively followed on days 14, 30 and 90 post-treatment discharge to assess cocaine relapse outcomes. Time to cocaine relapse, number of days of cocaine use (frequency), and amount of cocaine use (quantity) were the main outcome measures. Results High correlations in serum BDNF across days indicated reliable and stable serum BDNF measurements. Significantly higher mean serum BDNF levels were observed for the cocaine-dependent patients compared to healthy control participants (p<.001). Higher serum BDNF levels predicted shorter subsequent time to cocaine relapse (hazard ratio: HR: 1.09, p<.05), greater number of days (p<.05) and higher total amounts of cocaine used (p = .05). Conclusions High serum BDNF levels in recovering cocaine-dependent individuals are predictive of future cocaine relapse outcomes and may represent a clinically relevant marker of relapse risk. These data suggest that serum BDNF levels may provide an indication of relapse risk during early recovery from cocaine dependence. PMID:21741029

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

    PubMed

    Raivio, Noora; Miettinen, Pekka; Kiianmaa, Kalervo

    2014-09-01

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

  14. Comparison of high-intensity vs. high-volume resistance training on the BDNF response to exercise.

    PubMed

    Church, David D; Hoffman, Jay R; Mangine, Gerald T; Jajtner, Adam R; Townsend, Jeremy R; Beyer, Kyle S; Wang, Ran; La Monica, Michael B; Fukuda, David H; Stout, Jeffrey R

    2016-07-01

    This study compared the acute and chronic response of circulating plasma brain-derived neurotrophic factor (BDNF) to high-intensity low-volume (HI) and low-intensity high volume (HV) resistance training. Twenty experienced resistance-trained men (23.5 ± 2.6 y, 1.79 ± 0.05 m, 75.7 ± 13.8 kg) volunteered for this study. Before the resistance training program (PRE), participants performed an acute bout of exercise using either the HI [3-5 reps; 90% of one repetition maximum (1RM)] or HV (10-12 reps; 70% 1RM) training paradigm. The acute exercise protocol was repeated after 7 wk of training (POST). Blood samples were obtained at rest (BL), immediately (IP), 30 min (30P), and 60 min (60P) post exercise at PRE and POST. A three-way repeated measure ANOVA was used to analyze acute changes in BDNF concentrations during HI and HV resistance exercise and the effect of 7 wk of training. No training × time × group interaction in BDNF was noted (P = 0.994). Significant main effects for training (P = 0.050) and time (P < 0.001) in BDNF were observed. Significant elevations in BDNF concentrations were seen from BL at IP (P = 0.001), 30P (P < 0.001), and 60P (P < 0.001) in both HI and HV combined during PRE and POST. BDNF concentrations were also observed to increase from PRE to POST when collapsed across groups and time. No significant group × training interaction (P = 0.342), training (P = 0.105), or group (P = 0.238) effect were noted in the BDNF area under the curve response. Results indicate that BDNF concentrations are increased after an acute bout of resistance exercise, regardless of training paradigm, and are further increased during a 7-wk training program in experienced lifters.

  15. Effects of ganoderic acids on epileptiform discharge hippocampal neurons: insights from alterations of BDNF,TRPC3 and apoptosis.

    PubMed

    Yang, Zhi-wei; Wu, Fei; Zhang, Sheng-Li

    2016-06-01

    Recently, Ganoderma lucidum spores (GLS) have shown anti-epileptic effects. However, there are no reports on the anti-epileptic effects of its chemical constituents ganoderic acids (GAs), and more research is needed to better understand the mechanism of GLS activity. In this work, rat primary hippocampal neurons in an in vitro model were used to assess the intervention effects of GAs on epileptiform discharge hippocampal neurons and expression of both BDNF and TRPC3, with the aid of immunofluorescence, MTT method and flow cytometry. It was found that BDNF and TRPC3 are expressed in all cells and were mainly localized in the cytoplasm. The fluorescence intensities of BDNF and TRPC3 in GAs groups were higher than those of normal control and model groups, especially at 80 μg/ml (P < 0.05). The apoptosis rate of neurons was inversely proportional to BDNF and TRPC3 changes (P < 0.01). Therefore, BDNF and TRPC3 should be involved in the occurrence and development of epilepsy. GAs might indirectly inhibit mossy fiber sprouting and adjust the synaptic reconstructions by promoting the expression of BDNF and TRPC3. Besides, GAs could exert a protective effect on hippocampal neurons by promoting neuronal survival and the recovery of injured neurons. PMID:27455554

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

    PubMed

    Chourbaji, Sabine; Brandwein, Christiane; Gass, Peter

    2011-01-01

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

  17. Effects of ganoderic acids on epileptiform discharge hippocampal neurons: insights from alterations of BDNF,TRPC3 and apoptosis.

    PubMed

    Yang, Zhi-wei; Wu, Fei; Zhang, Sheng-Li

    2016-06-01

    Recently, Ganoderma lucidum spores (GLS) have shown anti-epileptic effects. However, there are no reports on the anti-epileptic effects of its chemical constituents ganoderic acids (GAs), and more research is needed to better understand the mechanism of GLS activity. In this work, rat primary hippocampal neurons in an in vitro model were used to assess the intervention effects of GAs on epileptiform discharge hippocampal neurons and expression of both BDNF and TRPC3, with the aid of immunofluorescence, MTT method and flow cytometry. It was found that BDNF and TRPC3 are expressed in all cells and were mainly localized in the cytoplasm. The fluorescence intensities of BDNF and TRPC3 in GAs groups were higher than those of normal control and model groups, especially at 80 μg/ml (P < 0.05). The apoptosis rate of neurons was inversely proportional to BDNF and TRPC3 changes (P < 0.01). Therefore, BDNF and TRPC3 should be involved in the occurrence and development of epilepsy. GAs might indirectly inhibit mossy fiber sprouting and adjust the synaptic reconstructions by promoting the expression of BDNF and TRPC3. Besides, GAs could exert a protective effect on hippocampal neurons by promoting neuronal survival and the recovery of injured neurons.

  18. 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

  19. BDNF-induced LTP is associated with rapid Arc/Arg3.1-dependent enhancement in adult hippocampal neurogenesis

    PubMed Central

    Kuipers, Sjoukje D.; Trentani, Andrea; Tiron, Adrian; Mao, Xiaosong; Kuhl, Dietmar; Bramham, Clive R.

