Moderator Effects of Life Stress on the Association between MAOA-uVNTR, Depression, and Burnout.

BACKGROUND: The serotonergic and noradrenergic systems have a strong impact on several affective disorders and are key targets for psychopharmacological therapy. With respect to pathogenesis, there is a growing body of evidence showing an influence of a promoter repeat polymorphism (MAOA-uVNTR) altering the expression rate of monoamine oxidase A. However, only a few studies investigate its influence on depression with only 2 of them considering the moderating effects of life stress. For burnout, there are no studies so far investigating the genetic basis. OBJECTIVES: The aim of the present study was to replicate an interaction effect of MAOA-uVNTR and life stress on depression, and extend these possible findings to the burnout syndrome. Especially, the latter one might help in understanding the underlying mechanisms of burnout and its association to depression. METHOD: A total of n = 1,541 participants (n = 1,099 healthy controls, n = 442 inpatients with affective disorders) provided genetic samples and filled in self-report questionnaires measuring depression, burnout, and the extent of experienced stressful life events (SLEs). RESULTS: A life stress x MAOA-uVNTR interaction on depression and burnout was observed in women suggesting that carriers of the high expressing allele (MAO-H) with many SLEs had the highest scores in both burnout and depression. In men, there was only a weak effect of MAOA-uVNTR on depression. CONCLUSIONS: The results suggest a more pronounced reactivity to adverse environmental factors in carriers of the MAO-H allele. Especially the effect of life stress and MAOA-uVNTR on burnout should be independently replicated in the future as this is the first study showing this association.

A Deletion Variant of the α2b-Adrenoceptor Modulates the Stress-Induced Shift from "Cognitive" to "Habit" Memory.

Stress induces a shift from hippocampus-based "cognitive" toward dorsal striatum-based "habitual" learning and memory. This shift is thought to have important implications for stress-related psychopathologies, including post-traumatic stress disorder (PTSD). However, there is large individual variability in the stress-induced bias toward habit memory, and the factors underlying this variability are completely unknown. Here we hypothesized that a functional deletion variant of the gene encoding the α2b-adrenoceptor (ADRA2B), which has been linked to emotional memory processes and increased PTSD risk, modulates the stress-induced shift from cognitive toward habit memory. In two independent experimental studies, healthy humans were genotyped for the ADRA2B deletion variant. After a stress or control manipulation, participants completed a dual-solution learning task while electroencephalographic (Study I) or fMRI measurements (Study II) were taken. Carriers compared with noncarriers of the ADRA2B deletion variant exhibited a significantly reduced bias toward habit memory after stress. fMRI results indicated that, whereas noncarriers of the ADRA2B deletion variant showed increased functional connectivity between amygdala and putamen after stress, this increase in connectivity was absent in carriers of the deletion variant, who instead showed overall enhanced connectivity between amygdala and entorhinal cortex. Our results indicate that a common genetic variation of the noradrenergic system modulates the impact of stress on the balance between cognitive and habitual memory systems, most likely via altered amygdala orchestration of these systems.SIGNIFICANCE STATEMENT Stressful events have a powerful effect on human learning and memory. Specifically, accumulating evidence suggests that stress favors more rigid dorsal striatum-dependent habit memory, at the expense of flexible hippocampus-dependent cognitive memory. Although this shift may have important implications for understanding mental disorders, such as post-traumatic stress disorder, little is known about the source of individual differences in the sensitivity for the stress-induced bias toward habit memory. We report here that a common genetic variation of the noradrenergic system, a known risk factor for post-traumatic stress disorder, modulates the stress-induced shift from cognitive to habit memory, most likely through altered crosstalk between the hippocampus and dorsal striatum with the amygdala, a key structure in emotional memory.

A common polymorphism on the oxytocin receptor gene (rs2268498) and resting-state functional connectivity of amygdala subregions - A genetic imaging study.

