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

ABSTRACT: 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.

SUBMITTER: Redlich R

PROVIDER: S-EPMC7268057 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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The role of BDNF methylation and Val<sup>66</sup> Met in amygdala reactivity during emotion processing.

Redlich Ronny R Schneider Ilona I Kerkenberg Nicole N Opel Nils N Bauhaus Jonas J Enneking Verena V Repple Jonathan J Leehr Elisabeth J EJ Grotegerd Dominik D Kähler Claas C Förster Katharina K Dohm Katharina K Meinert Susanne S Hahn Tim T Kugel Harald H Schwarte Kathrin K Schettler Christiane C Domschke Katharina K Arolt Volker V Heindel Walter W Baune Bernhard T BT Zhang Weiqi W Hohoff Christa C Dannlowski Udo U

Human brain mapping 20191015 3

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-Val<sup>66</sup> 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 emotion ...[more]

PMID: 31617281

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Project description:Cognitive control represents an essential neuropsychological characteristic that allows for the rapid adaption of a changing environment by constant re-allocation of cognitive resources. This finely tuned mechanism is impaired in psychiatric disorders such as schizophrenia and contributes to cognitive deficits. Neuroimaging has highlighted the contribution of the anterior cingulate cortex (ACC) and prefrontal regions (PFC) on cognitive control and demonstrated the impact of genetic variation, as well as genetic liability for schizophrenia. In this study, we aimed to examine the influence of the functional single-nucleotide polymorphism (SNP) rs6265 of a plasticity-related neurotrophic factor gene, BDNF (Val66Met), on cognitive control. Strong evidence implicates BDNF Val66Met in neural plasticity in humans. Furthermore, several studies suggest that although the variant is not convincingly associated with schizophrenia risk, it seems to be a modifier of the clinical presentation and course of the disease. In order to clarify the underlying mechanisms using functional magnetic resonance imaging (fMRI), we studied the effects of this SNP on ACC and PFC activation, and the connectivity between these regions in a discovery sample of 85 healthy individuals and sought to replicate this effect in an independent sample of 253 individuals. Additionally, we tested the identified imaging phenotype in relation to schizophrenia familial risk in a sample of 58 unaffected first-degree relatives of schizophrenia patients. We found a significant increase in interregional connectivity between ACC and PFC in the risk-associated BDNF 66Met allele carriers. Furthermore, we replicated this effect in an independent sample and demonstrated its independence of structural confounds, as well as task specificity. A similar coupling increase was detectable in individuals with increased familial risk for schizophrenia. Our results show that a key neural circuit for cognitive control is influenced by a plasticity-related genetic variant, which may render this circuit particular susceptible to genetic and environmental risk factors for schizophrenia.

Project description:BackgroundThe brain-derived neurotrophic factor (BDNF) protein plays a prominent role in the capacity for neuroplastic change. However, a single nucleotide polymorphism at codon 66 of the BDNF gene results in significant reductions in neuroplastic change. Potentially, this polymorphism also contributes to the weaker somatosensory cortical activity that has been extensively reported in the neuroimaging literature on cerebral palsy (CP).AimsThe primary objective of this study was to use magnetoencephalography (MEG) to probe if BDNF genotype affects the strength of the somatosensory-evoked cortical activity seen within individuals with CP.Methods and proceduresand Procedures: Twenty individuals with CP and eighteen neurotypical controls participated. Standardized low resolution brain electromagnetic tomography (sLORETA) was used to image the somatosensory cortical activity evoked by stimulation of the tibial nerve. BDNF genotypes were determined from saliva samples.Outcomes and resultsThe somatosensory cortical activity was weaker in individuals with CP compared to healthy controls (P = 0.04). The individuals with a Val66Met or Met66Met BDNF polymorphism also showed a reduced response compared to the individuals without the polymorphism (P = 0.03), had higher GMFCS levels (P = 0.04), and decreased walking velocity (P = 0.05).Conclusions and implicationsThese results convey that BDNF genotype influences the strength of the somatosensory activity and mobility in individuals with CP.What this paper addsPrevious literature has extensively documented altered sensorimotor cortical activity in individuals with CP, which ultimately contributes to the clinical deficits in sensorimotor processing documented in this population. While some individuals with CP see vast improvements in their sensorimotor functioning following therapeutic intervention, others are clear non-responders. The underlying basis for this discrepancy is not well understood. Our study is the first to identify that a polymorphism at the gene that codes for brain derived neurotrophic factor (BDNF), a protein well-known to be involved in the capacity for neuroplastic change, may influence the altered sensorimotor cortical activity within this population. Potentially, individuals with CP that have a polymorphism at the BDNF gene may reflect those that have difficulties in achieving beneficial outcomes following intervention. Thus, these individuals may require different therapeutic approaches in order to stimulate neuroplastic change and get similar benefits from therapy as their neurotypical peers.