    2016-01-01

    Adult neurogenesis in the hippocampus is a remarkable phenomenon involved in various aspects of learning and memory as well as disease pathophysiology. Brain-derived neurotrophic factor (BDNF) represents a major player in the regulation of this unique form of neuroplasticity, yet the mechanisms underlying its pro-neurogenic actions remain unclear. Here, we examined the effects associated with brief (25 min), unilateral infusion of BDNF in the rat dentate gyrus. Acute BDNF infusion induced long-term potentiation (LTP) of medial perforant path-evoked synaptic transmission and, concomitantly, enhanced hippocampal neurogenesis bilaterally, reflected by increased dentate gyrus BrdU + cell numbers. Importantly, inhibition of activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) translation through local, unilateral infusion of anti-sense oligodeoxynucleotides (ArcAS) prior to BDNF infusion blocked both BDNF-LTP induction and the associated pro-neurogenic effects. Notably, basal rates of proliferation and newborn cell survival were unaltered in homozygous Arc/Arg3.1 knockout mice. Taken together these findings link the pro-neurogenic effects of acute BDNF infusion to induction of Arc/Arg3.1-dependent LTP in the adult rodent dentate gyrus. PMID:26888068

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

    PubMed

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

    2015-02-28

    Brain-derived neurotrophic factor (BDNF) is involved in cocaine craving in humans and drug seeking in rodents. Based on this, the aim of this study was to explore the possible role of serum BDNF in cocaine relapse in abstinent addicts. Forty cocaine dependent subjects (DSM-IV criteria) were included in an inpatient 2 weeks abstinence program. Organic and psychiatric co-morbidities were excluded. Two serum samples were collected for each subject at baseline and at after 14 abstinence days. After discharge, all cocaine addicts underwent a 22 weeks follow-up, after which they were classified into early relapsers (ER) (resumed during the first 14 days after discharge,) or late relapsers (LR) (resumed beyond 14 days after discharge). The only clinical differences between groups were the number of consumption days during the last month before detoxification. Serum BDNF levels increased significantly across the 12 days of abstinence in the LR group (p=0.02), whereas in the ER group BDNF remained unchanged. In the ER group, the change of serum BDNF during abstinence negatively correlated with the improvement in depressive symptoms (p=0.02). These results suggest that BDNF has a role in relapse to cocaine consumption in abstinent addicts, although the underlying neurobiological mechanisms remain to be clarified. PMID:25592977

  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.

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

    PubMed

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

    2015-03-30

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

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

    PubMed

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

    2015-02-28

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

  4. Neuropeptides and nasal secretion.

    PubMed

    Baraniuk, J N; Kaliner, M

    1991-10-01

    The nasal mucosa is innervated by the sensory, parasympathetic, and sympathetic nervous systems. Nociceptive sensory nerves are stimulated by mucosal injury, inhalation of irritants, or mast cell degranulation and release of the calcitonin gene-related peptide, the tachykinins substance P and neurokinin A, and other peptides by the axon response mechanism. Sensory nerve stimulation initiates systemic reflexes, such as the sneeze, and central parasympathetic reflexes which release acetylcholine, vasoactive intestinal peptide, and other peptides and lead to glandular secretion. In concert, these proinflammatory neural responses lead to vasodilation, vascular permeability, and glandular secretion. Sympathetic nerves release neuropeptide Y and norepinephrine, potent vasoconstrictors which act to decompress the nasal mucosa and produce nasal patency. The balance between the effects of parasympathetic and sympathetic neurotransmitters may regulate nasal homeostasis, whereas the nociceptive sensory system may be held in reserve as a defense mechanism. Dysfunction of these systems may lead to pathological nasal syndromes. In the future, specific neuropeptide agonists and antagonists may be useful for the treatment of human rhinitic diseases. PMID:1928355

  5. Modeling mechanisms of cell secretion.

    PubMed

    Tsaneva-Atanasova, Krasimira; Osinga, Hinke M; Tabak, Joël; Pedersen, Morten Gram

    2010-12-01

    Secretion is a fundamental cellular process involving the regulated release of intracellular products from cells. Physiological functions such as neurotransmission, or the release of hormones and digestive enzymes, are all governed by cell secretion. Anomalies in the processes involved in secretion contribute to the development and progression of diseases such as diabetes and other hormonal disorders. To unravel the mechanisms that govern such diseases, it is essential to understand how hormones, growth factors and neurotransmitters are synthesized and processed, and how their signals are recognized, amplified and transmitted by intracellular signaling pathways in the target cells. Here, we discuss diverse aspects of the detailed mechanisms involved in secretion based on mathematical models. The models range from stochastic ones describing the trafficking of secretory vesicles to deterministic ones investigating the regulation of cellular processes that underlie hormonal secretion. In all cases, the models are closely related to experimental results and suggest theoretical predictions for the secretion mechanisms.

  6. Protecting Trade Secrets in Canada.

    PubMed

    Courage, Noel; Calzavara, Janice

    2015-01-01

    Patents in the life sciences industries are a key form of intellectual property (IP), particularly for products such as brand-name drugs and medical devices. However, trade secrets can also be a useful tool for many types of innovations. In appropriate cases, trade secrets can offer long-term protection of IP for a lower financial cost than patenting. This type of protection must be approached with caution as there is little room for error when protecting a trade secret. Strong agreements and scrupulous security can help to protect the secret. Once a trade secret is disclosed to the public, it cannot be restored as the owner's property; however, if the information is kept from the public domain, the owner can have a property right of unlimited duration in the information. In some situations patents and trade secrets may be used cooperatively to protect innovation, particularly for manufacturing processes. PMID:25986591

  7. Homeostatic Activity-Dependent Tuning of Recurrent Networks for Robust Propagation of Activity

    PubMed Central

    Evers, Jan Felix; Eglen, Stephen J.

    2016-01-01

    Developing neuronal networks display spontaneous bursts of action potentials that are necessary for circuit organization and tuning. While spontaneous activity has been shown to instruct map formation in sensory circuits, it is unknown whether it plays a role in the organization of motor networks that produce rhythmic output. Using computational modeling, we investigate how recurrent networks of excitatory and inhibitory neuronal populations assemble to produce robust patterns of unidirectional and precisely timed propagating activity during organism locomotion. One example is provided by the motor network in Drosophila larvae, which generates propagating peristaltic waves of muscle contractions during crawling. We examine two activity-dependent models, which tune weak network connectivity based on spontaneous activity patterns: a Hebbian model, where coincident activity in neighboring populations strengthens connections between them; and a homeostatic model, where connections are homeostatically regulated to maintain a constant level of excitatory activity based on spontaneous input. The homeostatic model successfully tunes network connectivity to generate robust activity patterns with appropriate timing relationships between neighboring populations. These timing relationships can be modulated by the properties of spontaneous activity, suggesting its instructive role for generating functional variability in network output. In contrast, the Hebbian model fails to produce the tight timing relationships between neighboring populations required for unidirectional activity propagation, even when additional assumptions are imposed to constrain synaptic growth. These results argue that homeostatic mechanisms are more likely than Hebbian mechanisms to tune weak connectivity based on spontaneous input in a recurrent network for rhythm generation and robust activity propagation. SIGNIFICANCE STATEMENT How are neural circuits organized and tuned to maintain stable function

