Final Report Summary - OXYGENE (Genetic predictors of brain responses underlying social behavior and implications for oxytocin treatment) Social interactions play a prominent part in the lives of human beings. Humans have developed complex systems of verbal and non-verbal communication exchange to interact with each other, thus defining a system of values, social norms and rituals, which are the basis of human society. Evidence shows that oxytocin (OXT) and dopamine (DA) can mediate social behavior in multiple mammal species (see for a review, Insel, 2010). In humans, intranasal administration of OXT affects numerous brain functions associated with social behavior. OXT enhances the ability to identify facial emotions (Guastella et al., 2008; Fischer-Shofty et al., 2010), promotes prosocial behavior (Kosfeld et al., 2005; Zak et al., 2007), and reduces aversion to negative social interaction (Baumgartner et al., 2008; Petrovic et al., 2008). DA has been shown to play a role in socio-affiliative behavior modulating reward systems and salience attribution (Wang et al., 1999; Gingrich et al., 2000; Silva et al., 2003). Mesolimbic DA via signaling through its receptor D2 can induce feelings of desire, wanting, enthusiasm, energy and self-efficacy, thereby modulating the appetitive phase of reward, which encourages approach in affiliative behaviors (Depue and Morrone- Strupinsky, 2005). Neuroanatomically, OXT and D2 pathways modulate activity in the brain regions, including amygdala, basal ganglia and medial prefrontal cortex, where their receptors are highly expressed (Kirsch et al., 2005; Gibbs et al., 2007; Baumgartner et al., 2008; Blasi et al., 2009). Importantly, disturbances in both OXT and D2 systems have been associated with high heritable severe psychiatric conditions, including autism spectrum disorders (ASD) and schizophrenia, two diseases that are characterized by critical impairments in social behavior. Preclinical studies have shown that DA and OXT cross-talk at different levels. DA modulates the number and the function of OXT receptors (Jarrett et al., 2006), and in so doing it affects anxiety and sexual behavior (Lindvall et al., 1984; Bale et al., 2001). OXT activates maternal behavior through stimulation of DA-innervated areas (Pedersen et al., 1994). Evidence from animal studies suggests also the interaction of these two systems at the level of pair-bonding (Young, 1999; Liu and Wang, 2003), and male sexual behavior (Melis et al., 2006). Among several candidates, genes in the neurotransmitter pathways underlying complex social behavior have been proposed to play a role in mediating heritability. Indeed, genetic variation in D2 receptor gene (DRD2) predicts amygdala activity and connectivity in response to facial emotional stimuli and emotional control (Blasi et al., 2009). Genetic variants of OXT receptors (OXTR) have been implicated in social behavioral domains including empathy (Rodrigues et al., 2009), attachment (Costa et al., 2009), and positive affect (Lucht et al., 2009), and predict amygdala reactivity to emotional stimuli (Tost et al., 2010). Although this evidence strongly support that DA and OXT systems may interact to regulate social-affiliative behaviors, to which extent this interaction affects social behavior and the mechanism underlying this phenomenon in humans is yet to be determined. Moreover, the role of DRD2 genetic variants in social behavior and in response to OXT remains to be clarified.The goal of this study was to tease out direct effects genetic variants of D2 pathway and its interaction with OXT pathway on brain structure, function and social behavior. The objectives of this proposal were to characterize the impact of two components on social behavior: 1) D2 and 2) OXT signaling. We wanted test our central hypothesis that polymorphisms of D2 modulate social behavior.First, we showed the neural effects of genetic variation of D2 signaling. Second, we identified the brain circuits involved in social behavior in normal controls using probing the cognitive control of emotional regulation and in patients with prominent alterations of social behavior.The grantee carried out the first aim of the project and performed the preliminary work for the second and the third aims. This research was then halted for the resignation following a change of job.First, we have characterized the neural effects of a functional genetic polymorphism of dopamine D2 receptor gene (rs1076560, G->T) on the default mode network (DMN), a network implicated in social function, and striatal connectivity and on their relationship with striatal D2 signaling. In this study we used underwent functional magnetic resonance imaging and Single Photon Emission Computed Tomography to measure dopamine transporter [DAT] binding. Our results show that DRD2 rs1076560 modulates DMN connectivity in medial prefrontal cortex as well as in the posterior cingulate and these changes are associated with DAT binding which is an indirect measure of D2 receptors. Additionally, rs1076560 genotype predicted connectivity differences within a striatal network, and these changes were correlated with connectivity in MPFC and posterior cingulate within the DMN. These results suggest that genetically determined D2 receptor signaling is associated with DMN connectivity that is an important network for social cognition and behavior.Second, we designed the functional tasks and identified the brain regions associated with social behavior that could be modulated by oxytocin treatment. To examine the brain activity associated with social and cognitive task we also designed, piloted and administered a battery of tasks to probe the brain circuits involved in social cognition. This battery included an implicit and explicit facial emotional task, a resting state scan along with an associative memory task. In particular, we identified the neural networks associated with the cognitive control of emotional regulation that play an important role in social behavior. We found an association between the salience network, the default mode network and the executive networks with specific features of attention. Furthermore, to characterize the brain regions of interest for social interaction, we carried out a structural and functional meta-analysis of the neural correlates of altered social and emotional function in a psychiatric disorder with prominent alterations of these functions that is the borderline personality disorder (Visintin et al., under review). Notably, genetic variation of the receptor for oxytocin (Hammen et al., 2014) and reduced levels of the this endogenous hormone (Bertsch et al., 2013) have been associated with this disorder. Also, its exogenous administration have been shown to reduce social behavior impairments in this disorder (Simeon et al., 2011; Bartz et al., 2011; Bertsch et al., 2013; Brüne et al., 2013; Ebert et al., 2013). In these patients, we found increased activity in right temporal lobe, amygdala, and insula along with decreased activity in the anterior cingulate cortex that is a brain region spanning across attentional networks (see above) involved in emotional regulation.The identification of the neural effects of genetic variation within the dopaminergic D2 signaling on the brain system underlying affective cognition could open new avenues of treatment for the psychiatric disorders with altered social function. In particular, given the role of D2 signaling on the effects of antipsychotic drugs, the results of this study could also contribute to ascertain how the effects of D2 blockade translate at the level of brain systems. The identification of effective treatments for psychiatric disorders with impaired social cognition has a remarkable repercussion on social and economic aspects of the European and Third Country community given that these chronic and disabling disorders altogether are among the foremost contributors to the global burden of disease.