Andrea Felten

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.

Intrinsic connectivity networks and personality: The temperament dimension harm avoidance moderates functional connectivity in the resting brain

Recent functional imaging studies that examined functional connectivity in the resting brain have demonstrated various intrinsic connectivity networks (ICNs). Certain patterns of over- and underactivity in various ICNs have been hypothesized to form the neural basis of psychiatric disorders. Furthermore, activity in the ICNs does not reflect ongoing mental activity but the maintenance of neural circuits in a ready state suggesting not only relationships between ICNs and disorders but also correlations between ICNs and personality. In the present study, we assess the relationship between trait anxiety, a well established endophenotype of anxiety disorders, and functional connectivities within the insular salience ICN in a sample of healthy female subjects. Based on a previous study that demonstrated the functional relevance of the insular salience ICN for state anxiety, we used the harm avoidance scale from the Temperament and Character Inventory (TCI) as a trait marker to demonstrate increased functional connectivity within the insular salience ICN. Specifically, the functional connectivity between the anterior insula and the anterior cingulate and between the anterior insula and the dorsolateral prefrontal cortex were positively correlated with individual harm avoidance scores. The results fit into previous work, provide evidence for a potential biomarker of anxiety disorders and, most importantly, demonstrate a direct neural correlate of the personality trait harm avoidance in the absence of external stimulation.

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.

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.

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.

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

ABSTRACT 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.

Oxytocin, trust, and trustworthiness: The moderating role of music.

Evidence has indicated that the neuroactive hormone oxytocin is essential for prosocial behavior, particularly trust. Exogenous administration of oxytocin has been shown to increase trust in humans. However, one may argue that, except the administration of oxytocin in nonhealthy patient groups (e.g., those with autism or anxiety disorders) to alleviate negative symptoms, external administration of oxytocin has little relevance in normal life. Music, a ubiquitous stimulus in human society, has been shown to increase oxytocin in medical therapy scenarios. Considering this evidence, we conducted a trust game experiment with a sample of healthy humans and investigated music’s effects on the (a) trustor’s oxytocin levels (blood sample measurement), (b) investment amount (trust behavior measurement), and (c) perception of the other player’s trustworthiness (self-report). The results of our exploratory study show that an increase in oxytocin levels over 40 trials in a trust game increased perceived trustworthiness in the no-music condition but had no impact on investment amount (i.e., trust behavior). Moreover, music had no effect on oxytocin, trust behavior, or perceived trustworthiness. Thus, unlike prior research showing that music listening may increase self-reported trust in another individual, in the present study we found no effect of music on trust (on either a physiological or behavioral level). We surmise that this finding is a result of both the type of music played during task execution and music preferences. Thus, future research must carefully manipulate music features (e.g., pitch, rhythm, timbre, tempo, meter, contour, loudness, and spatial location) and consider a listener’s music preferences to better understand music’s effects on physiological, perceived, and behavioral trust.

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

ABSTRACT 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.

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

&NA; 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. HighlightsWe present a genetic imaging study on the oxytocin system.Variation on the oxytocin receptor gene modulates amygdala functional connectivity.OXTR rs2268498 is a polymorphism which is known to affect receptor expression.Connectivity of amygdala subregions is differentially modulated by genotype.Target areas include face processing areas, the salience network, and the brain stem.