Impaired fear memory in a rat model of the brain-derived neurotrophic factor Val66Met polymorphism is reversed by chronic exercise.

The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with reduced activity-dependent BDNF release in the brain and has been implicated in fear and anxiety disorders, including post-traumatic stress disorder. Exercise has been shown to have benefits in affective disorders but the role of BDNF Val66Met remains unclear. Male and female BDNF Val66Met rats were housed in automated running-wheel cages from weaning while controls were housed in standard cages. During adulthood, all rats underwent standard three-day fear conditioning testing, with three tone/shock pairings on day 1 (acquisition), and extinction learning and memory (40 tones/session) on day 2 and day 3. Expression of BDNF and stress-related genes were measured in the frontal cortex. Extinction testing on day 2 revealed significantly lower freezing in response to initial cue exposure in control Met/Met rats, reflecting impaired fear memory. This deficit was reversed in both male and female Met/Met rats exposed to exercise. There were no genotype effects on acquisition or extinction of fear, however chronic exercise increased freezing in all groups at every stage of testing. Exercise furthermore led to increased expression of Bdnf in the prefrontal cortex of females and its isoforms in both sexes, as well as increased expression of FK506 binding protein 51 (Fkpb5) in females and decreased expression of Serum/glucocorticoid-regulated kinase (Sgk1) in males independent of genotype. These results show that the Met/Met genotype of the Val66Met polymorphism affects fear memory, and that chronic exercise selectively reverses this genotype effect. Chronic exercise also led to an overall increase in freezing in all genotypes which may contribute to results.

Correlation between nocturnal intermittent hypoxemia and mild cognitive impairment in the older adult and the role of BDNF Val66Met polymorphism: a hospital-based cross-sectional study.

PURPOSE: To explore the prevalence of nocturnal intermittent hypoxemia (NIH) in a tertiary hospital geriatric department and the relationship between NIH and mild cognitive impairment (MCI) in older adults, and to examine the role of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism. METHODS: Older adults aged ≥ 60 were enrolled. NIH and cognitive assessments were conducted. BDNF concentrations and BDNF Val66Met polymorphism were detected for a preliminary exploration of the possible mechanism of the process. RESULTS: Of 325 older adults enrolled, 157 (48%) had NIH and were further divided into mild, moderate, and severe NIH groups according to their oxygen desaturation of ≥ 4% per hour of sleep (ODI4). MCI detection rate in the four groups gradually increased, and the differences were statistically significant (chi-square = 4.457, P = 0.035). ODI4 was negatively correlated with MoCA score in all participants (r = - 0.115, P = 0.039) and patients with NIH (r = - 0.199, P = 0.012). After adjusting for sex, age, and cardiovascular risk factors, NIH and MCI remained independently associated (OR = 3.13, 95% CI 1.03-9.53, P = 0.045). BDNF levels were positively correlated with MoCA score (r = 0.169, P = 0.028) and negatively correlated with nocturnal average oxygen saturation in patients with NIH (r = - 0.288, P = 0.008). Older adults with different BDNF Val66Met genotypes did not show significant differences in MCI rate and BDNF levels (P > 0.05). CONCLUSION: The older adults with NIH have a higher MCI detection rate. BDNF levels may be a potential biomarker for cognitive dysfunction in patients with NIH.

Chronic running-wheel exercise from adolescence leads to increased anxiety and depression-like phenotypes in adulthood in rats: Effects on stress markers and interaction with BDNF Val66Met genotype.

