Associations between oxytocin receptor gene (OXTR) methylation, plasma oxytocin, and attachment across adulthood.

The neuropeptide oxytocin (OT) has been implicated in a wide range of affiliative processes. OT exerts its functions via OT receptors, which are encoded by the oxytocin receptor gene (OXTR). Epigenetic modification of OXTR through the process of DNA methylation has been associated with individual differences in behavioral phenotypes. Specifically, lower levels of OXTR methylation have been linked to better social and affective functioning. However, research on epigenetic mechanisms of OXTR is scarce in non-clinical populations, and even less is known about epigenetic variability across adulthood. The present study assessed methylation levels at OXTR CpG site -934 and plasma OT levels in 22 young (20-31 years, M = 23.6) and 34 older (63-80 years, M = 71.4) participants. Lower levels of OXTR methylation and higher plasma OT levels were associated with less self-reported attachment anxiety in young but not older participants, with largely independent contributions of OXTR methylation and plasma OT levels. In contrast, in the overall sample, lower levels of OXTR methylation were associated with higher self-reported attachment avoidance. Age analysis suggested that these results were largely driven by young adults. Plasma OT levels were unrelated to attachment avoidance. Taken together, these findings support the emerging notion in the literature that epigenetic properties of OXTR, in addition to endogenous OT levels, are related to adult attachment. Further, the age effects observed in the associations between OXTR methylation, plasma OT, and adult attachment emphasize the importance of adopting a developmental perspective when studying properties of the OT system and their relation to affiliative processes. Findings contribute to growing evidence suggesting that epigenetic modification of genes regulating OT pathways and endogenous OT levels are associated with the way people form and maintain intimate social relationships.

Peripheral oxytocin and vasopressin modulates regional brain activity differently in men and women with schizophrenia.

BACKGROUND: Oxytocin (OT) and arginine vasopressin (AVP) exert sexually dimorphic effects on cognition and emotion processing. Abnormalities in these hormones are observed in schizophrenia and may contribute to multiple established sex differences associated with the disorder. Here we examined sex-dependent hormone associations with resting brain activity and their clinical associations in schizophrenia patients. METHODS: OT and AVP serum concentrations were assayed in 35 individuals with schizophrenia (23 men) and 60 controls (24 men) from the Chicago BSNIP study site. Regional cerebral function was assessed with resting state fMRI by measuring the amplitude of low-frequency fluctuations (ALFF) which are believed to reflect intrinsic spontaneous neuronal activity. RESULTS: In female patients, lower OT levels were associated with lower ALFF in frontal and cerebellar cortices (p's < 0.05) and in female controls AVP levels were inversely associated with ALFF in the frontal cortex (p = 0.01). In male patients, lower OT levels were associated with lower ALFF in the posterior cingulate and lower AVP levels were associated with lower ALFF in frontal cortex (p's < 0.05). In male controls, lower OT levels were associated with lower ALFF in frontal cortex and higher ALFF in the thalamus (p's < 0.05). There were some inverse ALFF-behavior associations in patients. CONCLUSIONS: Alterations in peripheral hormone levels are associated with resting brain physiology in a sex-dependent manner in schizophrenia. These effects may contribute to sex differences in psychiatric symptom severity and course of illness in schizophrenia.

The Role of Endogenous Oxytocin in Anxiolysis: Structural and Functional Correlates.

BACKGROUND: Oxytocin is anxiolytic, and administration of synthetic oxytocin in humans reduces amygdala reactivity to negative stimuli. However, it is unknown whether endogenous oxytocin levels-which are heritable and stable across time-attenuate anxiety via similar mechanisms. METHODS: In this study, we used plasma assays and structural and functional neuroimaging to examine potential anxiolytic effects of endogenous oxytocin in 73 participants. RESULTS: We found that higher endogenous oxytocin levels are associated with reduced central amygdala volume and blood oxygen level-dependent activity in response to aversive stimuli. In contrast to previous reports, we found that oxytocin was not related to patterns of functional connectivity between the amygdala and other brain regions. CONCLUSIONS: Together, our results underscore the importance of considering individual differences in participants' endogenous oxytocin with respect to anxiety-related neural activity and neuromorphology.

The Effects of Equine Assisted Therapy on Plasma Cortisol and Oxytocin Concentrations and Heart Rate Variability in Horses and Measures of Symptoms of Post-Traumatic Stress Disorder in Veterans.