Across species, the neuropeptide oxytocin has been associated with affiliative and social approach behavior. It has been suggested to exert its effects by modulating neural circuitry underlying anxiety, affiliative motivation, and social salience. The present study aims to investigate differences in subregional amygdala resting-state connectivity in healthy adult carriers of different genotypes of the oxytocin receptor (OXTR) gene polymorphism rs2268498. Previous studies have associated this polymorphic locus with social cognitive and affiliative phenotypes. The amygdala qualifies as a reasonable target due to its broad implication in emotional and social cognitive processing as well as its key role in mediating the behavioral effects of oxytocin. Whole brain seed-based functional connectivity analyses for the basolateral, centromedial and superficial amygdala revealed stronger resting-state connectivity of all amygdala subregions to the fusiform and inferior occipital gyrus in TT-carriers compared to C-allele carriers. Additional modulations were found for the centromedial amygdala which showed stronger resting-state connectivity to inferior frontal regions and the insula in C-allele carriers and to brainstem regions in TT-carriers. Our findings not only show the importance of oxytocin functioning in amygdalar neuronal signaling but also emphasize the need to investigate the amygdalar subregions individually instead of the amygdala as a whole. In summary, the present study is the first to characterize the impact of genetic variation of the OXTR gene with known functional consequences on widespread changes in a functional brain network originating from the amygdala.

The impact of acute stress on cognitive functioning: a matter of cognitive demands?

INTRODUCTION: There is a controversy in the literature whether stress and related cortisol responses are beneficial or impairing for cognitive functioning. Conflicting results might be due to individual differences in stress reactivity and cognitive load of the applied tasks. METHODS: N = 48 participants underwent the Socially Evaluated Cold Pressor Test and were confronted with the Frankfurter Aufmerksamkeits-Inventar-2 (FAIR-2) which is a low-load attention task and two subscales of the Intelligenz-Struktur-Test 2000 R (I-S-T 2000R) as a high-load reasoning task before and after the stressor. Participants were post hoc divided into high (stress induced cortisol increase of ≥1.5 nmol/l) vs. low-cortisol responders. RESULTS: Cortisol responders showed an increased attentional performance in the post-stress condition (η2 > .14). However, there were neither stress or responder main effects nor an interaction effect on reasoning abilities. CONCLUSIONS: Results of the present study show that stress related changes in cognitive performance are due to individual differences in cortisol response and the cognitive load of the performed task. Future studies will show if these results are also valid for alternative cognitive tasks and if they can be replicated in female participants.

The serotonin transporter polymorphism (5-HTTLPR) and personality: response style as a new endophenotype for anxiety.

Although the serotonin transporter length polymorphic region (5-HTTLPR) polymorphism is an extensively-investigated genetic marker of anxiety related personality traits (neuroticism and harm avoidance) and affective disorders, effect sizes in meta-analyses are small, if present at all, and all available primary studies to date lack mandatory statistical power. Moreover, questionnaire data is prone to confounding by variables such as social desirability. Therefore, extreme response style (ERS) is suggested as a new approach to elucidate the relationship between 5-HTTLPR and negative emotionality, as it is more implicit and of high reliability. N = 1075 healthy subjects were genotyped for 5-HTTLPR and a flanking polymorphism (rs25531) and filled out the NEO Five Factor Inventory and the Temperament Character Inventory. As dependent variable the number of extreme responses across all items was calculated. Using the common genotype or the triallelic approach (including rs25531) the meta-analytic findings could not be replicated. However, there was a significant association between 5-HTTLPR and extreme response style. Carriers of the L-allele or the L'-allele, respectively, had a significantly higher number of extreme responses than homozygous SS carriers across all items of the NEO Five Factor Inventory. This finding could be replicated in an alternative personality questionnaire (Affective Neuroscience Personality Scales, ANPS). There is a long tradition in psychological assessment indicating that ERS is an implicit measure of personality. Given the positive findings of the present study, ERS qualifies as a promising endophenotype in future genetic association studies on personality and affective disorders.

Ignorance is no excuse: moral judgments are influenced by a genetic variation on the oxytocin receptor gene.

Perspective-taking has become a main focus of studies on moral judgments. Recent fMRI studies have demonstrated that individual differences in brain activation predict moral decision making. In particular, pharmacological studies highlighted the crucial role for the neuropeptide oxytocin in social behavior and emotional perception. In the present study N=154 participants were genotyped for a functional polymorphism (rs2268498) in the promoter region of the OXTR gene. We found a significant difference between carriers and non-carriers of the C-allele in exculpating agents for accidental harms (F((1,152))=11.49, p=.001, η(2)=.07) indicating that carriers of the C-allele rated accidentally committed harm as significantly more blameworthy than non-carriers. This is the first study providing evidence for a genetic contribution to moral judgments.