Exercise has been shown to be beneficial in reducing symptoms of affective disorders and to increase the expression of brain-derived neurotrophic factor (BDNF). The BDNF Val66Met polymorphism is associated with reduced activity-dependent BDNF release and increased risk for anxiety and depression. Male and female Val66Met rats were given access to running wheels from 3 weeks of age and compared to sedentary controls. Anxiety- and depression-like behaviors were measured in adulthood using the elevated plus maze (EPM), open field (OF), and forced swim test (FST). Expression of BDNF and a number of stress-related genes, the glucocorticoid receptor (Nr3c1), serum/glucocorticoid-regulated kinase 1 (Sgk1), and FK506 binding protein 51 (Fkbp5) in the hippocampus were also measured. Rats given access to running wheels developed high levels of voluntary exercise, decreased open-arm time on the EPM and center-field time in the OF, reduced overall exploratory activity in the open field, and increased immobility time in the FST with no differences between genotypes. Chronic exercise induced a significant increase in Bdnf mRNA and BDNF protein levels in the hippocampus with some of these effects being genotype specific. Exercise decreased the expression of Nr3c1 and Sgk1, but increased the expression of Fkbp5. These results suggest that chronic running-wheel exercise from adolescence increased anxiety and depression-like phenotypes in adulthood, independent of BDNF Val66Met genotype. Further studies are required to confirm that increased indices of anxiety-like behavior are independent from reduced overall locomotor activity.

Acute stress induces an aberrant increase of presynaptic release of glutamate and cellular activation in the hippocampus of BDNFVal/Met mice.

Stressful life events are considered major risk factors for the development of several psychiatric disorders, though people differentially cope with stress. The reasons for this are still largely unknown but could be accounted for by individual genetic variants, previous life events, or the kind of stressors. The human brain-derived neurotrophic factor (BDNF) Val66Met variant, which was found to impair intracellular trafficking and activity-dependent secretion of BDNF, has been associated with increased susceptibility to develop several neuropsychiatric disorders, although there is still some controversial evidence. On the other hand, acute stress has been consistently demonstrated to promote the release of glutamate in cortico-limbic regions and altered glutamatergic transmission has been reported in psychiatric disorders. However, it is not known if the BDNF Val66Met single-nucleotide polymorphism (SNP) affects the stress-induced presynaptic glutamate release. In this study, we exposed adult male BDNFVal/Val and BDNFVal/Met knock-in mice to 30 min of acute restraint stress. Plasma corticosterone levels, glutamate release, protein, and gene expression in the hippocampus were analyzed immediately after the end of the stress session. Acute restraint stress similarly increased plasma corticosterone levels and nuclear glucocorticoid receptor levels and phosphorylation in both BDNFVal/Val and BDNFVal/Met mice. However, acute restraint stress induced higher increases in hippocampal presynaptic release of glutamate, phosphorylation of cAMP-response element binding protein (CREB), and levels of the immediate early gene c-fos of BDNFVal/Met compared to BFNFVal/Val mice. Moreover, acute restraint stress selectively increased phosphorylation levels of synapsin I at Ser9 and at Ser603 in BDNFVal/Val and BDNFVal/Met mice, respectively. In conclusion, we report here that the BDNF Val66Met SNP knock-in mice display an altered response to acute restraint stress in terms of hippocampal glutamate release, CREB phosphorylation, and neuronal activation, compared to wild-type animals. Taken together, these results could partially explain the enhanced vulnerability to stressful events of Met carriers reported in both preclinical and clinical studies.

BDNF Val66Met genotype and adolescent glucocorticoid treatment induce sex-specific disruptions to fear extinction and amygdala GABAergic interneuron expression in mice.