With the increase in the number of horses being used in Equine-Assisted Activities and Therapies (EAAT) programs and with the increasing concern for animal welfare, it is important to understand the impact of such interventions on the stress level and quality of life for the horses involved. The purpose of the present pilot study was to test the hypothesis that participation in EAAT would acutely alter physiological markers of stress and well-being, including plasma cortisol, plasma oxytocin, and heart rate variability (HRV), in horses and that symptoms of posttraumatic stress disorder (PTSD) would be reduced after five sessions of EAAT in veterans who had previously been diagnosed with PTSD. Nine healthy geldings, of various breeds, ages 10-23 years, conditioned and experienced as therapeutic riding horses, were selected to participate in the study. Of these, seven were selected at random to wear electrocardiogram units, and all nine were used for blood sampling to measure plasma cortisol and oxytocin. Each horse was randomly assigned to partner with a veteran for five EAAT sessions, 1 hour in duration. A standing control was conducted on a later date on which horses did not participate in EAAT. Measurement after 5 days of EAAT was conducted immediately after the end of the last session on day 5 using the Brief Symptom Inventory and the PCL-5 (a 20 item self-report measure of the Diagnostic and Statistical Manual of Mental Disorders - 5 for symptoms of PTSD). Two way repeated measure analysis of variance showed no significant day by time interactions for plasma cortisol (P = .821) or oxytocin (P = .861). There was a significant day by time interaction (P = .006) for heart rate (HR); where on day 1, HR (bpm) was significantly lower during the interaction with the veterans. There were no significant differences in HRV variables. Posttherapy measures in PTSD symptoms in veterans were significantly reduced except for interpersonal sensitivity (P = .08) and phobic anxiety (P = .17). There was an effect of EAAT on HR which was significantly reduced on day 2 during the actual EAAT session. Equine-Assisted Activities and Therapies had no effect on respiration rate and systolic or diastolic blood pressure in veterans involved in five sessions of EAAT, lasting 60 minutes in duration over the course of 5 days. Stress levels, as demonstrated by plasma cortisol concentrations and HRV, did not change in horses involved in EAAT sessions with veterans who had been previously diagnosed with PTSD. Furthermore, the horses used in this study did not demonstrate increased levels of well-being as demonstrated by the lack of change in plasma oxytocin concentrations after EAAT sessions. Symptoms of PTSD did change significantly in the veterans who participated in this study.

Sex differences in associations of arginine vasopressin and oxytocin with resting-state functional brain connectivity.

Oxytocin (OT) and arginine vasopressin (AVP) exert robust and sexually dimorphic influences on cognition and emotion. How these hormones regulate relevant functional brain systems is not well understood. OT and AVP serum concentrations were assayed in 60 healthy individuals (36 women). Brain functional networks assessed with resting-state functional magnetic resonance imaging (rs-fMRI) were constructed with graph theory-based approaches that characterize brain networks as connected nodes. Sex differences were demonstrated in rs-fMRI. Men showed higher nodal degree (connectedness) and efficiency (information propagation capacity) in left inferior frontal gyrus (IFG) and bilateral superior temporal gyrus (STG) and higher nodal degree in left rolandic operculum. Women showed higher nodal betweenness (being part of paths between nodes) in right putamen and left inferior parietal gyrus (IPG). Higher hormone levels were associated with less intrinsic connectivity. In men, higher AVP was associated with lower nodal degree and efficiency in left IFG (pars orbitalis) and left STG and less efficiency in left IFG (pars triangularis). In women, higher AVP was associated with lower betweenness in left IPG, and higher OT was associated with lower nodal degree in left IFG (pars orbitalis). Hormones differentially correlate with brain networks that are important for emotion processing and cognition in men and women. AVP in men and OT in women may regulate orbital frontal cortex connectivity, which is important in emotion processing. Hormone associations with STG and pars triangularis in men and parietal cortex in women may account for well-established sex differences in verbal and visuospatial abilities, respectively. © 2016 Wiley Periodicals, Inc.

Interaction of oxytocin level and past depression may predict postpartum depressive symptom severity.