  8. Activity-dependent regulation of calcium and ribosomes in the chick cochlear nucleus.

    PubMed

    Call, C L; Hyson, R L

    2016-03-01

    Cochlea removal results in the death of 20-30% of neurons in the chick cochlear nucleus, nucleus magnocellularis (NM). Two potentially cytotoxic events, a dramatic rise in intracellular calcium concentration ([Ca(2+)]i) and a decline in the integrity of ribosomes are observed within 1h of deafferentation. Glutamatergic input from the auditory nerve has been shown to preserve NM neuron health by activating metabotropic glutamate receptors (mGluRs), maintaining both normal [Ca(2+)]i and ribosomal integrity. One interpretation of these results is that a common mGluR-activated signaling cascade is required for the maintenance of both [Ca(2+)]i and ribosomal integrity. This could happen if both responses are influenced directly by a common messenger, or if the loss of mGluR activation causes changes in one component that secondarily causes changes in the other. The present studies tested this common-mediator hypothesis in slice preparations by examining activity-dependent regulation of [Ca(2+)]i and ribosomes in the same tissue after selectively blocking group I mGluRs (1-Aminoindan-1,5-dicarboxylic acid (AIDA)) or group II mGluRs (LY 341495) during unilateral auditory nerve stimulation. Changes in [Ca(2+)]i of NM neurons were measured using fura-2 ratiometric calcium imaging and the tissue was subsequently processed for Y10B immunoreactivity (Y10B-ir), an antibody that recognizes a ribosomal epitope. The group I mGluR antagonist blocked the activity-dependent regulation of both [Ca(2+)]i and Y10B-ir, but the group II antagonist blocked only the activity-dependent regulation of Y10B-ir. That is, even when group II receptors were blocked, stimulation continued to maintain low [Ca(2+)]i, but it did not maintain Y10B-ir. These results suggest a dissociation in how calcium and ribosomes are regulated in NM neurons and that ribosomes can be regulated through a mechanism that is independent of calcium regulation. PMID:26739326

  9. Activity-dependent regulation of calcium and ribosomes in the chick cochlear nucleus.

    PubMed

    Call, C L; Hyson, R L

    2016-03-01

    Cochlea removal results in the death of 20-30% of neurons in the chick cochlear nucleus, nucleus magnocellularis (NM). Two potentially cytotoxic events, a dramatic rise in intracellular calcium concentration ([Ca(2+)]i) and a decline in the integrity of ribosomes are observed within 1h of deafferentation. Glutamatergic input from the auditory nerve has been shown to preserve NM neuron health by activating metabotropic glutamate receptors (mGluRs), maintaining both normal [Ca(2+)]i and ribosomal integrity. One interpretation of these results is that a common mGluR-activated signaling cascade is required for the maintenance of both [Ca(2+)]i and ribosomal integrity. This could happen if both responses are influenced directly by a common messenger, or if the loss of mGluR activation causes changes in one component that secondarily causes changes in the other. The present studies tested this common-mediator hypothesis in slice preparations by examining activity-dependent regulation of [Ca(2+)]i and ribosomes in the same tissue after selectively blocking group I mGluRs (1-Aminoindan-1,5-dicarboxylic acid (AIDA)) or group II mGluRs (LY 341495) during unilateral auditory nerve stimulation. Changes in [Ca(2+)]i of NM neurons were measured using fura-2 ratiometric calcium imaging and the tissue was subsequently processed for Y10B immunoreactivity (Y10B-ir), an antibody that recognizes a ribosomal epitope. The group I mGluR antagonist blocked the activity-dependent regulation of both [Ca(2+)]i and Y10B-ir, but the group II antagonist blocked only the activity-dependent regulation of Y10B-ir. That is, even when group II receptors were blocked, stimulation continued to maintain low [Ca(2+)]i, but it did not maintain Y10B-ir. These results suggest a dissociation in how calcium and ribosomes are regulated in NM neurons and that ribosomes can be regulated through a mechanism that is independent of calcium regulation.

  10. Pleiotrophin promotes microglia proliferation and secretion of neurotrophic factors by activating extracellular signal-regulated kinase 1/2 pathway.

    PubMed

    Miao, Jiayin; Ding, Minghui; Zhang, Aiwu; Xiao, Zijian; Qi, Weiwei; Luo, Ning; Di, Wei; Tao, Yuqian; Fang, Yannan

    2012-12-01

    Pleiotrophin (PTN) is an effective neuroprotective factor and its expression is strikingly increased in microglia after ischemia/reperfusion injury. However, whether PTN could provide neurotrophic support to neurons by regulating microglia function is not clear. In this study, we demonstrated that the expression of PTN was induced in microglia after oxygen-glucose deprivation/reperfusion. PTN promoted the proliferation of microglia by enhancing the G1 to S phase transition. PTN also stimulated the secretion of brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF) and nerve growth factor (NGF) in microglia, but did not upregulate the expression of proinflammatory factors such as TNF-α, IL-1β and iNOS. Mechanistically, we found that PTN increased the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 in microglia in both concentration-dependent and time-dependent manners. In addition, ERK1/2 inhibitor U0126 abolished the proliferation and G1 to S phase transition of microglia stimulated by PTN, and inhibited the production of BDNF, CNTF and NGF induced by PTN. In conclusion, our results demonstrated that PTN-ERK1/2 pathway plays important role in regulating microglia growth and secretion of neurotrophic factors. These findings provide new insight into the neuroprotective role of PTN and suggest that PTN is a new target for therapeutic intervention of stroke.

  11. Estrogen therapy increases BDNF expression and improves post-stroke depression in ovariectomy-treated rats

    PubMed Central

    Su, Qiaoer; Cheng, Yifan; Jin, Kunlin; Cheng, Jianhua; Lin, Yuanshao; Lin, Zhenzhen; Wang, Liuqing; Shao, Bei

    2016-01-01

    The present study investigated the effect of exogenous estrogen on post-stroke depression. Rats were exposed to chronic mild stress following middle cerebral artery occlusion. The occurrence of post-stroke depression was evaluated according to the changes in preference for sucrose and performance in a forced swimming test. Estrogen therapy significantly improved these neurological symptoms, indicating that estrogen is effective in treating post-stroke depression. Increased brain-derived neurotrophic factor (BDNF) expression was reported in the hippocampus of rats that had been treated with estrogen for two weeks, suggesting that BDNF expression may be an important contributor to the improvement of post-stroke depression that is observed following estrogen therapy.