BACKGROUND: The BDNF Val66Met single nucleotide polymorphism has been implicated in stress sensitivity and Post-Traumatic Stress Disorder (PTSD) risk. We previously reported that chronic young-adult stress hormone treatment enhanced fear memory in adult BDNFVal66Met mice with the Met/Met genotype. This study aimed to extend this work to fear extinction learning, spontaneous recovery of fear, and neurobiological correlates in the amygdala. METHODS: Male and female Val/Val and Met/Met mice received corticosterone in their drinking water during late adolescence to model chronic stress. Following a 2-week recovery period, the mice underwent fear conditioning and extinction training. Immunofluorescent labelling was used to assess density of three interneuron subtypes; somatostatin, parvalbumin and calretinin, within distinct amygdala nuclei. RESULTS: No significant effects of genotype, treatment or sex were found for fear learning. However, adolescent CORT treatment selectively abolished fear extinction of female Met/Met mice. No effect of genotype, sex, or treatment was observed for spontaneous recovery of fear. Significant main effects of genotype and CORT emerged for somatostatin and calretinin cell density, again in females only, further supporting sex-specific effects of the Met/Met genotype and chronic CORT exposure. CONCLUSION: BDNF Val66Met genotype interacts with chronic adolescent stress hormone exposure to abolish fear extinction in female Met/Met mice in adulthood. This effect was associated with female-specific interneuron dysfunction induced by either genotype or stress hormone exposure, depending on the interneuron subtype. These data provide biological insight into the role of BDNF in sex differences in sensitivity to stress and vulnerability to stress-related disorders in adulthood.

Interactions of dietary insulin index and dietary insulin load with brain-derived neurotrophic factor (BDNF) Val66Met polymorphism in relation to cardiometabolic markers in Iranian diabetic patients: a cross-sectional study.

The progression of cardiometabolic diseases is determined by both genetic and environmental factors. Gene-diet interactions may therefore be important in modulating the risks of developing metabolic diseases. The objectives were to investigate the effect of the interaction between brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms and dietary insulin index (DII) and dietary insulin load (DIL) on cardiometabolic markers among diabetic patients. In this cross-sectional study, blood samples were collected from 667 patients. DIL and DII were defined using a validated FFQ. Genotyping the BDNF Val66Met polymorphism was conducted by the PCR-Restriction fragment length polymorphism (RFLP) method. Interactions between dietary indices and gene variants were evaluated using a generalised linear model. PGF2a concentrations were significantly higher among Val homozygotes than Met-allele carrier. This study revealed that, compared with individuals with the Val/Val genotype, those with the Met/Val or Met/Met genotype had lower BMI (Pinteraction = 0·04), TAG (Pinteraction = 0·04), leptin (Pinteraction = 0·01), LDL (Pinteraction = 0·04) and total cholesterol (Pinteraction = 0·01) when they consumed diets higher on the DIL index. Moreover, the highest quartile of the DIL, compared with the lowest, showed increase in waist circumference (Pinteraction = 0·02) and LDL/HDL (Pinteraction = 0·04) for Val/Val homozygotes compared with Met-allele carriers. BDNF Val66Met variants may interact with DIL and DII, thus be involved in the development of cardiometabolic risk factors. If diabetic patients with Met alleles regulate dietary intakes, they have a protective opportunity to regulate their cardiometabolic markers.

Impact of brain-derived neurotrophic factor Val66Met polymorphism and response to escitalopram or paroxetine in obsessive-compulsive disorder.

OBJECTIVE: Obsessive-compulsive disorder (OCD) is a severe psychiatric disorder characterized by its heterogeneous nature and by different dimensions of obsessive-compulsive (OC) symptoms. Serotonin reuptake inhibitors (SRIs) are used to treat OCD, but up to 40% to 60% of patients do not show a significant improvement with these medications. In this study, we aimed to test the impact of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on the efficacy of antidepressants in OCD overall, and in relation to the different OC dimensions. METHODS: In a 6-month prospective treatment study, 69 Caucasian OCD patients were treated with escitalopram for 24 weeks or with escitalopram for 12 weeks followed by paroxetine for an additional 12-week period. Patients were genotyped and assessed for treatment response. The main clinical outcomes were improvement of the Yale-Brown Obsessive-Compulsive Scale score and in different OC symptom dimension scores. RESULTS: The Val/Val group comprised 43 (62%) patients, the Val/Met and Met/Met group comprised 26 (38%) patients. Forty-two patients were classified as responders at 12 weeks and 38 at 24 weeks; no significant association was found between BDNF Val66Met and SRIs response at 12 and 24 weeks. In analyses of the different OC symptom dimensions, the Met allele was associated with a slightly reduced score in the aggressive/checking dimension at 6 months (P = .048). CONCLUSIONS: Our findings do not support the usefulness of BDNF Val66Met genotyping to predict overall response to treatment with SRIs in OCD; they did however suggest a better outcome at 6 months for the aggressive/checking symptom dimension for patients carrying the Met allele.

