Human Brain-derived Neurotrophic Factor Research Articles

BDNF as a novel therapeutic candidate for Kennedy's disease.

BDNF as a novel therapeutic candidate for Kennedy's disease.

Muscle BDNF improves synaptic and contractile muscle strength in Kennedy's disease mice in a muscle-type specific manner.

Muscle-derived neurotrophic factors may offer therapeutic promise for treating neuromuscular diseases. We report that a muscle-derived neurotrophic factor, BDNF, rescues synaptic and muscle function in a muscle-type specific manner in mice modelling Kennedy's disease (KD). We also find that BDNF rescues select molecular mechanisms in slow and fast muscle that may underlie the improved cellular function. We also report for the first time that expression of BDNF, but not other members of the neurotrophin family, is perturbed in muscle from patients with KD. Given that muscle BDNF had divergent therapeutic effects that depended on muscle type, a combination of neurotrophic factors may optimally rescue neuromuscular function via effects on both pre- and postsynaptic function, in the face of disease. Deficits in muscle brain-derived neurotrophic factor (BDNF) correlate with neuromuscular deficits in mouse models of Kennedy's disease (KD), suggesting that restoring muscle BDNF might restore function. To test this possibility, transgenic mice expressing human BDNF in skeletal muscle were crossed with '97Q' KD mice. We found that muscle BDNF slowed disease, doubling the time between symptom onset and endstage. BDNF also improved expression of genes in muscle known to play key roles in neuromuscular function, including counteracting the expression of neonatal isoforms induced by disease. Intriguingly, BDNF's ameliorative effects differed between muscle types: synaptic strength was rescued only in slow-twitch muscle, while contractile strength was improved only in fast-twitch muscle. In sum, muscle BDNF slows disease progression, rescuing select cellular and molecular mechanisms that depend on fibre type. Muscle BDNF expression was also affected in KD patients, reinforcing its translational and therapeutic potential for treating this disorder.

BDNF Val66Met polymorphism alters food intake and hypothalamic BDNF expression in mice.

Obesity, a rising public health burden, is a multifactorial disease with an increased risk for patients to develop several pathological conditions including type 2 diabetes mellitus, hypertension, and cardiovascular disease. Increasing evidence suggests a relationship between the human brain-derived neurotrophic factor (BDNF) Val66Met single-nucleotide polymorphism (SNP) and obesity, although the underlying mechanisms of this connection are still not completely understood. In the present study, we found that homozygous knock-in BDNFMet/Met mice were overweight and hyperphagic compared to wildtype BDNFVal/Val mice. Increased food intake was associated withreduction of total BDNF and BDNF1, BDNF4 and BDNF6 transcripts in the hypothalamus of BDNFMet/Met mice. Incontrast, in the white adipose tissue total BDNF and Glut4 expression levels were augmented, while sirtuin 1 and leptin receptor (Ob-R) expression levels were reduced in BDNFMet/Met mice. Moreover, plasmatic leptin levels were decreased in BDNFMet/Met mice. However, BDNFVal/Val and BDNFMet/Met mice showed a similar response to the insulin tolerance test and glucose tolerance test. Altogether, these results suggest that BDNF Val66Met SNP strongly contributes to adipose tissue pathophysiology, resulting in reduced circulating leptin levels and hypothalamic expression of BDNF, which, in turn, promote increased food intake and overweight in BDNFMet/Met mice.

Impact of BDNF Val66Met Polymorphism on Myocardial Infarction: Exploring the Macrophage Phenotype.