  12. Soya phytoestrogens change cortical and hippocampal expression of BDNF mRNA in male rats.

    PubMed

    File, Sandra E; Hartley, David E; Alom, Nazmul; Rattray, Marcus

    2003-02-27

    Adult male hooded Lister rats were either fed a diet containing 150 microg/g soya phytoestrogens or a soya-free diet for 18 days. This concentration of phytoestrogens should have been sufficient to occupy the oestrogen-beta, but not the oestrogen-alpha, receptors. Using in situ hybridisation, significant reductions were found in brain-derived neurotrophic factor (BDNF) mRNA expression in the CA3 and CA4 region of the hippocampus and in the cerebral cortex in the rats fed the diet containing phytoestrogens, compared with those on the soya-free diet. No changes in glutamic acid decarboxylase-67 or glial fibrillary acidic protein mRNA were found. This suggests a role for oestrogen-beta receptors in regulating BDNF mRNA expression.

  13. Early-life cocaine interferes with BDNF-mediated behavioral plasticity.

    PubMed

    Hinton, Elizabeth A; Wheeler, Marina G; Gourley, Shannon L

    2014-05-01

    An important aspect of goal-directed action selection is differentiating between actions that are more or less likely to be reinforced. With repeated performance or psychostimulant exposure, however, actions can assume stimulus-elicited-or "habitual"-qualities that are resistant to change. We show that selective knockdown of prelimbic prefrontal cortical Brain-derived neurotrophic factor (Bdnf) increases sensitivity to response-outcome associations, blocking habit-like behavioral inflexibility. A history of adolescent cocaine exposure, however, occludes the "beneficial" effects of Bdnf knockdown. This finding highlights a challenge in treating addiction-that drugs of abuse may bias decision-making toward habit systems even in individuals with putative neurobiological resiliencies. PMID:24737916

  14. Estrogen therapy increases BDNF expression and improves post-stroke depression in ovariectomy-treated rats

    PubMed Central

    Su, Qiaoer; Cheng, Yifan; Jin, Kunlin; Cheng, Jianhua; Lin, Yuanshao; Lin, Zhenzhen; Wang, Liuqing; Shao, Bei

    2016-01-01

    The present study investigated the effect of exogenous estrogen on post-stroke depression. Rats were exposed to chronic mild stress following middle cerebral artery occlusion. The occurrence of post-stroke depression was evaluated according to the changes in preference for sucrose and performance in a forced swimming test. Estrogen therapy significantly improved these neurological symptoms, indicating that estrogen is effective in treating post-stroke depression. Increased brain-derived neurotrophic factor (BDNF) expression was reported in the hippocampus of rats that had been treated with estrogen for two weeks, suggesting that BDNF expression may be an important contributor to the improvement of post-stroke depression that is observed following estrogen therapy. PMID:27602095

  15. Salmonella-secreted Virulence Factors

    SciTech Connect

    Heffron, Fred; Niemann, George; Yoon, Hyunjin; Kidwai, Afshan S.; Brown, Roslyn N.; McDermott, Jason E.; Smith, Richard D.; Adkins, Joshua N.

    2011-05-01

    In this short review we discuss secreted virulence factors of Salmonella, which directly affect Salmonella interaction with its host. Salmonella secretes protein to subvert host defenses but also, as discussed, to reduce virulence thereby permitting the bacteria to persist longer and more successfully disperse. The type III secretion system (TTSS) is the best known and well studied of the mechanisms that enable secretion from the bacterial cytoplasm to the host cell cytoplasm. Other secretion systems include outer membrane vesicles, which are present in all Gram-negative bacteria examined to date, two-partner secretion, and type VI secretion will also be addressed. Excellent reviews of Salmonella secreted effectors have focused on themes such as actin rearrangements, vesicular trafficking, ubiquitination, and the activities of the virulence factors themselves. This short review is based on S. Typhimurium infection of mice because it is a model of typhoid like disease in humans. We have organized effectors in terms of events that happen during the infection cycle and how secreted effectors may be involved.

  16. Expansible quantum secret sharing network

    NASA Astrophysics Data System (ADS)

    Sun, Ying; Xu, Sheng-Wei; Chen, Xiu-Bo; Niu, Xin-Xin; Yang, Yi-Xian

    2013-08-01

    In the practical applications, member expansion is a usual demand during the development of a secret sharing network. However, there are few consideration and discussion on network expansibility in the existing quantum secret sharing schemes. We propose an expansible quantum secret sharing scheme with relatively simple and economical quantum resources and show how to split and reconstruct the quantum secret among an expansible user group in our scheme. Its trait, no requirement of any agent's assistant during the process of member expansion, can help to prevent potential menaces of insider cheating. We also give a discussion on the security of this scheme from three aspects.

  17. 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.

  18. Suppression of choriocarcinoma invasion and metastasis following blockade of BDNF/TrkB signaling.

    PubMed

    Kawamura, Kazuhiro; Kawamura, Nanami; Okamoto, Naoki; Manabe, Motomu

    2013-12-01

    Brain-derived neurotrophic factor (BDNF) acts through its cognate receptor tyrosine kinase-B (TrkB) to regulate diverse physiological functions in reproductive and other tissues. In normal and malignant trophoblastic cells, the BDNF/TrkB signaling promotes cell growth. Due to the highly malignant nature of choriocarcinoma, we investigated possible involvement of this system in choriocarcinoma cell invasion and metastasis. We demonstrated that treatment of cultured choriocarcinoma cells, known to express both BDNF and TrkB, with a soluble TrkB ectodomain or a Trk receptor inhibitor K252a suppressed cell invasion accompanied with decreased expression of matrix metalloproteinase-2, a cell invasion marker. In vivo studies using a tumor xenograft model in athymic nude mice further showed inhibition of cell invasion from tumors to surrounding tissues following the suppression of endogenous TrkB signaling. For an in vivo model of choriocarcinoma metastasis, we performed intravenous injections of JAR cells expressing firefly luciferase into severe combined immunodeficiency (SCID) mice. Treatment with K252a inhibited metastasis of tumors to distant organs. In vivo K252a treatment also suppressed metastatic tumor growth as reflected by decreased cell proliferation and increased apoptosis and caspases-3/7 activities, together with reduced tissue levels of a tumor marker, human chorionic gonadotropin-β. In vivo suppression of TrkB signaling also led to decreased expression of angiogenic markers in metastatic tumor, including cluster of differentiation 31 and vascular endothelial growth factor A. Our findings suggested essential autocrine/paracrine roles of the BDNF/TrkB signaling system in choriocarcinoma invasion and metastasis. Inhibition of this signaling could serve as the basis to develop a novel therapy for patients with choriocarcinoma.

  19. 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

  20. Prenatal opiate exposure impairs radial arm maze performance and reduces levels of BDNF precursor following training.