We examined plasma oxytocin concentration and postpartum depression (PPD) symptom severity in women who were not depressed during pregnancy and whether this differed by major depressive disorder (MDD) history. We assessed psychiatric history and plasma oxytocin in 66 healthy pregnant women in the third trimester (M = 35 ± 3 weeks) and depressive symptoms at 6 weeks postpartum (M = 5.9 ± 0.8 weeks). Linear regression analysis was used to examine oxytocin and PPD symptom severity and moderation of oxytocin and PPD by past MDD. Women with (n = 13) and without (n = 53) past MDD differed in third trimester depressive symptom severity, but not oxytocin level, demographic factors, or birth outcomes. Controlling for third trimester depressive symptoms, oxytocin level was unrelated to PPD symptom severity [B(SE) = -.019 (.084); ß = -.025; t = -.227; p = .821]. However, oxytocin level interacted with past MDD to predict PPD symptom severity [B(SE) = 7.489 (2.429); ß = .328; t = 3.084; p = .003]. Higher oxytocin predicted greater PPD symptom severity in women with past MDD (p = .019), but not in women without (p = .216). Replication in a larger sample and methodologic challenges are discussed.

Sex and diagnosis specific associations between DNA methylation of the oxytocin receptor gene with emotion processing and temporal-limbic and prefrontal brain volumes in psychotic disorders.

BACKGROUND: The oxytocin (OT) system, including receptor epigenetic mechanisms, has been shown to influence emotion processing, especially in females. Whether OT receptor (OXTR) epigenetic alterations occur across psychotic disorders in relation to illness-related disturbances in social cognition and brain anatomy is unknown. METHODS: Participants with affective and nonaffective psychotic disorders (92 women, 75 men) and healthy controls (38 women, 37 men) from the Chicago site of the BSNIP study completed the Penn Emotion Recognition Test (ER-40), a facial emotion recognition task. We measured cytosine methylation at site -934 upstream of the OXTR start codon in DNA from whole blood, and for the first time their relationship with plasma OT levels assessed by enzyme-immunoassay. Volumes of brain regions supporting social cognition were measured from MRI scans using FreeSurfer. RESULTS: Patients with prototypic schizophrenia features showed higher levels of DNA methylation than those with prototypic bipolar features. Methylation was higher in women than men, and was associated with poorer emotion recognition only in female patients and controls. Greater methylation was associated with smaller volumes in temporal-limbic and prefrontal regions associated previously with social cognition, but only in healthy women and females with schizophrenia. CONCLUSION: DNA methylation of the OXTR site -934 was higher in schizophrenia spectrum than bipolar patients. Among patients, it was linked to behavioral deficits in social cognition and neuroanatomic structures known to support emotion processing only in schizophrenia spectrum individuals.

Effects of sex, menstrual cycle phase, and endogenous hormones on cognition in schizophrenia.

BACKGROUND: In women with schizophrenia, cognition has been shown to be enhanced following administration of hormone therapy or oxytocin. We examined how natural hormonal changes across the menstrual cycle influence cognition in women with schizophrenia. We hypothesized that female patients would perform worse on "female-dominant" tasks (verbal memory/fluency) and better on "male-dominant" tasks (visuospatial) during the early follicular phase (low estradiol and progesterone) compared to midluteal phase (high estradiol and progesterone) in relation to estradiol but not progesterone. METHODS: Fifty-four women (23 with schizophrenia) completed cognitive assessments and provided blood for sex steroid assays and oxytocin at early follicular (days 2-4) and midluteal (days 20-22) phases. Men were included to verify the expected pattern of sex differences on cognitive tests. RESULTS: Expected sex differences were observed on "female-dominant" and "male-dominant" tasks (p<0.001), but the magnitude of those differences did not differ between patients and controls (p=0.44). Cognitive performance did not change across the menstrual cycle on "female-dominant" or "male-dominant" tasks in either group. Estradiol and progesterone levels were unrelated to cognitive performance. Oxytocin levels did not change across the menstrual cycle but were positively related to performance on "female-dominant" tasks in female patients only (p<0.05). CONCLUSIONS: Sex differences in cognitive function are preserved in schizophrenia. Oxytocin levels do not change across the cycle, but relate to enhanced performance on female dominant tests in women. Physiological levels of oxytocin may thus have a more powerful benefit in some cognitive domains than estrogens in schizophrenia.

Plasma oxytocin explains individual differences in neural substrates of social perception.