Persistence of learning-induced synapses depends on neurotrophic priming of glucocorticoid receptors.

Stress can either promote or impair learning and memory. Such opposing effects depend on whether synapses persist or decay after learning. Maintenance of new synapses formed at the time of learning upon neuronal network activation depends on the stress hormone-activated glucocorticoid receptor (GR) and neurotrophic factor release. Whether and how concurrent GR and neurotrophin signaling integrate to modulate synaptic plasticity and learning is not fully understood. Here, we show that deletion of the neurotrophin brain-derived neurotrophic factor (BDNF)-dependent GR-phosphorylation (PO4) sites impairs long-term memory retention and maintenance of newly formed postsynaptic dendritic spines in the mouse cortex after motor skills training. Chronic stress and the BDNF polymorphism Val66Met disrupt the BDNF-dependent GR-PO4 pathway necessary for preserving training-induced spines and previously acquired memories. Conversely, enrichment living promotes spine formation but fails to salvage training-related spines in mice lacking BDNF-dependent GR-PO4 sites, suggesting it is essential for spine consolidation and memory retention. Mechanistically, spine maturation and persistence in the motor cortex depend on synaptic mobilization of the glutamate receptor subunit A1 (GluA1) mediated by GR-PO4 Together, these findings indicate that regulation of GR-PO4 via activity-dependent BDNF signaling is important for the formation and maintenance of learning-dependent synapses. They also define a signaling mechanism underlying these effects.

The BDNF Val66Met polymorphism (rs6265) enhances dopamine neuron graft efficacy and side-effect liability in rs6265 knock-in rats.

Prevalent in approximately 20% of the worldwide human population, the rs6265 (also called 'Val66Met') single nucleotide polymorphism (SNP) in the gene for brain-derived neurotrophic factor (BDNF) is a common genetic variant that can alter therapeutic responses in individuals with Parkinson's disease (PD). Possession of the variant Met allele results in decreased activity-dependent release of BDNF. Given the resurgent worldwide interest in neural transplantation for PD and the biological relevance of BDNF, the current studies examined the effects of the rs6265 SNP on therapeutic efficacy and side-effect development following primary dopamine (DA) neuron transplantation. Considering the significant reduction in BDNF release associated with rs6265, we hypothesized that rs6265-mediated dysfunctional BDNF signaling contributes to the limited clinical benefit observed in a subpopulation of PD patients despite robust survival of grafted DA neurons, and further, that this mutation contributes to the development of aberrant graft-induced dyskinesias (GID). To this end, we generated a CRISPR knock-in rat model of the rs6265 BDNF SNP to examine for the first time the influence of a common genetic polymorphism on graft survival, functional efficacy, and side-effect liability, comparing these parameters between wild-type (Val/Val) rats and those homozygous for the variant Met allele (Met/Met). Counter to our hypothesis, the current research indicates that Met/Met rats show enhanced graft-associated therapeutic efficacy and a paradoxical enhancement of graft-derived neurite outgrowth compared to wild-type rats. However, consistent with our hypothesis, we demonstrate that the rs6265 genotype in the host rat is strongly linked to development of GID, and that this behavioral phenotype is significantly correlated with neurochemical signatures of atypical glutamatergic neurotransmission by grafted DA neurons.

A Meta-Analysis of Brain-Derived Neurotrophic Factor Effects on Brain Volume in Schizophrenia: Genotype and Serum Levels.