    PubMed

    Schrott, Lisa M; Franklin, La 'Tonya M; Serrano, Peter A

    2008-03-10

    Prenatal exposure to opiates, which is invariably followed by postnatal withdrawal, can affect cognitive performance. To further characterize these effects, we examined radial 8-arm maze performance and expression of brain derived neurotrophic factor (BDNF) in male rats prenatally exposed to the opiate l-alpha-acetylmethadol (LAAM). Female rats received 1.0 mg/kg/day LAAM or water via daily oral gavage for 28 days prior to breeding, during breeding, and throughout pregnancy. Pups were fostered to non-treated lactating dams at birth and underwent neonatal opiate withdrawal. At 5-6 months, prenatal water- and LAAM-exposed males (n=6 each; non-littermates) received radial arm maze training consisting of ten trials a day for five days and three retention trials on day six. Rats prenatally exposed to LAAM had poorer maze performance, decreased percent correct responding and more reference and working memory errors than prenatal water-treated controls. However, they were able to acquire the task by the end of training. There were no differences between the groups on retention 24 h after testing. Following retention testing, hippocampi were removed and protein extracted from cytosol and synaptic fractions. Western blots were used to measure levels of mature and precursor BDNF protein, as well as the BDNF receptor TrkB. BDNF precursor protein was significantly decreased in the synaptic fraction of trained prenatal LAAM-treated rats compared to prenatal water-treated trained controls. No effects were found for the full-length or truncated TrkB receptor. In untrained rats, prenatal treatment did not affect any of the measures. These data suggest that prenatal opiate exposure and/or postnatal withdrawal compromise expression of proteins involved in the neural plasticity underlying learning. PMID:18262500

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

    PubMed

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

    2008-06-01

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

  2. 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

  3. 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

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

    PubMed

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

    2013-11-01

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

  5. Protracted alcohol abstinence induces analgesia in rats: Possible relationships with BDNF and interleukin-10.

    PubMed

    Schunck, Rebeca Vargas Antunes; Torres, Iraci L S; Laste, Gabriela; de Souza, Andressa; Macedo, Isabel Cristina; Valle, Marina Tuerlinckx Costa; Salomón, Janaína L O; Moreira, Sonia; Kuo, Jonnsin; Arbo, Marcelo Dutra; Dallegrave, Eliane; Leal, Mirna Bainy

    2015-08-01

    Exposure to ethanol alters the expression of brain-derived neurotrophic factor (BDNF) in central regions such as, the hippocampus, cortex and striatum. Moreover, chronic alcohol intake is known to induce selective neuronal damage associated with an increase in the inflammatory cascade, resulting in neuronal apoptosis and neurodegeneration. In the present study, we investigated the nociceptive response after 24h of protracted alcohol abstinence. Rats were submitted to a model of alcohol withdrawal syndrome and the nociceptive response was assessed by the tail-flick and the hot plate tests. In addition, we evaluated BDNF and interleukin-10 (IL-10) in the cerebral prefrontal cortex, brainstem and hippocampus of rats after protracted alcohol abstinence. Male adult Wistar rats were divided into three groups: non-treated group (control group), treated with water (water group), and alcohol (alcohol group). The water and alcohol administrations were done by oral gavage and were performed over three periods of five days of treatment with two intervals of two days between them. Alcohol (20%w/v) was given at 4g/kg of body weight. There was a significant effect of treatment in the tail-flick and hot plate latencies with greater latencies in alcohol-treated rats after 10days of abstinence. There was a significant increase in the prefrontal cortex BDNF levels in the alcohol group in relation to the water group, after 11days of alcohol abstinence. In addition, alcohol withdrawal induced a significant increase in the hippocampus, prefrontal cortex and brainstem IL-10 levels compared with control group. Thus, the present study demonstrates that protracted alcohol withdrawal produced an analgesic effect indexed via increased nociceptive threshold. We suggest that these effects could be related to the increased levels of BDNF and IL-10 observed in the central nervous system.

  6. 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.

  7. VAMP4 Is an Essential Cargo Molecule for Activity-Dependent Bulk Endocytosis.

    PubMed

    Nicholson-Fish, Jessica C; Kokotos, Alexandros C; Gillingwater, Thomas H; Smillie, Karen J; Cousin, Michael A

    2015-12-01

    The accurate formation of synaptic vesicles (SVs) and incorporation of their protein cargo during endocytosis is critical for the maintenance of neurotransmission. During intense neuronal activity, a transient and acute accumulation of SV cargo occurs at the plasma membrane. Activity-dependent bulk endocytosis (ADBE) is the dominant SV endocytosis mode under these conditions; however, it is currently unknown how ADBE mediates cargo retrieval. We examined the retrieval of different SV cargo molecules during intense stimulation using a series of genetically encoded pH-sensitive reporters in neuronal cultures. The retrieval of only one reporter, VAMP4-pHluorin, was perturbed by inhibiting ADBE. This selective recovery was confirmed by the enrichment of endogenous VAMP4 in purified bulk endosomes formed by ADBE. VAMP4 was also essential for ADBE, with a cytoplasmic di-leucine motif being critical for this role. Therefore, VAMP4 is the first identified ADBE cargo and is essential for this endocytosis mode to proceed.

  8. Rapid and continuous activity-dependent plasticity of olfactory sensory input

    PubMed Central

    Cheetham, Claire E. J.; Park, Una; Belluscio, Leonardo

    2016-01-01

    Incorporation of new neurons enables plasticity and repair of circuits in the adult brain. Adult neurogenesis is a key feature of the mammalian olfactory system, with new olfactory sensory neurons (OSNs) wiring into highly organized olfactory bulb (OB) circuits throughout life. However, neither when new postnatally generated OSNs first form synapses nor whether OSNs retain the capacity for synaptogenesis once mature, is known. Therefore, how integration of adult-born OSNs may contribute to lifelong OB plasticity is unclear. Here, we use a combination of electron microscopy, optogenetic activation and in vivo time-lapse imaging to show that newly generated OSNs form highly dynamic synapses and are capable of eliciting robust stimulus-locked firing of neurons in the mouse OB. Furthermore, we demonstrate that mature OSN axons undergo continuous activity-dependent synaptic remodelling that persists into adulthood. OSN synaptogenesis, therefore, provides a sustained potential for OB plasticity and repair that is much faster than OSN replacement alone. PMID:26898529