The neuropeptide oxytocin plays a critical role in social cognition and behavior. A number of studies using intranasal administration have demonstrated that oxytocin improves social perception. However, little is known about the relationship between individual differences in endogenous levels of oxytocin and social cognition. In the current study, we assessed the relationship between endogenous oxytocin and brain activity during an animacy perception paradigm. Thirty-seven male participants underwent scanning and provided a blood sample for oxytocin analysis. In line with previous research, perception of animacy was associated with activations in superior temporal sulcus, inferior frontal gyrus, and medial prefrontal cortex (mPFC). Notably, participants' levels of plasma oxytocin robustly predicted activation in areas critical for social cognitive processes, such that higher oxytocin levels were related to increased activity in dorsal mPFC, ventral mPFC, dorsolateral PFC, superior temporal gyrus, and temporoparietal junction (TPJ), suggesting differential processing of social stimuli. Together these results show that stable variations in endogenous oxytocin levels explain individual differences in social perception.

Changes in social functioning and circulating oxytocin and vasopressin following the migration to a new country.

Prior studies have reported associations between plasma oxytocin and vasopressin and markers of social functioning. However, because most human studies have used cross-sectional designs, it is unclear whether plasma oxytocin and vasopressin influences social functioning or whether social functioning modulates the production and peripheral release of these peptides. In order to address this question, we followed individuals who experienced major changes in social functioning subsequent to the migration to a new country. In this study, 59 new international students were recruited shortly after arrival in the host country and reassessed 2 and 5 months later. At each assessment participants provided information on their current social functioning and blood samples for oxytocin and vasopressin analysis. Results indicated that changes in social functioning were not related to changes in plasma oxytocin. Instead, baseline oxytocin predicted changes in social relationship satisfaction, social support, and loneliness over time. In contrast, plasma vasopressin changed as a function of social integration. Baseline vasopressin was not related to changes in social functioning over time. These results emphasize the different roles of plasma oxytocin and vasopressin in responses to changes in social functioning in humans.

Reduced levels of vasopressin and reduced behavioral modulation of oxytocin in psychotic disorders.

Oxytocin (OT) and arginine vasopressin (AVP) exert robust influence on social affiliation and specific cognitive processes in healthy individuals. Abnormalities in these neuroendocrine systems have been observed in psychotic disorders, but their relation to impairments in behavioral domains that these endocrines modulate is not well understood. We compared abnormalities of OT and AVP serum concentrations in probands with schizophrenia (n = 57), schizoaffective disorder (n = 34), and psychotic bipolar disorder (n = 75); their first-degree relatives without a history of psychosis (n = 61, 43, 91, respectively); and healthy controls (n = 66) and examined their association with emotion processing and cognition. AVP levels were lower in schizophrenia (P = .002) and bipolar probands (P = .03) and in relatives of schizophrenia probands (P = .002) compared with controls. OT levels did not differ between groups. Familiality estimates were robust for OT (h(2) = 0.79, P = 3.97e-15) and AVP (h(2) = 0.78, P = 3.93e-11). Higher levels of OT were associated with better emotion recognition (ß = 0.40, P < .001) and general neuropsychological function (ß = 0.26, P = .04) in healthy controls as expected but not in any proband or relative group. In schizophrenia, higher OT levels were related to greater positive symptom severity. The dissociation of OT levels and behavioral function in all proband and relative groups suggests that risk and illness factors associated with psychotic disorders are not related to reduced OT levels but to a disruption in the ability of physiological levels of OT to modulate social cognition and neuropsychological function. Decreased AVP levels may be a marker of biological vulnerability in schizophrenia because alterations were seen in probands and relatives, and familiality was high.

Oxytocin in pregnancy and the postpartum: relations to labor and its management.

The purpose of this study was to examine variations in endogenous oxytocin levels in pregnancy and postpartum state. We also explored the associations between delivery variables and oxytocin levels. A final sample of 272 mothers in their first trimester of pregnancy was included for the study. Blood samples were drawn during the first trimester and third trimester of pregnancy and at 8 weeks postpartum. Socio-demographic data were collected at each time point and medical files were consulted for delivery details. In most women, levels of circulating oxytocin increased from the first to third trimester of pregnancy followed by a decrease in the postpartum period. Oxytocin levels varied considerably between individuals, ranging from 50 pg/mL to over 2000 pg/mL. Parity was the main predictor of oxytocin levels in the third trimester of pregnancy and of oxytocin level changes from the first to the third trimester of pregnancy. Oxytocin levels in the third trimester of pregnancy predicted a self-reported negative labor experience and increased the chances of having an epidural. Intrapartum exogenous oxytocin was positively associated with levels of oxytocin during the postpartum period. Our exploratory results suggest that circulating oxytocin levels during the third trimester of pregnancy may predict the type of labor a woman will experience. More importantly, the quantity of intrapartum exogenous oxytocin administered during labor predicted plasma oxytocin levels 2 months postpartum, suggesting a possible long-term effect of this routine intervention, the consequences of which are largely unknown.