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin growth factor family, well known for its role in the homeostasis of the cardiovascular system. Recently, the human BDNF Val66Met single nucleotide polymorphism has been associated with the increased propensity for arterial thrombosis related to acute myocardial infarction (AMI). Using cardiac magnetic resonance imaging and immunohistochemistry analyses, we showed that homozygous mice carrying the human BDNF Val66Met polymorphism (BDNFMet/Met) undergoing left anterior descending (LAD) coronary artery ligation display an adverse cardiac remodeling compared to wild-type (BDNFVal/Val). Interestingly, we observed a persistent presence of pro-inflammatory M1-like macrophages and a reduced accumulation of reparative-like phenotype macrophages (M2-like) in the infarcted heart of mutant mice. Further qPCR analyses showed that BDNFMet/Met peritoneal macrophages are more pro-inflammatory and have a higher migratory ability compared to BDNFVal/Val ones. Finally, macrophages differentiated from circulating monocytes isolated from BDNFMet/Met patients with coronary heart disease displayed the same pro-inflammatory characteristics of the murine ones. In conclusion, the BDNF Val66Met polymorphism predisposes to adverse cardiac remodeling after myocardial infarction in a mouse model and affects macrophage phenotype in both humans and mice. These results provide a new cellular mechanism by which this human BDNF genetic variant could influence cardiovascular disease.

The mouse-equivalent of the human BDNF VAL66MET polymorphism increases dorsal hippocampal volume and does not interact with developmental ethanol exposure

A relatively common polymorphism in the human brain-derived neurotrophic factor (BDNF) gene (Val66Met, which corresponds to Val68Met in mice) has been shown to modulate cognitive function and vulnerability to mental health disorders. This substitution impairs trafficking and activity-dependent release of BDNF. A number of studies with both humans and transgenic mice suggest that carriers of the Metallele have deficits in the structure and/or function of the hippocampal formation. Using a relatively new transgenic mouse model of this polymorphism, we recently demonstrated that it modulates the effects of developmental ethanol exposure in the hippocampus. Here, we further characterized the effect of this polymorphism on hippocampal morphology and its interaction with ethanol vapor exposure during the 2nd and 3rd trimester equivalents of human pregnancy. We found that BDNFmet/met mice have slightly larger hippocampal volumes than BDNFval/val mice. Ethanol vapor exposure during the 2nd and 3rd trimester equivalents of human pregnancy increased hippocampal volume in a single hippocampal subregion, the CA1 stratum radiatum. Ethanol exposure did not interact with BDNF genotype to affect volume in any hippocampal subregion. These results suggest that the Val66Met polymorphism does not reduce hippocampal size (i.e., it rather increases it slightly) or increase susceptibility to prenatal ethanol exposure-induced structural hippocampal damage during adulthood.

Human Brain-Derived Neurotrophic Factor Gene-Modified Bone Marrow Mesenchymal Stem Cells Combined With Erythropoietin Can Improve Acute Spinal Cord Injury.

Objective:To assess the effect as well as mechanism of bone marrow mesenchymal stem cells (BMSCs) modified by the human brain–derived neurotrophic factor gene combined with erythropoietin (EPO) in the treatment of acute spinal cord injury (SCI) in rats.Methods:The Brain-derived neurotrophic factor (BDNF) gene was transected by a virus vector. Rats with SCI were randomly split into following groups: The normal saline (NS) group, the EPO group, The Basso, Beattie, and Bresnahan scores, messenger RNA BDNF expression, and apoptosis rates were compared between the 4 groups at 1, 3, 7, 14, and 21 days after SCI.Results:At 7, 14, and 21 days after operation, the expression of the BDNF gene in the other 3 groups was higher than that of the NS group, and the difference was statistically significant (P < .05). The apoptosis rate in the combined group was less than that of NS, EPO, and BDNF/BMSC groups, and the differences were statistically significant (P < .05).Conclusion:Brain-derived neurotrophic factor gene-modified BMSC transplantation combined with EPO can promote the repair of nerve function after SCI in rats.

BDNF Val66Met Polymorphism, the Allele-Specific Analysis by qRT-PCR - a Novel Protocol.