AIM: The Val66Met single-nucleotide polymorphism (SNP) on the BDNF gene has established pleiotropic effects on schizophrenia incidence and morphologic alterations in the illness. The effects of brain-derived neurotrophic factor (BDNF) on brain volume measurements are however mixed seeming to be less established for most brain regions. The current meta-analytic review examined (1) the association of the Val66Met SNP and brain volume alterations in schizophrenia by comparing Met allele carriers to Val/Val homozygotes and (2) the association of serum BDNF with brain volume measurements. METHOD: Studies included in the meta-analyses were identified through an electronic search of PubMed and PsycInfo (via EBSCO) for English language publications from January 2000 through December 2017. Included studies had conducted a genotyping procedure of Val66Met or obtained assays of serum BDNF and obtained brain volume data in patients with psychotic disorders. Nonhuman studies were excluded. RESULTS: Study 1 which included 52 comparisons of Met carriers and Val/Val homozygotes found evidence of lower right and left hippocampal volumes among Met allele carriers with schizophrenia. Frontal measurements, while also lower among Met carriers, did not achieve statistical significance. Study 2 which included 7 examinations of the correlation between serum BDNF and brain volume found significant associations between serum BDNF levels and right and left hippocampal volume with lower BDNF corresponding to lower volumes. DISCUSSION: The meta-analyses provided evidence of associations between brain volume alterations in schizophrenia and variations on the Val66Met SNP and serum BDNF. Given the limited number of studies, it remains unclear if BDNF effects are global or regionally specific.

Association of Serum Biomarker Levels and BDNF Gene Polymorphism with Response to Selective Serotonin Reuptake Inhibitors in Indian Patients with Major Depressive Disorder.

INTRODUCTION: Depression is a major public health problem. Response to selective serotonin reuptake inhibitor (SSRI) treatment varies considerably between patients. In the context of polygenic diseases like depression, measurement of a panel of biomarkers involved in the pathophysiology of depression might help predict outcome to treatment with SSRIs. OBJECTIVE: The objective was to establish the relationship between serum biomarker levels and the brain-derived neurotrophic factor (BDNF) val66met polymorphism and response to SSRIs in patients with major depressive disorder. METHODS: 50 patients with moderate to severe depression were recruited from the Department of Psychiatry, Sri Ra-machandra Institute of Higher Education and Research. Blood samples were collected, and Hamilton Depression Rating Scale scoring was done at baseline and after 8 weeks of treatment with SSRIs. Baseline and post-treatment levels of high-sensitivity C-reactive protein (hsCRP), BDNF and neuregulin 1ß1 (NRG1ß1) were analysed using commercially available ELISA kits. Genotyping of the BDNF Val66Met polymorphism was performed using a PCR-RFLP method. RESULTS: Following treatment, there was a significant decrease in the mean hsCRP and NRG1ß1 levels and a significant increase in the mean BDNF level. Responders had significantly lower baseline hsCRP and higher baseline BDNF levels when compared to non-responders. Response rates were significantly higher in the Val/Val group when compared to the Val/Met group. CONCLUSIONS: Baseline serum levels of hsCRP and BDNF predicted response to SSRIs in major depressive disorder, and Val/Val patients responded better when compared to patients carrying the Met allele.

Sex-Based Differences in Cardiac Gene Expression and Function in BDNF Val66Met Mice.