  9. Developmental and activity-dependent plasticity of filiform hair receptors in the locust

    PubMed Central

    Pflüger, Hans-Joachim; Wolf, Harald

    2013-01-01

    A group of wind sensitive filiform hair receptors on the locust thorax and head makes contact onto a pair of identified interneuron, A4I1. The hair receptors' central nervous projections exhibit pronounced structural dynamics during nymphal development, for example, by gradually eliminating their ipsilateral dendritic field while maintaining the contralateral one. These changes are dependent not only on hormones controlling development but on neuronal activity as well. The hair-to-interneuron system has remarkably high gain (close to 1) and makes contact to flight steering muscles. During stationary flight in front of a wind tunnel, interneuron A4I1 is active in the wing beat rhythm, and in addition it responds strongly to stimulation of sensory hairs in its receptive field. A role of the hair-to-interneuron in flight steering is thus suggested. This system appears suitable for further study of developmental and activity-dependent plasticity in a sensorimotor context with known connectivity patterns. PMID:23986712

  10. Molecular Remodeling of the Presynaptic Active Zone of Drosophila Photoreceptors via Activity-Dependent Feedback.

    PubMed

    Sugie, Atsushi; Hakeda-Suzuki, Satoko; Suzuki, Emiko; Silies, Marion; Shimozono, Mai; Möhl, Christoph; Suzuki, Takashi; Tavosanis, Gaia

    2015-05-01

    Neural activity contributes to the regulation of the properties of synapses in sensory systems, allowing for adjustment to a changing environment. Little is known about how synaptic molecular components are regulated to achieve activity-dependent plasticity at central synapses. Here, we found that after prolonged exposure to natural ambient light the presynaptic active zone in Drosophila photoreceptors undergoes reversible remodeling, including loss of Bruchpilot, DLiprin-α, and DRBP, but not of DSyd-1 or Cacophony. The level of depolarization of the postsynaptic neurons is critical for the light-induced changes in active zone composition in the photoreceptors, indicating the existence of a feedback signal. In search of this signal, we have identified a crucial role of microtubule meshwork organization downstream of the divergent canonical Wnt pathway, potentially via Kinesin-3 Imac. These data reveal that active zone composition can be regulated in vivo and identify the underlying molecular machinery.

  11. Mapping neural circuits with activity-dependent nuclear import of a transcription factor.

    PubMed

    Masuyama, Kaoru; Zhang, Yi; Rao, Yi; Wang, Jing W

    2012-03-01

    Abstract: Nuclear factor of activated T cells (NFAT) is a calcium-responsive transcription factor. We describe here an NFAT-based neural tracing method-CaLexA (calcium-dependent nuclear import of LexA)-for labeling active neurons in behaving animals. In this system, sustained neural activity induces nuclear import of the chimeric transcription factor LexA-VP16-NFAT, which in turn drives green fluorescent protein (GFP) reporter expression only in active neurons. We tested this system in Drosophila and found that volatile sex pheromones excite specific neurons in the olfactory circuit. Furthermore, complex courtship behavior associated with multi-modal sensory inputs activated neurons in the ventral nerve cord. This method harnessing the mechanism of activity-dependent nuclear import of a transcription factor can be used to identify active neurons in specific neuronal population in behaving animals. PMID:22236090

  12. BDNF-mediates Down-regulation of MicroRNA-195 Inhibits Ischemic Cardiac Apoptosis in Rats

    PubMed Central

    Hang, Pengzhou; Sun, Chuan; Guo, Jing; Zhao, Jing; Du, Zhimin

    2016-01-01

    Background: Our previous studies suggested that brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) axis inhibited cardiomyocyte apoptosis in myocardial infarction (MI). However, the relationship between BDNF and microRNA (miRNA) in cardiomyocytes are unclear. The present study was performed to investigate the role of miR-195 and the interplay between BDNF and miR-195 in ischemic cardiomyocyte apoptosis. Methods: Male Wistar rats were subjected to coronary artery ligation, and primary neonatal rat ventricular myocytes were treated with hypoxia or hydrogen peroxide (H2O2). BDNF level in rat ventricles was measured by enzyme linked immunosorbent assay (ELISA). miR-195 mimic, inhibitor or negative control was transfected into the cardiomyocytes. Cell viability and apoptosis were detected by MTT assay and TdT-mediated dUTP nick end labeling (TUNEL) staining, respectively. Cardiac function and apoptosis were detected in MI rats intravenously injected with antagomiR-195. Luciferase assay, Western blot and Real-time RT-PCR were employed to clarify the interplay between miR-195 and BDNF. Results: miR-195 level was dynamically regulated in response to MI and significantly increased in ischemic regions 24 h post-MI as well as in hypoxic or H2O2-treated cardiomyocytes. Meanwhile, BDNF protein level was rapidly increased in MI rats and H2O2-treated cardiomyocytes. Apoptosis in both hypoxic and H2O2-treated cardiomyocytes were markedly reduced and cell viability was increased by miR-195 inhibitor. Moreover, inhibition of miR-195 significantly improved cardiac function of MI rats. Bcl-2 but not BDNF was validated as the direct target of miR-195. Furthermore, BDNF abolished the pro-apoptotic role of miR-195, which was reversed by its scavenger TrkB-Fc. Conclusion: Up-regulation of miR-195 in ischemic cardiomyocytes promotes ischemic apoptosis by targeting Bcl-2. BDNF mitigated the pro-apoptotic effect of miR-195 in rat cardiomyocytes. These findings may

  13. Solubility and secretability.

    PubMed

    Schein, C H

    1993-08-01

    The solubility and secretability of proteins can often be affected by extremely small changes in their primary structure. Attempts to determine empirical rules for the alteration of protein structure to improve either of these characteristics have met with only partial success. Those (mostly serendipitous) improvements in solubility that have been obtained via mutagenesis cannot be considered to be 'protein engineering'. The most successful examples where directed mutagenesis has been used to alter protein solubility, hemoglobin and insulin, have relied on established crystal structures and a wealth of data about the relationship between sequence and structure of the targeted protein. Currently, optimizing culture growth conditions by trial and error remains the fastest way to improve expression.

  14. 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.

  15. Differential effects of BDNF val(66)met in repetitive associative learning paradigms.

    PubMed

    Freundlieb, Nils; Backhaus, Winifried; Brüggemann, Norbert; Gerloff, Christian; Klein, Christine; Pinnschmidt, Hans O; Hummel, Friedhelm C

    2015-09-01

    In healthy young subjects, the brain derived neurotropic factor (BDNF) val(66)met polymorphism negatively affects behavioural outcome in short-term motor cortex or hippocampus-based learning paradigms. In repetitive training paradigms over several days this effect can be overcome, in tests involving other brain areas even positive effects were found. To further specify the role of this polymorphism in cognitive processes, we used an associative vocabulary learning paradigm over four consecutive days and tested 38 young healthy subjects and 29 healthy elderly subjects. As a control paradigm, we designed a nonverbal haptic Braille letter-learning paradigm based on the same principles. Behavioural outcome was then associated with the BDNF-genotype. In the vocabulary learning task, met carrier (met/val and met/met) benefitted more from the repetitive training than val/val subjects. This was paralleled by a higher reduction of delayed answers during the course of the study, an effect that was also present in the haptic paradigm. However, in a group of healthy elderly subjects, no similar tendency was found. We conclude that the BDNF val(66)met polymorphism alters highly circumscribed answer behaviours in young healthy subjects. This might partly explain the high variability of previously published results.