Background: Alteration in brain-derived neurotrophic factor (BDNF) production is a marker of neuropathological conditions, which has led to the investigation of Val66Met polymorphism occurring in the human BDNF gene (BDNF). Presently, there are no reported methods available for the analysis of Val66Met impact on human BDNF functioning.Purpose: To develop a qRT-PCR protocol for the allele-specific expression evaluation of the Val66Met polymorphism in BDNF.Methods: Using RNA extracted from muscle samples of 9 healthy volunteers (32.9 ± 10.3 y) at rest and following a maximal effort aerobic capacity exercise test, a protocol was developed for the detection of Val66/Met66 allele-specific BDNF expression in Real-Time Quantitative Reverse Transcription PCR (qRT-PCR) - relative to housekeeping genes - and validated by absolute quantification in Droplet Digital Polymerase Chain Reaction (ddPCR).Results: Differences in the relative values of BDNF mRNA were confirmed by ddPCR analysis. HPRT1 and B2M were the most stable genes expressed in muscle tissue among different metabolic conditions, while GAPDH revealed to be metabolic responsive.Conclusion: Our qRT-PCR protocol successfully determines the allele-specific detection and changes in BDNF expression regarding the Val66Met polymorphism.

RELATIONSHIP BETWEEN STAGES OF DIABETIC RETINOPATHY AND LEVELS OF BRAIN-DERIVED NEUROTROPHIC FACTOR IN AQUEOUS HUMOR AND SERUM.

The aim of the study was to determine aqueous humor and serum levels of brain-derived neurotrophic factor (BDNF) in diabetic patients with and without retinopathy. The study included diabetic patients with or without retinopathy, who had an indication for cataract surgery. The study groups were diabetic patients without retinopathy (Group 2), with nonproliferative diabetic retinopathy (Group 3), and with proliferative retinopathy (Group 4). To quantitatively determine the amount of BDNF in samples, the RayBio Human BDNF ELISA kit (Norcross, GA), based on an enzyme-labeled immunosorbent assay was used. The median serum BDNF levels were significantly lower in all the study groups than in the control group (P values: 0.038 Group 2, 0.02 Group 3, and 0.002 Group 4). Serum BDNF was lower in Group 4 than in Group 3 (P = 0.030), and in Group 3 than in Group 2 (P = 0.04). The median aqueous humor BDNF levels were significantly decreased in all groups (P values: 0.047 Group 2, 0.021 Group 3, and 0.007 Group 4). There was no significant difference between Groups 2, 3, and 4 (P = 0.214). The serum and aqueous humor BDNF levels decreased in patients with diabetes mellitus (DM) before the emergence of clinical signs of retinopathy.

A Bicistronic Plasmid Encoding Brain-Derived Neurotrophic Factor and Urokinase Plasminogen Activator Stimulates Peripheral Nerve Regeneration After Injury.

Timely nerve restoration is an important factor for the successful regeneration of tissues and organs. It is known that axon regeneration following nerve injury is a multifactorial process that depends on the local expression of neurotrophins, including brain-derived neurotrophic factor (BDNF). Along with the survival of neurons, the active reorganization of the extracellular matrix is an important step for the growth of axons to their targets. Urokinase serine protease is part of the plasminogen activator system, which provides the vectoriality of the process of fibrinolysis and matrix reorganization, facilitating the growth of nerves to their targets. Based on this and in view of the results of our previous studies, we suggest that a combined bicistronic plasmid encoding the complementary proteins BDNF and urokinase may be beneficial in nerve regeneration. The ability of this bicistronic plasmid to stimulate nerve restoration was confirmed by in vitro stimulation of Neuro2a neurite growth and in vivo nerve conductivity and histology studies. To our knowledge, this is the first article that demonstrates the effectiveness of a bicistronic plasmid containing the human genes BDNF and urokinase plasminogen activator in the regeneration of the injured peripheral nerve. The results obtained demonstrate that plasmid vectors encoding several complementary-active therapeutic proteins may serve as a basis for developing prospective treatments for a wide range of multicomponent neural system disorders, such as nerve trauma. SIGNIFICANCE STATEMENT: This study is the first to show the effectiveness of using a bicistronic plasmid encoding complementary-active human protein brain-derived neurotrophic factor and urokinase plasminogen activator in the regeneration of the crushed peripheral nerve in a murine model.

