Oxytocin receptor and G-protein polymorphisms in patients with depression and separation anxiety

BACKGROUND: The impact of combined variants of Oxytocin Receptor (OXTR) and G protein β3 subunit genes was investigated in relation to retrospective reports of childhood as well as contemporary adult separation anxiety (SA), based on evidence of a β/γ dimer-mediated signaling for OXTR. METHODS: A case-control association study (225 healthy adults and 188 outpatients with depression) was performed to establish Risk-Combined Genotype (RCG) of the studied variants (OXTR rs53576 and the functional Gβ3 subunit rs5443). Current SA was evaluated by the ASA-27 and retrospective childhood symptoms by the SASI. GG genotype of OXTR rs53576 combined with T-carrier genotype of Gβ3 rs5443 represented the RCG. RESULTS: Compared to non-RCG, those with RCG had significantly higher levels of childhood and adult SA. The RCG was significantly associated with childhood SA threshold score (OR=2.85, 90%CI: 1.08-7.50). Childhood SA was, in turn, strongly associated with a threshold SA score in adulthood (OR=15.58; 95% CI: 4.62-52.59). LIMITATIONS: Although the overall sample size is sizable, comparisons among subgroups with specific combination of alleles are based on relatively small numbers. CONCLUSIONS: Our study indicates that variations in OXTR and Gβ3 genes are specifically associated with presence and severity of SA in childhood and adulthood, but not with depression or anxiety in general. Because there is increasing interest in oxytocin in social behavior, the gene-SA associations identified have potential translational and clinical relevance

Leaders-cheaters in male group cooperation: differences in nonverbal communication and genetic factors

Here we report on the results of an experimental study investigating "who?" emerges as a leader in the context of male group cooperation and "how?" they do that. The study was designed based on the iterated Public Goods Game, played face-to-face in groups composed of four male strangers. The game involved interactions both with and without communication to allow the assessment of individual cooperative strategies, leadership potential, and individual features of positive nonverbal expressiveness during interactions. Along with the individual behavioural characteristics we have addressed personality traits (the Big Five) and an oxytocin receptor gene polymorphism (OXTR: SNP rs53576; A/G) as putative markers of individual sociability. Our results revealed that emergent leaders most often employed the strategy of unconditional cooperation ("altruism") and were characterized by enhanced positive facial expressiveness and extraversion compared to non-leaders. However, a fraction of emergent leaders (25%) turned out to be occasional free-riders ("cheaters"). Their distinctive features were the highest scores on extraversion, exaggerated activity in negotiations, and over-expression of positive nonverbal elements. Given the high efficiency of leaders-cheaters' behaviour, we consider this result as the evidence for supernormal stimuli functioning in humans. Moreover, leaders-cheaters were characterized by a specific allelic frequency of OXTR rs53576 (heterozygosity: AG). The homozygous GG variant of this SNP is argued to be associated with prosociality, and the AA, on the contrary, with poor sociability. The heterozygous variant (AG) probably is a compromise that enables its carriers to successfully combine high social skills with anti-social behavior (free-riding). This finding supports existing evidence on the role of OXTR rs53576 in human social behaviour

Association between the oxytocin receptor (OXTR) gene and mesolimbic responses to rewards

Abstract Background There has been significant progress in identifying genes that confer risk for autism spectrum disorders (ASDs). However, the heterogeneity of symptom presentation in ASDs impedes the detection of ASD risk genes. One approach to understanding genetic influences on ASD symptom expression is to evaluate relations between variants of ASD candidate genes and neural endophenotypes in unaffected samples. Allelic variations in the oxytocin receptor (OXTR) gene confer small but significant risk for ASDs for which the underlying mechanisms may involve associations between variability in oxytocin signaling pathways and neural response to rewards. The purpose of this preliminary study was to investigate the influence of allelic variability in the OXTR gene on neural responses to monetary rewards in healthy adults using functional magnetic resonance imaging (fMRI). Methods The moderating effects of three single nucleotide polymorphisms (SNPs) (rs1042778, rs2268493 and rs237887) of the OXTR gene on mesolimbic responses to rewards were evaluated using a monetary incentive delay fMRI task. Results T homozygotes of the rs2268493 SNP demonstrated relatively decreased activation in mesolimbic reward circuitry (including the nucleus accumbens, amygdala, insula, thalamus and prefrontal cortical regions) during the anticipation of rewards but not during the outcome phase of the task. Allelic variation of the rs1042778 and rs237887 SNPs did not moderate mesolimbic activation during either reward anticipation or outcomes. Conclusions This preliminary study suggests that the OXTR SNP rs2268493, which has been previously identified as an ASD risk gene, moderates mesolimbic responses during reward anticipation. Given previous findings of decreased mesolimbic activation during reward anticipation in ASD, the present results suggest that OXTR may confer ASD risk via influences on the neural systems that support reward anticipation