Autonomic substrates of the response to pups in male prairie voles.

Caregiving by nonparents (alloparenting) and fathers is a defining aspect of human social behavior, yet this phenomenon is rare among mammals. Male prairie voles (Microtus ochrogaster) spontaneously exhibit high levels of alloparental care, even in the absence of reproductive experience. In previous studies, exposure to a pup was selectively associated with increased activity in oxytocin and vasopressin neurons along with decreased plasma corticosterone. In the present study, physiological, pharmacological and neuroanatomical methods were used to explore the autonomic and behavioral consequences of exposing male prairie voles to a pup. Reproductively naïve, adult male prairie voles were implanted with radiotransmitters used for recording ECG, temperature and activity. Males responded with a sustained increase in heart-rate during pup exposure. This prolonged increase in heart rate was not explained by novelty, locomotion or thermoregulation. Although heart rate was elevated during pup exposure, respiratory sinus arrhythmia (RSA) did not differ between these males and males exposed to control stimuli indicating that vagal inhibition of the heart was maintained. Blockade of beta-adrenergic receptors with atenolol abolished the pup-induced heart rate increase, implicating sympathetic activity in the pup-induced increase in heart rate. Blockade of vagal input to the heart delayed the males' approach to the pup. Increased activity in brainstem autonomic regulatory nuclei was also observed in males exposed to pups. Together, these findings suggest that exposure to a pup activates both vagal and sympathetic systems. This unique physiological state (i.e. increased sympathetic excitation of the heart, while maintaining some vagal cardiac tone) associated with male caregiving behavior may allow males to both nurture and protect infants.

In search of an adult attachment stress provocation to measure effect on the oxytocin system: a pilot validation study.

BACKGROUND: Oxytocin is a promising biomarker for psychiatric conditions arising from early relational trauma, childhood maltreatment, and attachment dysregulation, including posttraumatic stress and dissociative disorders. OBJECTIVE: This exploratory pilot study examined plasma oxytocin as a biomarker for alterations in the attachment system. DESIGN: We used a single group, repeated-measures design with 15 women. The protocol used a film clip previously validated as a provocation to the hypothalamic-pituitary-adrenal axis. RESULTS: The repeated-measures ANOVA showed differences in oxytocin across the three time points. Correlations with oxytocin indicated that measures of dissociation and somatization correlated most strongly with higher levels of oxytocin measured during exposure to the film's bonding scene and posttraumatic stress disorder correlated most strongly with lower levels at the film's abandonment scene. Post hoc analyses revealed differences in oxytocin response related to psychopathology. CONCLUSION: Replication studies should characterize participants on a range of psychiatric conditions associated with attachment dysregulation.

Peripheral vasopressin but not oxytocin relates to severity of acute psychosis in women with acutely-ill untreated first-episode psychosis.

BACKGROUND: In women with chronic schizophrenia, higher levels of peripheral oxytocin have been associated with lower levels of positive but not negative symptoms. Sex-specific associations between endogenous levels of oxytocin (OT) and arginine vasopressin (AVP) with clinical symptoms and cognition in untreated early course patients have not been examined. METHOD: Clinical ratings and neuropsychological testing were performed in thirty-eight acutely ill, unmedicated first-episode schizophrenia patients (14 women, 24 men). Serum hormone assays were obtained in patients and thirty-eight demographically similar healthy controls. RESULTS: Patients demonstrated increased AVP levels compared to controls (p = 0.01). Higher AVP levels were associated with greater positive symptoms (r = 0.58, p = 0.03) and worse verbal learning (r = -0.63, p = 0.02) in female, but not male, patients. OT levels did not statistically differ between patients and controls, and were unrelated to clinical symptoms or cognition in patients. CONCLUSION: Results suggest an association of endogenous AVP with increased positive symptom severity and worse cognition in untreated female, but not male, schizophrenia patients. Findings support the role of neuroendocrine alterations in acute psychosis and the importance of examining sex-specific neuroendocrine alterations early in the course of schizophrenia.