Brain-derived neurotrophic factor (BDNF) is a pleiotropic neuronal growth and survival factor that is indispensable in the brain, as well as in multiple other tissues and organs, including the cardiovascular system. In approximately 30% of the general population, BDNF harbors a nonsynonymous single nucleotide polymorphism that may be associated with cardiometabolic disorders, coronary artery disease, and Duchenne muscular dystrophy cardiomyopathy. We recently showed that transgenic mice with the human BDNF rs6265 polymorphism (Val66Met) exhibit altered cardiac function, and that cardiomyocytes isolated from these mice are also less contractile. To identify the underlying mechanisms involved, we compared cardiac function by echocardiography and performed deep sequencing of RNA extracted from whole hearts of all three genotypes (Val/Val, Val/Met, and Met/Met) of both male and female Val66Met mice. We found female-specific cardiac alterations in both heterozygous and homozygous carriers, including increased systolic (26.8%, p = 0.047) and diastolic diameters (14.9%, p = 0.022), increased systolic (57.9%, p = 0.039) and diastolic volumes (32.7%, p = 0.026), and increased stroke volume (25.9%, p = 0.033), with preserved ejection fraction and fractional shortening. Both males and females exhibited lower heart rates, but this change was more pronounced in female mice than in males. Consistent with phenotypic observations, the gene encoding SERCA2 (Atp2a2) was reduced in homozygous Met/Met mice but more profoundly in females compared to males. Enriched functions in females with the Met allele included cardiac hypertrophy in response to stress, with down-regulation of the gene encoding titin (Tcap) and upregulation of BNP (Nppb), in line with altered cardiac functional parameters. Homozygous male mice on the other hand exhibited an inflammatory profile characterized by interferon-γ (IFN-γ)-mediated Th1 immune responses. These results provide evidence for sex-based differences in how the BDNF polymorphism modifies cardiac physiology, including female-specific alterations of cardiac-specific transcripts and male-specific activation of inflammatory targets.

Association between the Val66Met polymorphism (rs6265/G196A) of the BDNF gene and cognitive performance with SSRI use in Arab Alzheimer's disease patients.

Brain derived neutrophic factor (BDNF) is a protein and a member of the neurotrophin family of growth factors, supports the survival of existing neurons and encourages the growth and differentiation of new neurons and synapses. The BDNF gene Val66Met polymorphism (rs6265/G196A) is responsible for BDNF synthesis that impact BDNF function that includes memory and cognition. This study investigated whether the BDNF gene Val66Met polymorphism (rs6265/G196A) is associated with cognitive function changes in both Alzheimer disease (AD) patients and elderly participants. In addition the impact of SSRI use on cognition improvement will be assessed. Healthy young, middle ages (25-59 years old) and elderly (more than 60 years old) participants (140) as well as 40 AD patients of whom are both of Saudi Arabian origin were recruited. The genotyping for the association study was performed by real-time PCR using Taqman chemistry in the ABI Prism 7900HT Sequence Detection System. Both Mini-Mental Status Examination (MMSE) and Clinical Dementia Rating (CDR) were used to assess cognitive function of healthy and AD participants, respectively. The findings showed that the BDNF Val66Met genotype distributions and allele frequencies have significant association with cognitive performance in both elderly control group and AD patients. The main findings showed that carriers of GG homozygotes (Val/Val) have superior cognitive performance among AD patients and elderly control subjects. In addition the use of SSRIs in 13 AD patients and 17 elderly participants positively improved cognitive function in elderly (p > 0.001) but not in AD patients (p = 0.1).

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 with reduction of total BDNF and BDNF1, BDNF4 and BDNF6 transcripts in the hypothalamus of BDNFMet/Met mice. In contrast, 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.

BDNF and Cortisol integrative system - Plasticity vs. degeneration: Implications of the Val66Met polymorphism.

BDNF is the neurotrophin mediating pro-neuronal survival and plasticity. Cortisol (COR), in turn, is engaged in the coordination of several processes in the brain homeostasis. Stress-responsive, both factors show an integrative role through their receptor's dynamics in neurophysiology. Furthermore, the Val66Met BDNF polymorphism may play a role in this mechanism. AIM: to investigate BDNF-COR interaction in the human neurophysiology context. METHODS: We collected all papers containing BDNF and COR parameters or showing COR analyses in genotyped individuals in a PubMed search - full description available on PROSPERO - CRD42016050206. DISCUSSION: BDNF and COR perform distinct roles in the physiology of the brain whose systems are integrated by glucocorticoid receptors dynamics. The BDNF polymorphism appears to have an influence on individual COR responsivity to stress. BDNF and COR play complementary roles in the nervous system where COR is a regulator of positive/negative effects. Exercise positively regulates both factors, regardless of BDNF polymorphism.

The role of BDNF methylation and Val66 Met in amygdala reactivity during emotion processing.

