A common polymorphism on the oxytocin receptor gene (rs2268498) and resting-state functional connectivity of amygdala subregions - A genetic imaging study
Introduction
In the past decades the neuropeptide oxytocin has been shown to be involved in human and animal affiliative and social approach behavior as well as emotional and socio-cognitive processing (Meyer-Lindenberg et al., 2011; Insel and Young, 2001). A wide range of pharmacological studies has demonstrated rather consistent effects of intranasal oxytocin administration on prosocial behavior such as enhanced positive communication behavior during couple conflict (Ditzen et al., 2009), generosity (Zak et al., 2007), trust and cooperation (Kosfeld et al., 2005) as well as the perception of trustworthiness and attractiveness (Theodoridou et al., 2009). Newer evidence, however, suggests that oxytocin effects might rely stronger on contextual factors than previously thought (Declerck et al., 2014; Nave et al., 2015).
In contrast to pharmacological studies, molecular genetic approaches focus on individual differences in the genetic makeup underlying certain phenotypic features or behavior, i.e. dispositional differences that are not caused by pharmacological manipulations. The oxytocin receptor (OXTR) gene has been repeatedly associated with social cognition and behavior (e.g. Kumsta and Heinrichs, 2013; Rodrigues et al., 2009; Skuse et al., 2014). The OXTR gene is located at 3p25–3p26.2 and consists of approximately 17 kb containing three intronic and four exonic regions (Gimpl and Fahrenholz, 2001). Especially one single nucleotide polymorphism (SNP) has been repeatedly linked to social processing and functioning: the rs2268498 T/C polymorphism, presumably located in the promoter region of the OXTR gene. Functional relevance of this SNP has been recently demonstrated by mRNA expression analysis in brain tissue as well as by in vitro reporter gene expression analysis (Reuter et al., 2017), suggesting a two-fold increase in mRNA expression in carriers of the C-variant. On the behavioral level, variants of the rs2268498 polymorphism have been associated with emotion recognition (Melchers et al., 2013), social perception abilities (Melchers et al., 2015), attention to detail in social contexts (Melchers et al., 2017), empathic concern (Christ et al., 2015) and moral decision making (Walter et al., 2012). A recent study demonstrated that the TT genotype is also associated with lowest autistic traits in healthy individuals (Montag et al., 2017). Throughout these literatures, carriers of the low-expression T-variant showed better task performance as well as self-report ratings that suggest higher empathic skills (Melchers et al., 2015). On the neural level, increased activity in the inferior occipital gyrus, a brain region considered important for face processing, has been reported among OXTR TT-carriers when confronted with fearful faces (O'Connell et al., 2012). Altogether, previous research indicates that rs2268498 seems to be intriguingly involved in social cognitive processes and behavior, and links the T-allele to more prosocial phenotypic outcomes.
The present study seeks to investigate effects of genetic variation of the rs2268498 on intrinsic brain activity. The examination of the brain's intrinsic activity in the so called resting-state, a state not characterized by a behavioral task protocol where subjects are lying still and not thinking of anything in particular, proofs a very promising research avenue (Raichle, 2011; van den Heuvel and Hulshoff Pol, 2010; Raichle and Snyder, 2007). Resting-state functional connectivity, i.e. the statistical dependency of the BOLD-time courses of two brain regions, a supposed proxy for ongoing neuronal communication taking place regularly, could serve as one of many neuronal endophenotypes that bridge the gap between genetic variation and phenotypic behavior (Biswal et al., 1995; Gottesmann and Gould, 2003). Here, evidence on differences in functional coupling of the human brain depending on the genetic properties of the oxytocin system is scarce and thus the aim of the present study is to investigate this matter.
Pharmacological studies investigating oxytocin effects on the neural level have defined the amygdala as major key neural target (Wigton et al., 2015). The amygdala is a region commonly known for its implication in emotional processing and the evaluation of biologically relevant signals from the environment as well as for the initiation of behavioral reactions (LeDoux and Phelps, 2008; Sander et al., 2003; Pape, 2010). There is also a whole body of evidence suggesting that amygdala functioning and oxytocinergic signaling are densely entwined (Boccia et al., 2013; Domes et al., 2007; Kirsch et al., 2005; Riem et al., 2012; Gao et al., 2016). First, oxytocin receptors are widely expressed throughout the human amygdala (Gimpl and Fahrenholz, 2002; Bethlehem et al., 2017). Second, neuroimaging studies employing intranasally administered oxytocin provide evidence for its modulatory effects on amygdala activity as well as its functional connectivity to other brain regions in task based designs such as the presentation of emotional facial expressions (Domes et al., 2007), the experience of pain (Singer et al., 2008), socially-facilitated learning (Hu et al., 2015), social threat stimuli (Kirsch et al., 2005), threatening stimuli and infant laughter (Riem et al., 2012).