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

    PubMed

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

    2013-12-01

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

  17. 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

  18. 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

  19. Aberrant hippocampal neurogenesis after limbic kindling: Relationship to BDNF and hippocampal-dependent memory.

    PubMed

    Botterill, J J; Brymer, K J; Caruncho, H J; Kalynchuk, L E

    2015-06-01

    Seizures dramatically increase the number of adult generated neurons in the hippocampus. However, it is not known whether this effect depends on seizures that originate in specific brain regions or whether it is nonspecific to seizure activity regardless of origin. We used kindling of different brain sites to address this question. Rats received 99 kindling stimulations of the basolateral amygdala, dorsal hippocampus, or caudate nucleus over a 6-week period. After kindling, we counted the number of adult generated hippocampal neurons that were birth-dated with the proliferative marker bromodeoxyuridine (BrdU) to evaluate cell proliferation and survival under conditions of repeated seizures. Next, we counted the number of doublecortin immunoreactive (DCX-ir) cells and evaluated their dendritic complexity to determine if limbic and nonlimbic seizures have differential effects on neuronal maturation. We also quantified hippocampal brain-derived neurotrophin factor (BDNF) protein levels using an ELISA kit and assessed memory performance using a hippocampal-dependent fear conditioning paradigm. We found that limbic, but not nonlimbic, seizures dramatically increased hippocampal cell proliferation and the number of hilar-CA3 ectopic granule cells. Further, limbic kindling promoted dendritic outgrowth of DCX-ir cells and the number of DCX-ir cells containing basal dendrites. Limbic kindling also enhanced BDNF protein levels throughout the entire hippocampus and impaired the retrieval of fear memories. Collectively, our results suggest a relationship between limbic seizures, neurogenesis, BDNF protein, and cognition.

  20. Deep brain stimulation of the ventral striatum increases BDNF in the fear extinction circuit.

    PubMed

    Do-Monte, Fabricio H; Rodriguez-Romaguera, Jose; Rosas-Vidal, Luis E; Quirk, Gregory J

    2013-01-01

    Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) reduces the symptoms of treatment-resistant obsessive compulsive disorder (OCD), and improves response to extinction-based therapies. We recently reported that DBS-like stimulation of a rat homologue of VC/VS, the dorsal-VS, reduced conditioned fear and enhanced extinction memory (Rodriguez-Romaguera et al., 2012). In contrast, DBS of the ventral-VS had the opposite effects. To examine possible mechanisms of these effects, we assessed the effects of VS DBS on the expression of the neural activity marker Fos and brain-derived neurotrophic factor (BDNF), a key mediator of extinction plasticity in prefrontal-amygdala circuits. Consistent with decreased fear expression, DBS of dorsal-VS increased Fos expression in prelimbic and infralimbic prefrontal cortices and in the lateral division of the central nucleus of amygdala, an area that inhibits amygdala output. Consistent with improved extinction memory, we found that DBS of dorsal-VS, but not ventral-VS, increased neuronal BDNF expression in prelimbic and infralimbic prefrontal cortices. These rodent findings are consistent with the idea that clinical DBS of VC/VS may augment fear extinction through an increase in BDNF expression. PMID:23964215

  1. Expression of TRPC6 and BDNF in Cortical Lesions From Patients With Focal Cortical Dysplasia

    PubMed Central

    Zheng, Da-Hai; Guo, Wei; Sun, Fei-Ji; Xu, Guang-Zhen; Zang, Zhen-Le; Shu, Hai-Feng

    2016-01-01

    Focal cortical dysplasia (FCD) likely results from abnormal migration of neural progenitor cells originating from the subventricular zone. To elucidate the roles in molecules that are involved in neural migration pathway abnormalities in FCDs, we investigated the expression patterns of transient receptor potential canonical channel 6 (TRPC6) and brain-derived neurotrophic factor (BDNF) in cortical lesions from FCD patients and in samples of normal control cortex. TRPC6 and BDNF mRNA and protein levels were increased in FCD lesions. By immunohistochemistry, they were strongly expressed in microcolumns, heterotopic neurons, dysmorphic neurons, and balloon cells (BCs). Colocalization assays revealed that most of the misshapen TRPC6-positive or heterotopic cells had a neuronal lineage with the exception of TRPC6-positive FCDiib patient BCs, which had both neuronal and glial features. Most TRPC6-positive cells were glutamatergic neurons. There was also greater expression of calmodulin-dependent kinase IV (CaMKIV), the downstream factor of TRPC6, in FCD lesions, suggesting that TRPC6 expression promoted dendritic growth and the development of dendritic spines and excitatory synapses via the CaMKIV-CREB pathway in FCD. Thus, overexpression of BDNF and TRPC6 and activation of the TRPC6 signal transduction pathway in cortical lesions of FCD patients may contribute to FC pathogenesis and epileptogenesis. PMID:27288906

  2. New insights into brain BDNF function in normal aging and Alzheimer disease.

    PubMed

    Tapia-Arancibia, Lucia; Aliaga, Esteban; Silhol, Michelle; Arancibia, Sandor

    2008-11-01

    The decline observed during aging involves multiple factors that influence several systems. It is the case for learning and memory processes which are severely reduced with aging. It is admitted that these cognitive effects result from impaired neuronal plasticity, which is altered in normal aging but mainly in Alzheimer disease. Neurotrophins and their receptors, notably BDNF, are expressed in brain areas exhibiting a high degree of plasticity (i.e. the hippocampus, cerebral cortex) and are considered as genuine molecular mediators of functional and morphological synaptic plasticity. Modification of BDNF and/or the expression of its receptors (TrkB.FL, TrkB.T1 and TrkB.T2) have been described during normal aging and Alzheimer disease. Interestingly, recent findings show that some physiologic or pathologic age-associated changes in the central nervous system could be offset by administration of exogenous BDNF and/or by stimulating its receptor expression. These molecules may thus represent a physiological reserve which could determine physiological or pathological aging. These data suggest that boosting the expression or activity of these endogenous protective systems may be a promising therapeutic alternative to enhance healthy aging.