Genetic and epigenetic serotonergic markers predict the ability to recognize mental states.

The serotonergic (5-HT) system is related to affective and cognitive processes and explains behavioral variability in the normal and psychopathological range. For this reason, the hypothesis was put forward that genetic and epigenetic markers related to 5-HT metabolism predict individual differences in social cognitive functioning. Social cognitions are complex mental processes necessary for perceiving, interpreting and reacting to the behaviors of others. In order to test this hypothesis one of the most prominent theory of mind tasks, the reading the mind in the eye test (RMET), was administered to N = 435 participants and measures of performance were related to the functional MAO-A VNTR polymorphism (relevant for 5-HT catabolism) and to epigenetic markers in the promoter of the TPH-2 gene (relevant for 5-HT synthesis). It was postulated that genetic and epigenetic markers of high 5-HT activity are positively related to RMET performance. Results show that the MAO-A high activity allele, together with the degree of methylation at a promoter CpG site on the TPH-2 gene explain significant proportions of variance in the RMET performance even after controlling for age and sex effects. Present findings yield evidence for the importance of 5-HT for social cognition. Based on additional findings, the role of a TRP-rich diet for theory of mind functions is discussed.

Blood oxytocin levels are not associated with ADHD tendencies and emotionality in healthy adults.

Oxytocin (OT) regulates social and emotional behaviour. Core symptoms of attention-deficit/hyperactivity disorder (ADHD) include social and emotional dysfunctions potentially associated with lower endogenous OT levels. A dimensional approach was employed to examine relationships between plasma OT levels, ADHD tendencies, and emotionality in a healthy adult sample. Moreover, we aimed at replication of results regarding ADHD tendencies and emotionality from our previous work. Subjects were N = 110 healthy Chinese males (Mage: 22.01 ± 2.02 years). Variables of interest were plasma OT levels, individual variations in ADHD tendencies assessed via the Adult ADHD Self-Report Scale Symptom Checklist (ASRS), and positive and negative emotionality assessed via primary emotional traits of the Affective Neuroscience Personality Scales (ANPS). Hypotheses were tested by means of (partial) Spearman and Pearson correlations. Plasma OT levels were neither related to ADHD tendencies, nor to primary emotional traits. ADHD tendencies were significantly related to higher negative emotionality (correlation coefficients: r= .35 to r = .47) and lower positive emotionality (correlation coefficients: r= -.42 to r = -.36). The absence of associations between plasma OT levels and ADHD tendencies, primary emotional traits, and emotionality might be explained by the lack of robust associations between peripheral and central OT levels. Results regarding ADHD tendencies and emotionality replicate previous findings, emphasizing that (sub-clinically) elevated ADHD tendencies associate with dysregulated emotionality. Future studies examining the role of endogenous OT in ADHD should explore the generalizability of the present findings to women and patients with ADHD.

An endocannabinoid receptor polymorphism modulates affective processing under stress.

Stress has a critical impact on affective and cognitive processing. Based on rodent data suggesting that endocannabinoid signaling via CB1 receptors serves as an emotional buffer, we hypothesized that a common variant of the gene coding for the CB1 receptor modulates affective processing under stress (CNR1; rs1049353 A vs G allele). Therefore, 139 participants, genotyped for this polymorphism, underwent a stress or control manipulation before they viewed emotionally neutral and negative pictures in a magnetic resonance imaging scanner. The ventromedial prefrontal cortex, known for its crucial role in emotion regulation, was significantly more activated in AA/AG vs GG genotype carriers when viewing negative pictures after stress. Under no-stress conditions, AA/AG genotype carriers showed enhanced crosstalk between the ventrolateral prefrontal cortex and the amygdala. We further assessed participants' 24 h-delayed memory for the presented pictures and found that memory performance correlated with amygdala and hippocampus activity and connectivity in stressed carriers of the AA/AG but not the GG genotype. These findings underline the modulatory role of the endocannabinoid system in stress effects on emotion and cognition and provide insights into the neural mechanisms that may contribute to the suggested protective effect of the AA/AG genotype of the CB1 receptor polymorphism against stress-related psychopathologies.