Epigenetic alterations of the brain-derived neurotrophic factor (BDNF) gene have been associated with psychiatric disorders in humans and with differences in amygdala BDNF mRNA levels in rodents. This human study aimed to investigate the relationship between the functional BDNF-Val66 Met polymorphism, its surrounding DNA methylation in BDNF exon IX, amygdala reactivity to emotional faces, and personality traits. Healthy controls (HC, n = 189) underwent functional MRI during an emotional face-matching task. Harm avoidance, novelty seeking and reward dependence were measured using the Tridimensional Personality Questionnaire (TPQ). Individual BDNF methylation profiles were ascertained and associated with several BDNF single nucleotide polymorphisms surrounding the BDNF-Val66 Met, amygdala reactivity, novelty seeking and harm avoidance. Higher BDNF methylation was associated with higher amygdala reactivity (x = 34, y = 0, z = -26, t(166) = 3.00, TFCE = 42.39, p(FWE) = .045), whereby the BDNF-Val66 Met genotype per se did not show any significant association with brain function. Furthermore, novelty seeking was negatively associated with BDNF methylation (r = -.19, p = .015) and amygdala reactivity (r = -.17, p = .028), while harm avoidance showed a trend for a positive association with BDNF methylation (r = .14, p = .066). The study provides first insights into the relationship among BDNF methylation, BDNF genotype, amygdala reactivity and personality traits in humans, highlighting the multidimensional relations among genetics, epigenetics, and neuronal functions. The present study suggests a possible involvement of epigenetic BDNF modifications in psychiatric disorders and related brain functions, whereby high BDNF methylation might reduce BDNF mRNA expression and upregulate amygdala reactivity.

Kynurenine pathway is altered in BDNF Val66Met knock-in mice: Effect of physical exercise.

The Brain-Derived Neurotrophic Factor (BDNF) Val66Met polymorphism has been correlated with increased predisposition to develop cognitive and psychiatric disorders, and with a reduced response to some therapeutic treatments. However, the mechanisms underlying these impairments are currently not completely understood. Remarkably, kynurenine pathway alterations have also been implicated in cognitive and psychiatric disorders. Moreover, recent evidence suggests that physical exercise may promote beneficial effects by controlling kynurenine metabolism in the muscle. The aim of the present study was to assess whether the kynurenine pathway was differentially regulated in sedentary and exercising wild-type (BDNFVal/Val) and homozygous knock-in BDNF Val66Met (BDNFMet/Met) mice. We found that plasma and hippocampal levels of kynurenic acid and the hippocampal mRNA levels of IDO1 and KAT2 protein levels were increased in BDNFMet/Met mice and were not modulated by physical exercise. On the contrary, KAT1 protein levels in the gastrocnemius muscle were reduced, whereas MCP1 mRNA in the gastrocnemius muscle and GFAP protein in the hippocampus were increased in BDNFMet/Met mice compared to BDNFVal/Val mice, and reduced by physical exercise. Physical exercise increased plasmatic kynurenine levels only in BDNFMet/Met mice, and protein levels of KAT1 and KAT4 in the gastrocnemius muscle and hippocampus respectively, regardless of the genotype. Finally, we found that physical exercise was able to enhance the hippocampal-dependent memory only in the BDNFVal/Val mice. Overall our results showing an overactivation of the kynurenine pathway in the BDNFMet/Met mice may suggest a possible mechanism underlying the cognitive deficits reported in the BDNF Val66Met carriers.

Association between BDNF Polymorphism and Hypothalamic-Pituitary-Adrenal Activity in Later Adulthood.