  3. The Effects of Acute Physical Exercise on Memory, Peripheral BDNF, and Cortisol in Young Adults

    PubMed Central

    Röder, Brigitte; Schmidt-Kassow, Maren

    2016-01-01

    In animals, physical activity has been shown to induce functional and structural changes especially in the hippocampus and to improve memory, probably by upregulating the release of neurotrophic factors. In humans, results on the effect of acute exercise on memory are inconsistent so far. Therefore, the aim of the present study was to assess the effects of a single bout of physical exercise on memory consolidation and the underlying neuroendocrinological mechanisms in young adults. Participants encoded a list of German-Polish vocabulary before exercising for 30 minutes with either high intensity or low intensity or before a relaxing phase. Retention of the vocabulary was assessed 20 minutes after the intervention as well as 24 hours later. Serum BDNF and salivary cortisol were measured at baseline, after learning, and after the intervention. The high-intensity exercise group showed an increase in BDNF and cortisol after exercising compared to baseline. Exercise after learning did not enhance the absolute number of recalled words. Participants of the high-intensity exercise group, however, forgot less vocabulary than the relaxing group 24 hours after learning. There was no robust relationship between memory scores and the increase in BDNF and cortisol, respectively, suggesting that further parameters have to be taken into account to explain the effects of exercise on memory in humans. PMID:27437149

  4. 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

  5. Bi-directional regulation of postsynaptic cortactin distribution by BDNF and NMDA receptor activity.

    PubMed

    Iki, Junko; Inoue, Akihiro; Bito, Haruhiko; Okabe, Shigeo

    2005-12-01

    Abstract Cortactin is an F-actin-associated protein which interacts with the postsynaptic scaffolding protein Shank at the SH3 domain and is localized within the dendritic spine in the mouse neuron. Green fluorescent protein (GFP)-based time-lapse imaging revealed cortactin redistribution from dendritic cytoplasm to postsynaptic sites by application of brain-derived neurotrophic factor (BDNF). This response was mediated by mitogen-activated protein (MAP) kinase activation and was dependent on the C-terminal SH3 domain. In contrast, activation of N-methyl-D-aspartate (NMDA) receptors induced loss of cortactin from postsynaptic sites. This NMDA-dependent redistribution was blocked by an Src family kinase inhibitor. Conversely, increasing Src family kinase activity induced cortactin phosphorylation and loss of cortactin from the postsynaptic sites. Finally, blocking of endogenous BDNF reduced the amount of cortactin at the postsynaptic sites and an NMDA receptor antagonist prevented this reduction. These results indicate the importance of counterbalance between BDNF and NMDA receptor-mediated signalling in the reorganization of the postsynaptic actin cytoskeleton during neuronal development.

  6. 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

  7. Differential induction of Pax genes by NGF and BDNF in cerebellar primary cultures

    PubMed Central

    1994-01-01

    The Pax genes encode sequence-specific DNA binding transcription factors that are expressed in embryonic development of the nervous system. Primary neuronal cell cultures derived from the cerebellar cortex of embryonic day 14, newborn and 7-d old mice, were used to investigate the cell-type specific expression patterns of three members of the murine paired box containing gene family (Pax gene family), in vitro. Cell types which express Pax-2, Pax-3, and Pax-6 RNA in primary cultures correspond to those found in regions of the cerebellum which show RNA signals in sections of the developing mouse brain. To find mechanisms regulating Pax gene expression during cerebellar development, the differential regulation of Pax-2, Pax-3, and Pax-6 by NGF and BDNF, two structurally related neurotrophins, was studied in such primary cultures. Pax-2 and Pax-6 RNA increased slightly by 1 h and remained elevated throughout a 24-h treatment with BDNF and NGF. Pax-3 RNA was not detected in newborn cultures, but underwent a rapid (1 h) and transient (2 h) induction upon treatment with either BDNF or NGF. No response was seen with EGF or FGF. Cycloheximide treatment amplified Pax-3 induction and prolonged the signal. Thus, Pax-3 induction resembles that of the immediate-early gene c-fos, which transduces growth factor signals during the development of particular neuronal/glial cell types. The changes in Pax expression were inductive rather than trophic. PMID:8163557

  8. The Effects of Acute Physical Exercise on Memory, Peripheral BDNF, and Cortisol in Young Adults.

    PubMed

    Hötting, Kirsten; Schickert, Nadine; Kaiser, Jochen; Röder, Brigitte; Schmidt-Kassow, Maren

    2016-01-01

    In animals, physical activity has been shown to induce functional and structural changes especially in the hippocampus and to improve memory, probably by upregulating the release of neurotrophic factors. In humans, results on the effect of acute exercise on memory are inconsistent so far. Therefore, the aim of the present study was to assess the effects of a single bout of physical exercise on memory consolidation and the underlying neuroendocrinological mechanisms in young adults. Participants encoded a list of German-Polish vocabulary before exercising for 30 minutes with either high intensity or low intensity or before a relaxing phase. Retention of the vocabulary was assessed 20 minutes after the intervention as well as 24 hours later. Serum BDNF and salivary cortisol were measured at baseline, after learning, and after the intervention. The high-intensity exercise group showed an increase in BDNF and cortisol after exercising compared to baseline. Exercise after learning did not enhance the absolute number of recalled words. Participants of the high-intensity exercise group, however, forgot less vocabulary than the relaxing group 24 hours after learning. There was no robust relationship between memory scores and the increase in BDNF and cortisol, respectively, suggesting that further parameters have to be taken into account to explain the effects of exercise on memory in humans. PMID:27437149

  9. The Effects of Acute Physical Exercise on Memory, Peripheral BDNF, and Cortisol in Young Adults.

    PubMed

    Hötting, Kirsten; Schickert, Nadine; Kaiser, Jochen; Röder, Brigitte; Schmidt-Kassow, Maren

    2016-01-01

    In animals, physical activity has been shown to induce functional and structural changes especially in the hippocampus and to improve memory, probably by upregulating the release of neurotrophic factors. In humans, results on the effect of acute exercise on memory are inconsistent so far. Therefore, the aim of the present study was to assess the effects of a single bout of physical exercise on memory consolidation and the underlying neuroendocrinological mechanisms in young adults. Participants encoded a list of German-Polish vocabulary before exercising for 30 minutes with either high intensity or low intensity or before a relaxing phase. Retention of the vocabulary was assessed 20 minutes after the intervention as well as 24 hours later. Serum BDNF and salivary cortisol were measured at baseline, after learning, and after the intervention. The high-intensity exercise group showed an increase in BDNF and cortisol after exercising compared to baseline. Exercise after learning did not enhance the absolute number of recalled words. Participants of the high-intensity exercise group, however, forgot less vocabulary than the relaxing group 24 hours after learning. There was no robust relationship between memory scores and the increase in BDNF and cortisol, respectively, suggesting that further parameters have to be taken into account to explain the effects of exercise on memory in humans.

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

    PubMed

    Bechara, R G; Kelly, Á M

    2013-05-15

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