The role of genetic variation in the glucocorticoid receptor (NR3C1) and mineralocorticoid receptor (NR3C2) in the association between cortisol response and cognition under acute stress.

Although HPA - axis reactivity has repeatedly been related to cognitive functioning, ambiguity remains regarding the direction of the effect, i.e. whether it benefits or impairs functioning. Genetic factors that contribute to HPA - axis reactivity on the one hand and to cognitive functioning on the other could therefore help clarify the association between stress and cognition. We genotyped 10 single nucleotide polymorphisms (SNPs) on the NR3C1 gene (rs10482682, rs33389, rs10482633, rs10515522, rs2963156, rs4128428, rs9324918, rs41423247, rs6189, rs10052957) coding for the glucocorticoid receptor (GR) and 4 SNPs on the NR3C2 gene (rs6810951, rs4635799, rs11099695, rs2070950) coding for the mineralocorticoid receptor (MR) and required N=126 healthy males to perform tasks assessing attention and reasoning before and after experiencing an acute laboratory stressor (the Socially Evaluated Cold Pressor Test, SECPT). Haplotype analyses revealed significant effects of NR3C1 (p=0.011) and NR3C2 (p=0.034) on cortisol stress response. NR3C2 also influenced attentional performance via an interaction with stress-induced cortisol response (p<0.001). Neither NR3C1 haplotype nor NR3C2 haplotype was associated with reasoning abilities. Results suggest that the association between stress induced cortisol reactivity and cognition strongly depends on genetic variation. The idea of an optimal arousal level depending on stress reactivity and genetic disposition is discussed.

A Haplotype Associated with Enhanced Mineralocorticoid Receptor Expression Facilitates the Stress-Induced Shift from "Cognitive" to "Habit" Learning.

Stress induces a shift from hippocampus-dependent "cognitive" toward dorsal striatum-dependent "habit" memory. However, not all individuals are susceptible to this shift under stress. Based on pharmacological studies indicating a critical role of the mineralocorticoid receptor (MR) in the stress-induced bias toward dorsal striatal learning, we hypothesized that MR gene variants contribute to these individual differences. In two experiments, healthy participants were genotyped, exposed to a stressor or control manipulation and performed a learning task that can be solved using hippocampal or dorsal striatal systems, while electroencephalography (EEG; Experiment I) or functional magnetic resonance imaging (fMRI; Experiment II) measurements were taken. Stress led to a shift from hippocampal to dorsal striatal learning which was more pronounced in homo- and heterozygous carriers of a six single nucleotide polymorphisms (SNPs)-comprising haplotype containing the alleles of two MR SNPs associated with increased MR expression and transactivational activity (MR-2G/C C [rs2070951], MR-I180V A [rs5522]). This stress-induced shift toward habit memory was paralleled by an increased feedback-related negativity (FRN), which may reflect striatal processing, and increased caudate activation. Carriers of the MR haplotype showed a reduced P3a, an event-related potential thought to indicate cognitive processing, and reduced hippocampal activity after stress. Moreover, stress resulted in reduced amygdala-hippocampus connectivity and the decrease in amygdala connectivity to the parahippocampal cortex was particularly pronounced in MR haplotype carriers. Our findings indicate that genetic variants associated with enhanced MR expression facilitate a stress-induced shift from hippocampal toward dorsal striatal learning, most likely via impaired hippocampal processing and reduced amygdala-hippocampus cross talk, allowing the dorsal striatum to guide behavior under stress.

Functional characterization of an oxytocin receptor gene variant (rs2268498) previously associated with social cognition by expression analysis in vitro and in human brain biopsy.

