Abstract
The molecular and neural mechanisms regulating human social-emotional behaviors are fundamentally important but largely unknown; unraveling these requires a genetic systems neuroscience analysis of human models. Williams Syndrome (WS), a condition caused by deletion of ∼28 genes, is associated with a gregarious personality, strong drive to approach strangers, difficult peer interactions, and attraction to music. WS provides a unique opportunity to identify endogenous human gene-behavior mechanisms. Social neuropeptides including oxytocin (OT) and arginine vasopressin (AVP) regulate reproductive and social behaviors in mammals, and we reasoned that these might mediate the features of WS. Here we established blood levels of OT and AVP in WS and controls at baseline, and at multiple timepoints following a positive emotional intervention (music), and a negative physical stressor (cold). We also related these levels to standardized indices of social behavior. Results revealed significantly higher median levels of OT in WS versus controls at baseline, with a less marked increase in AVP. Further, in WS, OT and AVP increased in response to music and to cold, with greater variability and an amplified peak release compared to controls. In WS, baseline OT but not AVP, was correlated positively with approach, but negatively with adaptive social behaviors. These results indicate that WS deleted genes perturb hypothalamic-pituitary release not only of OT but also of AVP, implicating more complex neuropeptide circuitry for WS features and providing evidence for their roles in endogenous regulation of human social behavior. The data suggest a possible biological basis for amygdalar involvement, for increased anxiety, and for the paradox of increased approach but poor social relationships in WS. They also offer insight for translating genetic and neuroendocrine knowledge into treatments for disorders of social behavior.
Highlights
Social and emotional responses are so fundamental to human behavior that they are often taken for granted
The current study was approved by the Institutional Review Board at Cedars-Sinai Medical Center (CSMC) (IRB Protocol No 2476), written consent was obtained from participants or their parents/legally authorized representatives and studies were conducted at the CSMC General Clinical Research Center (GCRC)
Basal OT and arginine vasopressin (AVP) were positively skewed when expressed as raw data, but were approximately symmetric when shown on a logarithmic scale (Fig. 2)
Summary
Social and emotional responses are so fundamental to human behavior that they are often taken for granted. The genetic and neurobiological bases of social behavior are largely unknown as are the mechanisms for disruptions in social behavior and emotional regulation that appear throughout the lifespan as features of mental illnesses. These include autism spectrum disorder (ASD), schizophrenia, general social anxiety disorder, post-traumatic stress disorder and depression. Converging evidence from humans and other mammals suggests that social and emotional behaviors may be regulated by shared neuroendocrine and mesolimbic circuitry [1,2,3], closing the gaps between genetic variation and its effect on neuroendocrine and neural functions and between these and behavior requires a multidisciplinary and multisystems approach that captures each of these levels. WS serves as a unique model for the cross-disciplinary study of human genebrain-behavior relationships
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