Exposure to chronic isolation modulates receptors mRNAs for oxytocin and vasopressin in the hypothalamus and heart.

The goal of our study was to explore the effect of social isolation stress of varying durations on the plasma oxytocin (OT), messenger ribonucleic acid (mRNA) for oxytocin receptor (OTR), plasma arginine vasopressin (AVP) and mRNA for V1a receptor of AVP (V1aR) expression in the hypothalamus and heart of socially monogamous female and male prairie voles (Microtus ochrogaster). Continuous isolation for 4 weeks (chronic isolation) increased plasma OT level in females, but not in males. One hour of isolation every day for 4 weeks (repeated isolation) was followed by a significant increase in plasma AVP level. Chronic isolation, but not repeated isolation, significantly decreased OTR mRNA in the hypothalamus and heart in both sexes. Chronic isolation significantly decreased cardiac V1aR mRNA, but no effect on hypothalamic V1aR mRNA expression. We did not find a gender difference within repeated social isolation groups. The results of the present study reveal that although chronic social isolation can down-regulate gene expression for the OTR in both sexes, the release of the OT peptide was increased after chronic isolation only in females, possibly somewhat protecting females from the negative consequences of isolation. In both sexes repeated, but not chronic, isolation increased plasma AVP, which could be permissive for mobilization and thus adaptive in response to a repeated stressor. The differential effects of isolation on OT and AVP systems may help in understanding mechanisms through social interactions can be protective against emotional and cardiovascular disorders.

Preliminary evidence for lowered basal cortisol in a naturalistic sample of methamphetamine polydrug users.

The effects of chronic methamphetamine use on neuroendocrine functioning in humans are largely undocumented. Here we assessed basal plasma oxytocin, arginine vasopressin, and cortisol levels in a naturalistic sample of methamphetamine polydrug users (n = 12) compared with controls matched for age, gender, education, occupation status, and marital status (n = 17). All of the methamphetamine users tested positive for blood methamphetamine and/or its main metabolite, amphetamine. Other drugs of abuse were detected in a small number of methamphetamine users (MDMA [3,4-methylenedioxy-N-methylamphetamine; n = 2], THC [delta-9-tetrahydrocannabinol; n = 2]). Almost half of the methamphetamine users reported using methamphetamine intravenously, and others smoked or ingested the drug. Methamphetamine users had significantly lower basal plasma cortisol (p = .025), but similar basal plasma oxytocin and arginine vasopressin levels compared with controls. Basal plasma oxytocin was positively correlated (p = .011), with basal plasma arginine vasopressin in controls, but not in methamphetamine users. Methamphetamine users reported higher rates of psychiatric symptoms including substance use disorders, impulsivity, and positive, negative, manic, and disorientation symptoms compared with controls. Psychiatric symptoms were not related to neuroendocrine functioning in either group. These results provide preliminary evidence for lowered basal cortisol levels in methamphetamine polydrug users and encourage further research in to the effects of methamphetamine on neuroendocrine functioning in humans using more highly controlled experimental research designs.

Plasma vasopressin and interpersonal functioning.

The neuropeptide vasopressin has traditionally been associated with vasoconstriction and water reabsorption by the kidneys. However, data from experimental animal studies also implicate vasopressin in social bonding processes. Preliminary work suggests that vasopressin also plays a role in social behaviors in humans. The goal of this cross-sectional study was to evaluate associations among plasma vasopressin and self-reported interpersonal functioning in a sample of married couples. During a 24-h admission to a hospital-based research unit, 37 couples completed measures of interpersonal functioning and provided blood samples for neuropeptide analyses. Results showed that vasopressin was associated with markers of interpersonal functioning, but not with general psychological distress. Specifically, greater plasma vasopressin levels were related to a larger social network, fewer negative marital interactions, less attachment avoidance, more attachment security, and marginally greater spousal social support. These results indicate that vasopressin is likely implicated in different relationship maintenance processes in humans.

Oxytocin and vasopressin are dysregulated in Williams Syndrome, a genetic disorder affecting social behavior.

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.