Project description:BackgroundCommon genetic variants, such as the brain-derived neurotrophic factor (BDNF) Val/66/Met polymorphism (rs6265), are known to interact with environmental factors such as early adversity to increase the risk of subsequent major depression. Much less is known about how they interact with individual differences in cortisol, although these also represent a risk for major depression.AimsTo determine whether this BDNF variant moderated the risk represented by higher levels of morning salivary cortisol in adult women.MethodWe recruited 279 premenopausal women who were at high risk of major depressive disorder because of either negative self-evaluation, unsupportive core relationship or chronic subclinical symptoms of depression or anxiety. Morning salivary cortisol was measured daily for up to 10 days at entry. Participants were followed up for about 12 months by telephone calls at 3-4 monthly intervals. Major depression and severe life events were assessed through interviews at baseline and follow-up; DNA was obtained from the saliva.ResultsThere were 53 onsets (19%) of depressive episodes during follow-up. There was a significant U-shaped relationship between adjusted morning cortisol levels at baseline and the probability of depression onset during follow-up. In total, 51% experienced at least one severe life event/difficulty, and this strongly predicted subsequent onsets of depressive episodes. The BDNF Val/66/Met genotype was not directly associated with onsets of depression or with cortisol levels, but there was significant interaction between Val/66/Met and cortisol: the association between baseline cortisol and depression was limited to those with the Val/66/Val variant. There was no interaction between life events and either this BDNF polymorphism or cortisol levels.ConclusionsMorning salivary cortisol interacts with the BDNF Val/66/Met polymorphism in predicting new depressive episodes. This paper adds to the evidence that single gene polymorphisms interact with endogenous factors to predict depression.

Project description:Preclinical evidence suggests that the actions of ovarian steroid hormones and brain-derived neurotrophic factor (BDNF) are highly convergent on brain function. Studies in humanized mice document an interaction between estrus cycle-related changes in estradiol secretion and BDNF Val66Met genotype on measures of hippocampal function and anxiety-like behavior. We believe our multimodal imaging data provide the first demonstration in women that the effects of the BDNF Val/Met polymorphism on hippocampal function are selectively modulated by estradiol. In a 6-month pharmacological hormone manipulation protocol, healthy, regularly menstruating, asymptomatic women completed positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) scans while performing the n-back working memory task during three hormone conditions: ovarian suppression induced by the gonadotropin-releasing hormone agonist, leuprolide acetate; leuprolide plus estradiol; and leuprolide plus progesterone. For each of the three hormone conditions, a discovery data set was obtained with oxygen-15 water regional cerebral blood flow PET in 39 healthy women genotyped for BDNF Val66Met, and a confirmatory data set was obtained with fMRI in 27 women. Our results, in close agreement across the two imaging platforms, demonstrate an ovarian hormone-by-BDNF interaction on working memory-related hippocampal function (PET: F2,37=9.11, P=0.00026 uncorrected, P=0.05, familywise error corrected with small volume correction; fMRI: F2,25=5.43, P=0.01, uncorrected) that reflects differential hippocampal recruitment in Met carriers but only in the presence of estradiol. These findings have clinical relevance for understanding the neurobiological basis of individual differences in the cognitive and behavioral effects of ovarian steroids in women, and may provide a neurogenetic framework for understanding neuropsychiatric disorders related to reproductive hormones as well as illnesses with sex differences in disease expression and course.

Project description:ObjectiveEmotion dysregulation has been suggested to be a potent risk factor for multiple psychiatric conditions. Altered amygdala-prefrontal cortex (PFC) connectivity has been consistently linked to emotion dysregulation. Recent data indicate that amygdala-PFC functional connectivity undergoes a prolonged period of development, with amygdala reactivity during early childhood potentially shaping this unfolding process. Little is known about the relationships between amygdala-PFC functional connectivity, amygdala reactivity, and emotion regulation during early childhood. This information is likely critical for understanding early emotion dysregulation as a transdiagnostic risk factor for psychopathology. The current study examined the relationships between amygdala functional connectivity, amygdala reactivity, and emotion regulation in preschoolers.MethodA total of 66 medication-naive 4- to 6-year-olds participated in a study where resting-state functional magnetic resonance imaging (rs-fMRI) and parent-reported child emotion regulation ability data were collected. fMRI data collected during a face viewing task was also available for 24 children.ResultsRight amygdala-medial PFC (mPFC) functional connectivity was positively associated with child emotion regulation ability and negatively associated with child negative affect and right amygdala reactivity to facial expressions of emotion. Right amygdala-mPFC functional connectivity also statistically mediated the relationship between heightened right amygdala reactivity and elevated child negative affect.ConclusionStudy findings suggest that amygdala-mPFC functional connectivity during early childhood, and its relationships with amygdala reactivity and emotion regulation during this highly sensitive developmental period, may play an important role in early emotional development. These results inform the neurodevelopmental biology of emotion regulation and its potential relationship with risk for psychopathology.

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

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The role of BDNF methylation and Val<sup>66</sup> Met in amygdala reactivity during emotion processing.

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