The oxytocin system plays a prominent role in social behavior across species, and numerous genetic studies in humans have reported associations between polymorphisms on the oxytocin receptor (OXTR) gene and phenotypes related to social cognition, affiliation, perspective taking, and sociability in healthy subjects and in patients with atypical social behavior, such as in autism spectrum disorders (ASD). Recently, the first study demonstrating altered agonist-induced OXTR internalization and recycling for the exonic variant rs35062132 emerged. Beside this, there has been no further demonstration of the functionality of the OXTR variants especially there does not exist any for the regulatory units. To address this gap in the literature, we tested the functionality of the promoter flanking single nucleotide polymorphism (SNP) rs2268498, which has proven an interesting candidate for predicting social behavior in recent association studies. Results of genetic expression analyses in human hippocampal tissue showed a twofold difference in messenger RNA transcription, dependent on the presence or absence of the C-allele. This finding was corroborated by cloning, i.e., in vitro reporter gene expression analysis after transfection of OXTR promoter plasmids into HEK-293 cells. Our results underline the importance of OXTR rs2268498 for genetic research in social behavior and ASD.

The oxytocin receptor gene and social perception.

Social perception is an important prerequisite for successful social interaction, because it helps to gain information about behaviors, thoughts, and feelings of interaction partners. Previous pharmacological studies have emphasized the relevance of the oxytocin system for social perception abilities, while knowledge on genetic contributions is still scarce. In the endeavor to fill this gap in the literature, the current study searches for associations between participants' social perception abilities as measured by the interpersonal perception task (IPT) and the rs2268498 polymorphism on the OXTR-gene, which has repeatedly been linked to processes relevant to social functioning. N = 105 healthy participants were experimentally tested with the IPT and genotyped for the rs2268498 polymorphism. T-allele carriers (TT and TC genotypes) exhibited significantly better performance in the IPT than carriers of the CC-genotype. This difference was also significant for the subscales measuring the strength of social bonding (kinship and intimacy). As in previous studies, T-allele carriers exhibited better performance in measures of social processing indicating that the rs2268498 polymorphism is an important candidate for understanding the genetic basis of social functioning.

The role of the BDNF Val66Met polymorphism in individual differences in long-term memory capacity.

The protein brain-derived neurotrophic factor (BDNF) plays an important role in diverse memory processes and is strongly expressed in the hippocampus. The hippocampus itself is a key structure involved in the processing of information from short-term to long-term memory. Due to the putative role of BDNF in memory consolidation, a prominent single nucleotide polymorphism (SNP) on the BDNF gene (BDNF Val66Met) was investigated in the context of long-term memory performance. N=138 students were presented with 40 words from 10 categories, each consisting of eight words such as 'fruits' or 'vehicles' in a memory recognition task (specifically the Deese-Roediger-McDermott Paradigm). Recognition performance was analyzed 25 min after the initial presentation of the word list and subsequently 1 week after the initial presentation. Overall, individual long-term memory performance immediately after learning the word list (T1) and performance 1 week later (T2) did not differ on the basis of the BDNF SNP, but an interaction effect of BDNF Val66Met by time-of-recall was found: Carriers of the Met66+ variant showed the strongest decline in hit rate performance over time.

The DRD2 C957T polymorphism and the attentional blink--a genetic association study.

The attentional blink phenomenon (AB) describes a transient deficit in temporally selective visual attention regarding the processing of the second of two target stimuli in a rapid serial visual presentation (RSVP) task. The AB is a very prominent paradigm in the Cognitive Neurosciences that has been extensively studied by diverse psychophysiological techniques such as EEG or fMRI. Association studies from molecular genetics are scarce although the high heritability of higher cognitive functioning is proven. Only one seminal study reported an association between AB magnitude and the dopamine receptor D2 (DRD2) C957T polymorphism (Colzato et al., 2011). This functional polymorphism influences striatal D2 receptor binding affinity and thereby the efficacy of dopaminergic neurotransmission which is important for working memory and attentional processes. Colzato et al. (2011) reported that DRD2 C957T T/T-carriers exhibit a significant smaller AB than C-allele carriers. In the present study this influence of the DRD2 SNP on the AB could not be replicated in N=211 healthy participants. However, a significantly larger lag 1 sparing was observed for homozygous T/T-carriers. Moreover, carriers of at least one T-allele showed a significantly poorer performance in the identification of T1. In general, these results support the notion of a role of the dopaminergic system on the AB. However, as our results do not parallel previous findings the exact nature of this influence and its dependence on task parameters will have to be examined in further genetic association studies.