Geenid ja alkoholitarvitamine: levinud geenipolümorfismide mõju rahvastikus

Väitekirja elektrooniline versioon ei sisalda publikatsioone.Alkoholi kuritarvitamine on üks peamistest ennetatavate surmade ja terviserikete põhjustajatest. Lähtuvalt sellest, kui palju probleeme tekib tarvitajale endale ja teda ümbritsevatele, on alkohol loetud kõige kahjulikumaks uimastiks1. Kuigi olukord on tasapisi paranemas, paistab Eesti rahvusvahelisel tasandil veel jätkuvalt silma ohtra alkoholitarbimisega2. Mehed tarvitavad alkoholi ning kogevad alkoholiga seotud probleeme enamasti rohkem kui naised. Nii ka meie rahvastikupõhises pikaajalises sünnikohortide uuringus – poisid alustasid alkoholi tarvitamisega varem ning tegelesid sellega sagedamini kui tüdrukud. Nooreks täiskasvanueaks oli selle tulemusena meeste seas tunduvalt rohkem neid, kes alkoholi kuritarvitamisega hädas. Alkoholiprobleemide kogemise tõenäosust tõstsid ka stressirikkad elusündmused ning halvad suhted pereliikmete ja õpetajatega. Kuna alkoholism on krooniline ja ravile raskesti alluv, on selle haiguse tekkimist ennustavate bioloogiliste näitajate uurimine äärmiselt päevakajaline. Analüüsides geenide mõju alkoholitarbimisele, leidsime, et probleemset alkoholitarbimist ennustasid just sellised geneetilised eripärad, mis olid seotud madalama stressitaluvuse ja suurema avatusega keskkondlike mõjude suhtes. Seosed ei olnud aga üleüldised ja sõltusid suures osas sünnikohordist – perioodist, mil inimene sündinud oli. Sotsiaalsed normid ja hoiakud alkoholi tarbimisse koonduvad sünnikohortide kaupa ning mõjutavad otseselt uimastite tarvitamist. 1990. aastatel alguse saanud kiired ühiskondlikud muutused mõjutavad meie siirdeühiskonnas väärtushinnanguid, vaba aja tegevusi, suhteid ja igapäevast toimetulekut. Kultuurilised ja ühiskondlikud muutused vormivad pidevalt inimeste identiteeti ja elustiili ning võivad vahendada ka geeniefekte alkoholitarbimisele. [1 Nutt DJ, King LA, Phillips LD (2010) Drug harms in the UK: a multicriteria decision analysis. Lancet 376:1558-1565. 2 OECD (2015) Tackling harmful alcohol use: Economics and public health policy. OECD Publishing.]Problematic use of alcohol is one of the leading causes of preventable deaths and disability. Based on the harm to the user and others, alcohol has been considered to be the most harmful drug1. Men generally drink more alcohol and have more alcohol-related problems than women. Also in our population-representative longitudinal birth cohort study in Estonia, the boys started consuming alcohol earlier and were more frequent alcohol consumers than girls. By young adulthood, there were significantly more men than women diagnosed with alcohol use disorder. The more frequent was the alcohol consumption during the teenage years, the more problable was the occurrence of alcohol problems by young adulthood. In addition, the more stressful life events, the worse relationships with family members and with teachers the children experienced, the higher was the likelihood of developing alcohol use problems later on in life. The chronic nature of alcoholism is the reason why the search for predictive biomarkers is so urgent. When we analyzed the effects of common genetic variances on alcohol use and abuse, the genotypes associated with higher levels of stress reactivity and openness to environmental influences were the ones also linked to problematic alcohol use. However, the relations were not universal and strongly depended on birth cohort – the time period when one was born. Social norms and attitudes regarding alcohol use cluster in birth cohorts, and this clustering has a direct effect on drug use. The rapid socioeconomic changes that have taken place in Estonia since the beginning of 1990s and are still ongoing affect the values, activities, relationships, leisure time choices and everyday functioning of the people living in this transition society. Cultural transformation processes continuously shape the identities and lifestyles of individuals, and can also moderate the genetic effects on alcohol consumption. [1 Nutt DJ, King LA, Phillips LD (2010) Drug harms in the UK: a multicriteria decision analysis. Lancet 376:1558-1565.