Stress exposure over the lifespan is robustly associated with accelerated cognitive decline in later life. Brain-derived neurotrophic factor (BDNF) is shown to regulate activity of the hypothalamic-pituitary-adrenal axis. The objective of this study was to evaluate the association betweenthe BDNF polymorphism and indices of stress among adults aged 50+. Community-dwelling middle-aged and older adults provided a blood sample for BDNF genotyping. Participants also sampled their saliva 5 times/day for 3 consecutive days for the measurement of diurnal cortisol and underwent the Trier Social Stress Test (TSST) for the measurement of stress reactivity. Among 121 adults aged 50-67 years (78% female; 89% Caucasian), 74 participants were Val/Val carriers and 47 carried 1 copy of the Met allele. Repeated-measures analyses did not reveal an association between BDNF genotype and diurnal salivary cortisol (p = 0.63); however, analyses revealed that Met+ carriers displayed lower levels of cortisol secretion in response to the TSST compared with Val/Val carriers; F(4.43, 496.238) = 2.57, p = 0.032. This is the first study to evaluate the role of the BDNF polymorphism in stress physiology among older adults. Future studies are needed to evaluate the lifespan interconnections between BDNF and stress physiology.

The BDNF rs6265 Polymorphism is a Modifier of Cardiomyocyte Contractility and Dilated Cardiomyopathy.

Brain-derived neurotrophic factor (BDNF) is a neuronal growth and survival factor that harbors cardioprotective qualities that may attenuate dilated cardiomyopathy. In ~30% of the population, BDNF has a common, nonsynonymous single nucleotide polymorphism rs6265 (Val66Met), which might be correlated with increased risk of cardiovascular events. We previously showed that BDNF correlates with better cardiac function in Duchenne muscular dystrophy (DMD) patients. However, the effect of the Val66Met polymorphism on cardiac function has not been determined. The goal of the current study was to determine the effects of rs6265 on BDNF biomarker suitability and DMD cardiac functions more generally. We assessed cardiovascular and skeletal muscle function in human DMD patients segregated by polymorphic allele. We also compared echocardiographic, electrophysiologic, and cardiomyocyte contractility in C57/BL-6 wild-type mice with rs6265 polymorphism and in mdx/mTR (mDMD) mouse model of DMD. In human DMD patients, plasma BDNF levels had a positive correlation with left ventricular function, opposite to that seen in rs6265 carriers. There was also a substantial decrease in skeletal muscle function in carriers compared to the Val homozygotes. Surprisingly, the opposite was true when cardiac function of DMD carriers and non-carriers were compared. On the other hand, Val66Met wild-type mice had only subtle functional differences at baseline but significantly decreased cardiomyocyte contractility. Our results indicate that the Val66Met polymorphism alters myocyte contractility, conferring worse skeletal muscle function but better cardiac function in DMD patients. Moreover, these results suggest a mechanism for the relative preservation of cardiac tissues compared to skeletal muscle in DMD patients and underscores the complexity of BDNF signaling in response to mechanical workload.

Genetics of stroke recovery: BDNF val66met polymorphism in stroke recovery and its interaction with aging.

Stroke leads to long term sensory, motor and cognitive impairments. Most patients experience some degree of spontaneous recovery which is mostly incomplete and varying greatly among individuals. The variation in recovery outcomes has been attributed to numerous factors including lesion size, corticospinal tract integrity, age, gender and race. It is well accepted that genetics play a crucial role in stroke incidence and accumulating evidence suggests that it is also a significant determinant in recovery. Among the number of genes and variations implicated in stroke recovery the val66met single nucleotide polymorphism (SNP) in the BDNF gene influences post-stroke plasticity in the most significant ways. Val66met is the most well characterized BDNF SNP and is common (40-50 % in Asian and 25-32% in Caucasian populations) in humans. It reduces activity-dependent BDNF release, dampens cortical plasticity and is implicated in numerous diseases. Earlier studies on the effects of val66met on stroke outcome and recovery presented primarily a maladaptive role. Novel findings however indicate a much more intricate interaction between val66met and stroke recovery which appears to be influenced by lesion location, post-stroke stage and age. This review will focus on the role of BDNF and val66met SNP in relation to stroke recovery and try to identify potential pathophysiologic mechanisms involved. The effects of age on val66met associated alterations in plasticity and potential consequences in terms of stroke are also discussed.