Associations Between Circulating Basal BDNF, IGF-1 and Physical Fitness

Exercise-induced increase in circulating insulin-like growth factor 1 (IGF-1) levels might stimulate brain-derived neurotrophic factor (BDNF) expression. Thus, circulating IGF-1 can travel from the periphery to the brain and there stimulate the expression of BDNF and facilitate long-lasting changes in neural activity. It has been shown that chronic training leads to upregulation of basal levels of both BDNF and IGF-1. Several longitudinal studies have also shown that aerobic exercise acutely elevates circulating BDNF levels in humans. PURPOSE: To investigate associations of peripheral BDNF and IGF-1 with several physical fitness components at rest. METHODS: 792 adults (26±6 yr) men participated. BDNF and IGF-1 concentrations were analyzed from venous blood samples using an ELISA Assay (Human BDNF ELISA kit, ScienCell Research laboratories, San Diego, California) and Dynex DS 2 ELISA processing system (Dynex Technologies, Chantilly, Virginia). Cardiorespiratory fitness (VO2max) was determined using an indirect graded cycle ergometer test until exhaustion. Bilateral maximal isometric leg (MVCleg) and arm extension forces (MVCarm) were measured using dynamometers. Muscular endurance tests consisted of repeated 1-min push-ups and sit-ups, while standing long jump assessed muscular power. RESULTS: The mean±SD BDNF and IGF-1 concentrations were 15.20±3.96 ng/ml, 25.0±6.9nmol/l, respectively, while VO2max was 41.1±8.8ml/kg/min, MVCleg 3394±933N, MVCarm 871±216N, push-ups 28±14reps/min, sit-ups 35±12reps/min, standing long jump 227±26cm. BDNF and IGF-1 correlated weakly with each other (r=-0.146, p=0.003). Linear regression analysis (adjusted for age, smoking and education) revealed that associations between BDNF and physical fitness were weak for VO2max (β=-0.077, p=0.006) and muscle fitness (β=-0.077, p=0.895). This was also the case for IGF-1. CONCLUSIONS: The associations between peripheral BDNF, IGF-1 and physical fitness components were weak or non-existent at rest in the present cross-sectional design. Thus, it seems that only exercise-induced elevated values of BDNF and IGF-1 may associate with each other and physical fitness components. Therefore, their interactions should be investigated in future studies during acute and / or chronic exercises.

In silico analysis of the V66M variant of human BDNF in psychiatric disorders: An approach to precision medicine.

Brain-derived neurotrophic factor (BDNF) plays an important role in neurogenesis and synapse formation. The V66M is the most prevalent BDNF mutation in humans and impairs the function and distribution of BDNF. This mutation is related to several psychiatric disorders. The pro-region of BDNF, particularly position 66 and its adjacent residues, are determinant for the intracellular sorting and activity-dependent secretion of BDNF. However, it has not yet been fully elucidated. The present study aims to analyze the effects of the V66M mutation on BDNF structure and function. Here, we applied nine algorithms, including SIFT and PolyPhen-2, for functional and stability prediction of the V66M mutation. The complete theoretical model of BNDF was generated by Rosetta and validated by PROCHECK, RAMPAGE, ProSa, QMEAN and Verify-3D algorithms. Structural alignment was performed using TM-align. Phylogenetic analysis was performed using the ConSurf server. Molecular dynamics (MD) simulations were performed and analyzed using the GROMACS 2018.2 package. The V66M mutation was predicted as deleterious by PolyPhen-2 and SIFT in addition to being predicted as destabilizing by I-Mutant. According to SNPeffect, the V66M mutation does not affect protein aggregation, amyloid propensity, and chaperone binding. The complete theoretical structure of BDNF proved to be a reliable model. Phylogenetic analysis indicated that the V66M mutation of BDNF occurs at a non-conserved position of the protein. MD analyses indicated that the V66M mutation does not affect the BDNF flexibility and surface-to-volume ratio, but affects the BDNF essential motions, hydrogen-bonding and secondary structure particularly at its pre and pro-domain, which are crucial for its activity and distribution. Thus, considering that these parameters are determinant for protein interactions and, consequently, protein function; the alterations observed throughout the MD analyses may be related to the functional impairment of BDNF upon V66M mutation, as well as its involvement in psychiatric disorders.