Implications from social and non-social task-based and task-free neuroimaging studies

Research on the effects of oxytocin on social cognition and behavior is constantly growing. Moreover, oxytocin is already discussed to be used as a drug supporting common therapies for a range of disorders displaying deficits in social cognition. Although, the knowledge about its neurophysiological mechanisms lacks in particular regarding its functioning in the non-social domain of behavior, cognition and related brain responses. Therefore, the present thesis had the aim to explore whether the neuropeptide oxytocin has an effect on non-social cognitive processes and their underlying neural correlates, how the neural mechanisms of oxytocin are modulated by additional social input and which basal changes are driven by the effects of oxytocin. I addressed these questions by the use of functional magnetic resonance imaging (fMRI) with task-based and resting-state designs and with a neuroimaging genetics approach. Oxytocin is synthesized in subnuclei of the hypothalamus and was originally known for its involvement in inducing labor. The oxytocin receptor is distributed largely across the brain, covering areas of the mesolimbic system such as the ventral striatum (vStr), the ventral tegmental area (VTA) and the amygdala, but also frontal areas and regions which are not prominently involved in social cognition. Generally, oxytocin is thought to affect social behavior and cognition, including parenting, affiliative behavior, but also emotion-regulation. It is also assumed to be sensitive for context, gender and personality characteristics. Whereas many studies explored the impact of oxytocin on socio-emotional actions such as on emotion-processing in the amygdala, only very few studies focused on the non-socioemotional domain, as for example memory processing or reward-related decision-making. With regard to the aims of this thesis, two of the three experiments employed a non-social decision making paradigm to reveal effects of oxytocin on non-social behavior and related brain activity. Indeed, oxytocin also modulated neural circuits during non-social tasks and even during the resting-state paradigm in the third experiment. This indicates that a social context might not be required to observe changes in neural activity and connectivity by oxytocin. Several theories have been proposed to explain the mechanisms by which oxytocin might function. The social cognition theory suggests that oxytocin might modulate prosocial affiliative behaviors and self-referential processing, the fear/stress approach emphasized its anxiolytic and stress reducing effects, the general approach-avoidance hypothesis of oxytocin assumes that oxytocin acts on approach and avoidance motivation and the social salience hypothesis implies that oxytocin regulates the salience of social stimuli. In conclusion, currently there is no general theory accounting for all the social and non-social effects of oxytocin as described in the literature. In the same perspective, the overall results from the current thesis contradict aspects of each theory, while specific patterns of effects may be best reconciliated with the framework of the approach-avoidance theory and the social salience hypothesis. In the first study a neuroimaging genetics approach was applied to investigate whether common variants of the oxytocin receptor gene influenced behavior and neural responses in a non-social reward-based decision-making paradigm. Specifically, due to dopaminergic-oxytocinergic interactions oxytocin-induced changes were expected in bottom-up reward-related and in top-down cognitive control-related activity. Two of the three candidate single-nucleotide-polymorphism (SNP) of the oxytocin receptor gene (OXTR) were associated with a modulation of reward-related activity during desire and reason situations in the paradigm used. The desire context was formed by allowing to obtain a presented reward, whereas in the reason context the same reward had to be rejected. Participants who were homozygous for the major allele of the OXTR SNP rs1042778 expressed more bottom-up related activity in the vStr in the desire context. In contrast to this, minor allele carriers showed a greater suppression of the reward-related activity in the reason context. This might have led to better cognitive control and therefore to significantly better performance in the rejection of reward stimuli in reason situations. According to this, major allele carriers had a stronger coupling between the vStr and the VTA in desire contexts. Moreover, minor allele carriers displayed an enhanced connectivity between the vStr