The human amygdala is not a homogenous structure, but rather consists of three structurally and functionally distinguishable subregions: the basolateral, centromedial and superficial amygdala (Sah et al., 2003; LeDoux, 2007; Engman et al., 2016; Roy et al., 2009; Ball et al., 2007; Li et al., 2012; Brown et al., 2014). Nuclei in the basolateral amygdala receive afferent input from the thalamus, hippocampus, and cortical areas, and their functional role in Pavlovian and contextual fear conditioning has been extensively characterized (LeDoux, 2003). Nuclei in the centromedial amygdala receive afferent input from the basolateral amygdala and interface with motor systems on the efferent side. The centromedial amygdala plays a pivotal role in generating behavioral and autonomic responses in fear conditioning through connections to the brainstem, the basal ganglia, and the cortex (LeDoux, 2003). In contrast to the basolateral and centromedial amygdala, the superficial amygdala has not been as extensively functionally characterized. Given its cytoarchitectonic similarity with the olfactory cortex, the superficial amygdala has been implicated in olfactory processing, a view corroborated by a meta-analysis of human functional imaging studies (Bzdok et al., 2013). In addition to olfaction, the superficial amygdala seems to play a broader role in affective processing as well (Bzdok et al., 2013). Roy et al. (2009) have shown distinct patterns of intrinsic resting-state connectivity of different amygdala subregions. Previous intranasal oxytocin administration studies revealed subregion specific effects on task-induced amygdala activity (Gamer et al., 2011) as well as on the intrinsic connectivity of the amygdala (Eckstein et al., 2017), with differential effects of oxytocin on the functional connectivity of the superficial amygdala with prefrontal und parietal up-stream cortical nodes as well as basolateral and centromedial amygdala functional connectivity with cerebellar down-stream regions being reported.
In the present study, whole brain seed-based functional connectivity analyses were used to determine whether amygdala functional connectivity varies as a function of OXTR rs2268498 genotypes. Due to the need to segregate between amygdala subregions, basolateral, centromedial and superficial amygdalae were used as separate seed regions in the functional connectivity analyses. Based on previous pharmacological functional connectivity studies, we expected genetic associations with amygdala connectivity to occipital and temporal regions with implications for face processing (Domes et al., 2007: Riem et al., 2012: Eckstein et al., 2017), up-stream regions implicated in the salience network (Riem et al., 2012: Hu et al., 2015: Eckstein et al., 2017), and the brain stem (Kirsch et al., 2005; Domes et al., 2007).
Section snippets
Participants
Resting-state fMRI data were collected from N = 143 healthy participants (n = 52 males, n = 91 females, mean age M = 25.6, SD = 8.8), who took part in the Bonn Gene Brain Behavior Project (BGBBP). Informed written consent was provided by every subject prior to scanning. The study protocol was approved by the ethics committee of the university clinic Bonn.
Genotyping
DNA was extracted either from buccal (Schonlau et al., 2010) or blood cells. Purification of genomic DNA was conducted by means of MagNa Pure®
Results
The genotype frequencies for the OXTR rs2268498 polymorphism were as follows: CC n = 23, TC n = 75 and TT n = 45 resulting in the two allelic groups derived from existing literature (Reuter et al., 2017), namely C-allele carriers with n = 98 and TT-carriers with n = 45 participants. Genotype frequencies were in Hardy-Weinberg Equilibrium (χ2(1) = 0.79, p = 0.37). No significant differences in age (t(103.43) = 1.05, p = 0.297), head motion (t(141) = −0.89, p = 0.375) and the distribution of sex (
Discussion
The present study investigated individual differences in functional resting-state connectivity of different amygdala nuclei depending on different genotypes of the functionally relevant OXTR rs2268498 polymorphism. Results show differential connectivity of left basolateral, centromedial and superficial amygdala to fusiform and occipital gyri as well as differential connectivity of the right centromedial amygdala to brainstem regions, orbitofrontal cortex, insula and putamen between TT-carriers
Conclusion
In the present study we identified differential functional connectivity between amygdala subregions and brain regions involved in social and emotional processing depending on the genotypes of the rs2268498 on the OXTR gene. The present findings lay a foundation for future studies that may aim at the connection between genetic makeup, functional connectivity, and normal as well as pathological social cognition and behavior.
Acknowledgement
The position of CM is funded by Heisenberg-grant awarded by the German Research Foundation (DFG, MO 2363/3-2).
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2022, Neuroscience and Biobehavioral ReviewsCitation Excerpt :In terms of MRI resting state functional connectivity, the A allele was associated with a decrease between the posterior cingulate cortex and a set of other brain regions, extending from the right fronto-insular cortex to subcortical structures (such as the putamen, the globus pallidus and the bilateral dorsal ACC) (Wang et al., 2017), but an increase between all three amygdalar sub-nuclei and the visual processing areas. Interestingly, A allele was associated with reduced coupling of the centromedial amygdala with higher-order cognitive processing regions, such as the frontal cortex (Zimmermann et al., 2018). In another study, that allele was also associated with reduced DMN connectivity, which in turn has been associated with avoidant symptoms in early childhood and anxiety disorders in later childhood (Zeev-Wolf et al., 2020).
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2022, Journal of Affective DisordersCitation Excerpt :These seed regions are overlapped with the Julich histological atlas (Amunts et al., 2005). Considering that the centromedial-superficial (CSA) was divided into superficial (SF) and centromedial (CM) amygdala in previous studies (Yang et al., 2021; Zimmermann et al., 2018), the SF and CM amygdala were also regarded as seed regions for dFC analysis in this study. The results are detailed in the Supplementary Fig. S1.
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2020, Neuroscience and Biobehavioral ReviewsCitation Excerpt :Moreover, it is of importance to also test the effect of such a SNP in laboratory-based studies going beyond self-report. In line with the above mentioned finding the TT-variant of rs2268498 has also been associated with better performance in an emotion recognition task (Melchers et al., 2013), social perception/implicit learning (Melchers et al., 2015, 2017), and functional connectivity of amygdala subnuclei (Zimmermann et al., 2018). We suggest that only by testing a genetic variant with a multi-method mix, the effects of a genetic variant on human behavior can be best characterized and understood.