BDNF Val66Met genetic variation and its plasma level in patients with morbid obesity: A case-control study

Obesity is a major public health concern worldwide. Genetic, behavioral, and environmental factors contribute to the multifactorial etiology of obesity. Evidence suggests an association between human Brain-Derived Neurotrophic Factor (BDNF) Val66Met single nucleotide polymorphism (SNP) and obesity. Reduced plasma BDNF levels have also been reported in patients with eating disorders and obesity. We aimed to evaluate the BDNF Val66Met (rs6265) SNP and also plasma BDNF levels in morbidly obese patients compared with healthy normal controls in southern Iran. One hundred morbidly obese patients and one hundred eight healthy normal controls were enrolled. Blood-derived DNA samples were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and confirmed by DNA sequencing. Plasma BDNF levels were evaluated using a commercially available sandwich enzyme-linked immunosorbent assay (ELISA) kit for human BDNF. Data analysis was performed by SPSS software, version 18.0. Genotype distribution was not significantly different between obese patients and controls. However, plasma BDNF levels were significantly lower in obese patients compared with controls. Interestingly, a significant association was found between BDNF Val66Met SNP and plasma BDNF levels. No relationship was observed between BDNF Val66Met SNP and all assessed demographic and clinical characteristics of obese patients. It seems that plasma BDNF levels were associated with both obesity and BDNF Val66Met SNP. However, this association was not found between BDNF Val66Met SNP and obesity. Further studies with larger sample sizes are needed for more detailed assessment of this genetic variation as a potential biomarker for obesity.

Metabolomics and proteomics profiles of some medicinal plants and correlation with BDNF activity

BackgroundIdentification of the low abundance of phytochemicals in plant extracts is very difficult. Pharmacological activity observed in such plants is not due to a single compound. In most cases, plant extracts show activity based on synergistic or antagonistic effects. Therefore, the idea of a holistic approach is more rational. PurposeThis study was planned to compare the metabolomics and proteomics profiles of Valeriana officinalis L. (Valerianaceae), Melissa officinalis L. (Lamiaceae), Hypericum perforatum L. (Hypericaceae) and Passiflora incarnata L. (Passifloraceae) used in sedative anxiolytic and sleep disorders. Integrated omics analyses were used to provide a better understanding of the effect of plant extracts on the brain-derived neurotrophic factor (BDNF) expression levels on the SH-SY5Y cell line by a holistic approach. MethodsMetabolomic profiling of the plants was performed using the GC–MS and LC-qTOF-MS systems, and the proteomics analysis using the LC-qTOF-MS system after trypsin digestion. The Human BDNF Quantikine ELISA kit was utilized to test BDNF expression activity on the SH-SY5Y cell line. ResultsThe investigated plant extracts showed a significant increase in BDNF expression (p < 0.05). M. officinalis was found as the most active extract. According to the correlation analyses between BDNF activity and metabolomics or proteomics level, 94 metabolites had a positive correlation while 23 metabolites had a highly negative correlation; those for proteins are 24 and 6, respectively. ConclusionThe multivariate data analysis revealed a similar metabolomics profile of H. perforatum and P. incarnata, which also had a similar activity profile. Remarkably, all the primary metabolites belonging to the Krebs Cycle (citric acid, fumaric acid, succinic acid, pyruvic acid, malic acid and citramalic acid, an analog of malic acid) were positively correlated with BDNF activity. Secondary metabolites with a high BDNF expression belonged to flavonoids, xanthone, coumarines, tannin, naphtalenes, terpenoids and carotenoid skeleton. Two proteins from the cytochrome P450 family (P450 71B11 and P450 94B3) were positively correlated with BDNF activity. Employing omics technologies in the plant research area will offer a better understanding of the role of plant extracts and may lead to the discovery of new compounds with specific activity.