and the anteroventral prefrontal cortex (avPFC) in reason situations. For the OXTR SNP rs237897 an interaction of gender with the activity in the VTA could be detected. Female participants, homozygous for the major genotype, presented more activation in the left VTA compared to males. Altogether, this study could show that OXTR polymorphisms are able to modulate reward-related as well as control-related activity even in a non-social decision-making paradigm. In study 2 a neuroimaging experiment was performed with the application of intranasal oxytocin and a modified reward-based decision-making paradigm including non-social as well as social stimuli. The main question was whether exogenous oxytocin alters behavioral and neural processes during the non-social condition in this task. Additionally, I was interested in possible changes of oxytocin effects by the presentation of emotional stimuli. Furthermore, by the additional use of both positive and fearful stimuli, I wanted to shed light on the ongoing discussion whether oxytocin acts valence-dependent or irrespective of valence on the activity of the amygdala. An opposite modulation of activity and functional connectivity regarding non-social compared with social context was shown after oxytocin treatment. In the non-social desire situation oxytocin reduced bottom-up activity within the vStr, probably by enhancing top-down control due to strengthening the negative coupling to a frontal region. In contrast, in non-social reason contexts the vStr was less deactivated, maybe due to decreased top-down control. By presenting fearful faces in the social condition, the pattern of neural responses and functional connectivity reversed. In this condition, oxytocin increased the activation in the vStr in desire situations, while it reduced the activation in reason situations. This change in activity was paralleled by stronger positive coupling in the desire context and less coupling as well as negative coupling in the reason context. Furthermore, depending on valence oxytocin decreased amygdala activation for fearful faces and increased amygdala activation for positive faces. The altered activity within the reward system by oxytocin might be the reason for an impaired performance during both desire and reason trials. After oxytocin treatment participants were less accurate in selecting target stimuli than in rejecting the reward stimulus and vice versa for the placebo. This suggests rather an impaired working memory than disturbed stimulus-association learning. To sum up, the comparison between the effects of oxytocin in the non-social and social condition yielded that oxytocin influences corticomesolimbic regions in a context-sensitive manner. The last study used a resting-state fMRI technique with additional administration of intranasal oxytocin. Of particular interest was the possible alteration of functional connectivity within and between large-scale networks by oxytocin. The analysis focused on functional networks indicated to play a major role in salience processing (the salience network - CO), social cognition and self-referential processing (the default mode network - DM) and attention processing (the ventral attentional network - VA). Thereby, basal changes by which oxytocin might influence neuronal responses were shown providing results for the ongoing debate on the underlying function of oxytocin. Although, I expected significant changes of functional connectivity within the DM network. The modulation of the CO and the VA networks were seen. Indeed, oxytocin changed the functional connectivity within and between large-scale networks even without engagement in a task. Oxytocin mainly influenced the VA by decreasing the cross-talk to regions typically part of the DM nodes; and oxytocin strengthened the functional connectivity to the edges of the CO, involving regions linked to salience processing. Additionally, oxytocin directly impacted the functional connectivity within the CO. Therefore, one basic effect of oxytocin might be to redirect attention (VA) from self-referential processing (DM) to the external environment, preparing for reception of salient information (CO). Taken together, the purpose of the present thesis was to extend the knowledge about the effects of oxytocin as well as basic mechanisms of oxytocin’s influence on cognition, behavior and neural activation and connectivity in non-social, social and task-free conditions. The results clearly demonstrated effects on neural activation, functional connectivity and on behavior in all three studies; supporting the claim that oxytocin does not only play an important role in socio-emotional processing