The influence of dopaminergic gene variants on decision making in the ultimatum game.

One of the most prominent paradigms in neuroeconomics is the ultimatum game (UG) that provides a framework for the study of pro-social behavior in two players interacting anonymously with each other: Player 1 has to split an endowment with player 2. Player 2 can either accept or reject the offer from player 1. If player 2 accepts the offer then the money is split as proposed by player 1. In case of rejection both players get nothing. Until now only one twin study investigated the heritability of the behavior in the UG. Results indicated a strong heritability for the decision behavior of player 2 whereas no genetic influence on player 1 behavior could be detected. Further studies are mandatory to validate these heritability estimates. However, a first candidate polymorphism, the DRD4 exon III, constituting the biological basis of the heritability in the responder behavior has already been identified in a Chinese sample (Zhong et al., 2010). Until now genetic studies in Caucasians on the UG are lacking. The present study wants to fill this gap by investigating the UG in a healthy German sample. Moreover, we intend to find candidate genes that are associated with the first-mover-behavior. In a sample of N = 130 healthy participants an online version of the UG was conducted and polymorphisms of the dopamine D2 receptor gene (DRD2) and the DRD4 exon III VNTR were genotyped. We could confirm the DRD4 exon III effect on the responder behavior and the absence of an effect on the proposer behavior reported before. In line with Zhong et al. (2010) carriers of the 4/4 genotype showed a significant higher minimal acceptable offer (p = 0.023) than subjects with any other genotype. Furthermore, a DRD2-haplotype-block containing the single nucleotide polymorphisms rs1800497 and rs2283265 was significantly associated with the amount player1 offered (p = 0.005) but not with the decision of player 2. Results support the importance of the dopaminergic system for pro-social behavior.

Does excessive play of violent first-person-shooter-video-games dampen brain activity in response to emotional stimuli?

The present case-control study investigated the processing of emotional pictures in excessive first-person-shooter-video-players and control persons. All participants of the fMRI experiment were confronted with pictures from four categories including pleasant, unpleasant, neutral content and pictures from the first-person-shooter-video-game 'Counterstrike'. Compared to controls, gamers showed a significantly lower activation of the left lateral medial frontal lobe while processing negative emotions. Another interesting finding of the study represents the higher activation of frontal and temporal brain areas in gamers when processing screen-shots from the first-person-shooter-video-game 'Counterstrike'. Higher brain activity in the lateral prefrontal cortex could represent a protection mechanism against experiencing negative emotions by down-regulating limbic brain activity. Due to a frequent confrontation with violent scenes, the first-person-shooter-video-gamers might have habituated to the effects of unpleasant stimuli resulting in lower brain activation. Individual differences in brain activations of the contrast Counterstrike>neutral pictures potentially resemble the activation of action-scripts related to the video-game.

Genetically determined dopamine availability predicts disposition for depression.

Although prominent personality theories postulate orthogonality between traits of positive emotionality (PEM) and negative emotionality (NEM), empirical evidence often demonstrates the opposite indicating a negative relationship. Therefore, it is not surprising that dopaminergic (DA) gene loci have been related to traits of positive and of NEM. The present genetic association study investigates the influence of two functional DA gene polymorphisms on Sadness as defined by the Affective Neuroscience Personality Scales (ANPS) in healthy Caucasians (n = 1041). We observed a significant interaction effect between the 10-repeat (10R) allele of the dopamine transporter (DAT1) gene and the methionine (Met) allele of the catechol-O-methyltransferase (COMT) Val158Met polymorphism (F((1,1018)) = 11.11; P < 0.001). Carriers of the 9R/9R and the Val/Val genotype showed dramatically reduced Sadness scores in comparison to the other three genotype configurations. Both the 9R/9R and the Val/Val genotypes characterized by reduced transporter density and high dopamine catabolism, respectively, have been separately related to personality traits of PEM and externalizing behavior in the past. The present findings indicate that gene variations of the DA system previously associated with PEM are at the same time protective against high NEM and can therefore constitute a resilience factor against depression.