Effects of Cytochrome P450 2C19 Genetic Polymorphisms on Responses to Escitalopram and Levels of Brain-Derived Neurotrophic Factor in Patients With Panic Disorder.

The purpose of this study was to examine the relationships between ytochrome P450 family 2 subfamily C member 19 (CYP2C19) polymorphisms, brain-derived neurotrophic factor (BDNF) plasma levels, and treatment responses to escitalopram in Chinese patients with panic disorder (PD). Ninety patients with PD were administered the Panic Disorder Severity Scale-Chinese Version (PDSS-CV) and Hamilton Anxiety Scale (HAMA-14) from baseline to 8 weeks. Escitalopram treatment (10 mg/d) was administered for 8 consecutive weeks. Three CYP2C19 metabolizers, including extensive metabolizers, intermediate metabolizers, and poor metabolizers (PMs), and 5 CYP2C19 genotypes were detected by polymerase chain reaction-genotyping microarray analysis. Baseline plasma BDNF levels were tested using human BDNF enzyme-linked immunosorbent assay kits. Our findings showed no significant differences in demographic data, baseline PDSS-CV scores, or HAMA-14 scores between the 3 CYP2C19 metabolizer groups (P's > 0.05). Repeated-measures analysis showed a significant reduction in PDSS-CV (F = 221.49, df = 3, P < 0.001) and HAMA-14 (F = 260.47, df = 3, P < 0.001) scores over 8 weeks in PD patients. In addition, patients with PMs had a greater reduction in HAMA-14 scores (F = 2.14, P = 0.049) than did those with extensive metabolizers and intermediate metabolizers. Moreover, our findings showed that patients with *2/*2 genotypes had a greater reduction in PDSS-CV scores than did those with other genotypes (F = 2.14, df = 12, P = 0.015). Our study provides preliminary evidence of the effects of CYP2C19 PMs on treatment responses to escitalopram in Chinese PD patients, but no significant correlation between treatment responses and BDNF levels was found.

Neural differentiation of bone marrow mesenchymal stem cells with human brain-derived neurotrophic factor gene-modified in functionalized self-assembling peptide hydrogel in vitro.

To investigate the biocompatibility and differentiation of human brain-derived neurotrophic factor (hBDNF) gene-modified bone marrow mesenchymal stem cells (hBDNF-rMSCs) in a functionalized self-assembling peptide hydrogel. hBDNF was engineered in rMSCs using adenovirus vector and the enhanced green fluorescence protein (eGFP) was used as a reporter gene. Mesenchymal stem cell-specific surface markers (CD90, CD29, and CD45) were used for identifying rat-derived MSCs. Fluorescence microscope was used to detect the transfection of rMSCs. hBDNF-rMSCs and control cells (eGFP-rMSCs) were seeded in a functional self-assembling peptide hydrogel (RADA16-PRG hydrogel) and a control hydrogel (RADA16 hydrogel). Cells were divided into three groups (hBDNF-rMSCs + RADA16 hydrogel, hBDNF-rMSCs + RADA16-PRG hydrogel, and eGFP-rMSCs + RADA16-PRG hydrogel) and a control group (eGFP-rMSCs + RADA16 hydrogel). Cell growth, cell proliferation, expression of hBDNF-mRNA, the level of hBDNF, neuron-specific enolase (NSE), and glial fibrillary acidic protein (GFAP) protein were analyzed for each group. rMSCs were positive for CD90 and CD29 and negative for CD45, green fluorescence was strongly visible at 72 hours after transfection. Compared with control group, the expression of hBDNF-mRNA and levels of hBDNF protein in both hBDNF group were significantly increased (P < 0.01), the cell growth, cell proliferation, and levels of NSE and GFAP protein were significantly increased in three groups ( P < 0.01). Cell growth, cell proliferation, expression of hBDNF-mRNA, and levels of hBDNF, NSE, and GFAP protein in hBDNF-rMSCs + RADA16-PRG hydrogel group were significantly higher than that of hBDNF-rMSCs + RADA16 hydrogel group ( P < 0.01). Bone marrow MSCs can be induced into neural cells by the human brain-derived neurotrophic factor gene in a RADA16-PRG functionalized self-assembling peptide hydrogel.

Dimerization of the Trk receptors in the plasma membrane: effects of their cognate ligands.

Receptor tyrosine kinases (RTKs) are cell surface receptors which control cell growth and differentiation, and play important roles in tumorigenesis. Despite decades of RTK research, the mechanism of RTK activation in response to their ligands is still under debate. Here, we investigate the interactions that control the activation of the tropomyosin receptor kinase (Trk) family of RTKs in the plasma membrane, using a FRET-based methodology. The Trk receptors are expressed in neuronal tissues, and guide the development of the central and peripheral nervous systems during development. We quantify the dimerization of human Trk-A, Trk-B, and Trk-C in the absence and presence of their cognate ligands: human β-nerve growth factor, human brain-derived neurotrophic factor, and human neurotrophin-3, respectively. We also assess conformational changes in the Trk dimers upon ligand binding. Our data support a model of Trk activation in which (1) Trks have a propensity to interact laterally and to form dimers even in the absence of ligand, (2) different Trk unliganded dimers have different stabilities, (3) ligand binding leads to Trk dimer stabilization, and (4) ligand binding induces structural changes in the Trk dimers which propagate to their transmembrane and intracellular domains. This model, which we call the 'transition model of RTK activation,' may hold true for many other RTKs.

Human BDNF rs6265 polymorphism as a mediator for the generalization of contextual anxiety.

The Met allele of the human brain-derived neurotrophic factor (BDNF) gene might be a risk factor for anxiety disorders and is associated with reduced hippocampal volume. Notably, hippocampus plays a crucial role in contextual learning and generalization. The role of the BDNF gene variation in human context-conditioning and generalization is still unknown. We investigated 33 carriers of the Met allele (18 females) and 32 homozygous carriers of the Val allele (15 females) with a virtual-reality context-conditioning paradigm. Electric stimulations (unconditioned stimulus, US) were unpredictably delivered in one virtual office (CTX+), but never in another virtual office (CTX-). During generalization, participants revisited CTX+ and CTX- and a generalization office (G-CTX), which was a mix of the other two. Rating data indicated successful conditioning (more negative valence, higher arousal, anxiety and contingency ratings for CTX+ than CTX-), and generalization of conditioned anxiety by comparable ratings for G-CTX and CTX+. The startle data indicated discriminative learning for Met allele carriers, but not for Val homozygotes. Moreover, a trend effect suggests that startle responses of only the Met carriers were slightly potentiated in G-CTX versus CTX-. In sum, the BDNF polymorphism did not affect contextual learning and its generalization on a verbal level. However, the physiological data suggest that Met carriers are characterized by fast discriminative contextual learning and a tendency to generalize anxiety responses to ambiguous contexts. We propose that such learning may be related to reduced hippocampal functionality and the basis for the risk of Met carriers to develop anxiety disorders.

Global epigenetic analysis of BDNF Val66Met mice hippocampus reveals changes in dendrite and spine remodeling genes.

Brain-derived neurotrophic factor (BDNF), a neurotrophin highly expressed in the hippocampus, plays crucial roles in cognition, neuroplasticity, synaptic function, and dendritic remodeling. The common human Val66Met polymorphism of BDNF has been implicated in the pathophysiology of neuropsychiatric and neurodegenerative disorders, and in the outcome of pro-adaptive and therapeutic treatments. Altered gene-expression profile has been previously shown in BDNF Val66Met knock-in mice, which recapitulate the phenotypic hallmarks of individuals carrying the BDNF Met allele. The aim of this study was to investigate the impact of the BDNF Val66Met polymorphism in the knock-in mouse model on two hippocampal epigenetic marks for transcriptional repression and activation, respectively: trimethylation of lysine 27 on histone H3 (H3K27me3) and acetylation of histone H3 (AcH3), using a genome-wide approach. Chromatin immunoprecipitation followed by deep sequencing of immunoprecipitated DNA (ChIP-Seq) was carried out with specific antibodies for H3K27me3 and AcH3. Our results revealed broad alteration of H3K27me3 and AcH3 marks association profiles in BDNFMet/Met , compared to BDNFVal/Val mice. Bioinformatics analysis showed changes in several biological functions and related pathways, affected by the presence of the polymorphism. In particular, a number of networks of functional interaction contained BDNF as central node. Quantitative PCR analysis confirmed epigenetically related significant changes in the expression of five genes: Dvl1, Nos3, Reln, Lypd6, and Sh3gl2. The first three are involved in dendrite and spine remodeling, morphological features altered in BDNFMet/Met mice. This work in homozygous knock-in mice shows that the human BDNF Val66Met polymorphism induces an array of histone H3 epigenetic modifications, in turn altering the expression of select genes crucial for structural and functional neuronal features.

BDNF, Brain, and Regeneration: Insights from Zebrafish.

Zebrafish (Danio rerio) is a teleost fish widely accepted as a model organism for neuroscientific studies. The adults show common basic vertebrate brain structures, together with similar key neuroanatomical and neurochemical pathways of relevance to human diseases. However, the brain of adult zebrafish possesses, differently from mammals, intense neurogenic activity, which can be correlated with high regenerative properties. Brain derived neurotrophic factor (BDNF), a member of the neurotrophin family, has multiple roles in the brain, due also to the existence of several biologically active isoforms, that interact with different types of receptors. BDNF is well conserved in the vertebrate evolution, with the primary amino acid sequences of zebrafish and human BDNF being 91% identical. Here, we review the available literature regarding BDNF in the vertebrate brain and the potential involvement of BDNF in telencephalic regeneration after injury, with particular emphasis to the zebrafish. Finally, we highlight the potential of the zebrafish brain as a valuable model to add new insights on future BDNF studies.

Post-stroke BDNF Concentration Changes Following Physical Exercise: A Systematic Review.

Background: Research over the last two decades has highlighted the critical role of Brain-derived neurotrophic factor (BDNF) in brain neuroplasticity. Studies suggest that physical exercise may have a positive impact on the release of BDNF and therefore, brain plasticity. These results in animal and human studies have potential implications for the recovery from damage to the brain and for interventions that aim to facilitate neuroplasticity and, therefore, the rehabilitation process.Purpose: The aim of this study was to carry out a systematic review of the literature investigating how aerobic exercises and functional task training influence BDNF concentrations post-stroke in humans and animal models.Data Sources: Searches were conducted in PubMed (via National Library of Medicine), SCOPUS (Elsevier), CINAHL with Full Text (EBSCO), MEDLINE 1946—present with daily updates (Ovid) and Cochrane.Study Selection: All of the database searches were limited to the period from January, 2004 to May, 2017.Data Extraction: Two reviewers extracted study details and data. The methodological quality of the studies that used animal models was assessed using the ARRIVE Guidelines, and the study that evaluated human BDNF was assessed using the PEDro Scale.Data Synthesis: Twenty-one articles were included in this review. BDNF measurements were performed systemically (serum/plasma) or locally (central nervous system). Only one study evaluated human BDNF concentrations following physical exercise, while 20 studies were experimental studies using a stroke model in animals. A wide variation was observed in the training protocol between studies, although treadmill walking was the most common type of intervention among the studies. Studies were of variable quality: the studies that used animal models scored from 8/20 to 15/20 according to the ARRIVE Guidelines. The only study that evaluated human subjects scored 5/10 according to the PEDro scale and, which indicates a quality classified as “fair”.Conclusions: The results of the current systematic review suggest that aerobic exercise promotes changes in central BDNF concentrations post-stroke. On the other hand, BDNF responses following functional exercises, such as reaching training and Constraint Induced Movement Therapy (CIMT), seem to be still controversial. Given the lack of studies evaluating post-stroke BDNF concentration following physical exercise in humans, these conclusions are based on animal work.