Continued versus discontinued oxytocin stimulation in the active phase of labour (CONDISOX): individual management based on artificial intelligence - a secondary analysis.

BACKGROUND: Current guidelines regarding oxytocin stimulation are not tailored to individuals as they are based on randomised controlled trials. The objective of the study was to develop an artificial intelligence (AI) model for individual prediction of the risk of caesarean delivery (CD) in women with a cervical dilatation of 6 cm after oxytocin stimulation for induced labour. The model included not only variables known when labour induction was initiated but also variables describing the course of the labour induction. METHODS: Secondary analysis of data from the CONDISOX randomised controlled trial of discontinued vs. continued oxytocin infusion in the active phase of induced labour. Extreme gradient boosting (XGBoost) software was used to build the prediction model. To explain the impact of the predictors, we calculated Shapley additive explanation (SHAP) values and present a summary SHAP plot. A force plot was used to explain specifics about an individual's predictors that result in a change of the individual's risk output value from the population-based risk. RESULTS: Among 1060 included women, 160 (15.1%) were delivered by CD. The XGBoost model found women who delivered vaginally were more likely to be parous, taller, to have a lower estimated birth weight, and to be stimulated with a lower amount of oxytocin. In 108 women (10% of 1060) the model favoured either continuation or discontinuation of oxytocin. For the remaining 90% of the women, the model found that continuation or discontinuation of oxytocin stimulation affected the risk difference of CD by less than 5% points. CONCLUSION: In women undergoing labour induction, this AI model based on a secondary analysis of data from the CONDISOX trial may help predict the risk of CD and assist the mother and clinician in individual tailored management of oxytocin stimulation after reaching 6 cm of cervical dilation.

No impairment of contextual fear memory consolidation by oxytocin receptor antagonism in male rats.

Oxytocin is a peptide released into brain regions associated with the processing of aversive memory and threat responses. Given the expression of oxytocin receptors across this vigilance surveillance system of the brain, we investigated whether pharmacological antagonism of the receptor would impact contextual aversive conditioning and memory. Adult male rats were conditioned to form an aversive contextual memory. The effects of peripheral administration of either the competitive antagonist Atosiban or noncompetitive antagonist L-368,899 were compared to saline controls. Oxytocin receptor antagonism treatment did not significantly impact the consolidation of aversive contextual memory in any of the groups. We conclude that peripheral antagonism of oxytocin signalling did not impact the formation of aversive memory.

An evolutionary timeline of the oxytocin signaling pathway.

Oxytocin is a neuropeptide associated with both psychological and somatic processes like parturition and social bonding. Although oxytocin homologs have been identified in many species, the evolutionary timeline of the entire oxytocin signaling gene pathway has yet to be described. Using protein sequence similarity searches, microsynteny, and phylostratigraphy, we assigned the genes supporting the oxytocin pathway to different phylostrata based on when we found they likely arose in evolution. We show that the majority (64%) of genes in the pathway are 'modern'. Most of the modern genes evolved around the emergence of vertebrates or jawed vertebrates (540 - 530 million years ago, 'mya'), including OXTR, OXT and CD38. Of those, 45% were under positive selection at some point during vertebrate evolution. We also found that 18% of the genes in the oxytocin pathway are 'ancient', meaning their emergence dates back to cellular organisms and opisthokonta (3500-1100 mya). The remaining genes (18%) that evolved after ancient and before modern genes were classified as 'medium-aged'. Functional analyses revealed that, in humans, medium-aged oxytocin pathway genes are highly expressed in contractile organs, while modern genes in the oxytocin pathway are primarily expressed in the brain and muscle tissue.

Validation of two immunoassays for oxytocin measurements in human saliva.

The objective of this research was to develop and validate two immunoassays for oxytocin measurement in human saliva, one using a monoclonal and the other a polyclonal antibody against oxytocin, whose affinity for oxytocin was tested by an antibody mapping epitope analysis. These assays were analytically validated and used to compare oxytocin concentrations with those obtained with a commercial kit before and after the extraction or reduction/alkylation (R/A) treatments to saliva samples. The assays were also used to evaluate changes in salivary oxytocin concentrations following a physical effort and an induced psychological stress, which have previously been described as situations that cause an increase in salivary oxytocin. Both assays showed to be precise and accurate in the validation studies, and the antibodies used showed a defined binding region in case of the monoclonal antibody, whereas the polyclonal antibody showed binding events through all the oxytocin sequence. Although the monoclonal and polyclonal assays showed a positive correlation, they give results in a different range of magnitude. Both assays showed significant increases in oxytocin concentrations when applied after the physical effort and the psychological stress. This study shows that a variability in the reported values of oxytocin can occur depending on the assay and indicates that the use of different types of antibodies can give a different range of values when measuring oxytocin in saliva.

Oxytocin, GABA, and dopamine interplay in autism.

Oxytocin plays an important role in brain development and is associated with various neurotransmitter systems in the brain. Abnormalities in the production, secretion, and distribution of oxytocin in the brain, at least during some stages of the development, are critical for the pathogenesis of neuropsychiatric diseases, particularly in the autism spectrum disorder. The etiology of autism includes changes in local sensory and dopaminergic areas of the brain, which are also supplied by the hypothalamic sources of oxytocin. It is very important to understand their mutual relationship. In this review, the relationship of oxytocin with several components of the dopaminergic system, gamma-aminobutyric acid (GABA) inhibitory neurotransmission and their alterations in the autism spectrum disorder is discussed. Special attention has been paid to the results describing a reduced expression of inhibitory GABAergic markers in the brain in the context of dopaminergic areas in various models of autism. It is presumed that the altered GABAergic neurotransmission, due to the absence or dysfunction of oxytocin at certain developmental stages, disinhibits the dopaminergic signaling and contributes to the autism symptoms.

Social neuroscience: How we learn to avoid the bully.

During social interactions, individuals evaluate relationships with their peers and switch from approach to avoidance, particularly in response to aggressive encounters. A new study in mice investigated the underlying brain mechanisms and identified oxytocin as a key regulator of social avoidance learning.

Proteomic studies of VEGFR2 in human placentas reveal protein associations with preeclampsia, diabetes, gravidity, and labor.

VEGFR2 (Vascular endothelial growth factor receptor 2) is a central regulator of placental angiogenesis. The study of the VEGFR2 proteome of chorionic villi at term revealed its partners MDMX (Double minute 4 protein) and PICALM (Phosphatidylinositol-binding clathrin assembly protein). Subsequently, the oxytocin receptor (OT-R) and vasopressin V1aR receptor were detected in MDMX and PICALM immunoprecipitations. Immunogold electron microscopy showed VEGFR2 on endothelial cell (EC) nuclei, mitochondria, and Hofbauer cells (HC), tissue-resident macrophages of the placenta. MDMX, PICALM, and V1aR were located on EC plasma membranes, nuclei, and HC nuclei. Unexpectedly, PICALM and OT-R were detected on EC projections into the fetal lumen and OT-R on 20-150 nm clusters therein, prompting the hypothesis that placental exosomes transport OT-R to the fetus and across the blood-brain barrier. Insights on gestational complications were gained by univariable and multivariable regression analyses associating preeclampsia with lower MDMX protein levels in membrane extracts of chorionic villi, and lower MDMX, PICALM, OT-R, and V1aR with spontaneous vaginal deliveries compared to cesarean deliveries before the onset of labor. We found select associations between higher MDMX, PICALM, OT-R protein levels and either gravidity, diabetes, BMI, maternal age, or neonatal weight, and correlations only between PICALM-OT-R (p < 2.7 × 10-8), PICALM-V1aR (p < 0.006), and OT-R-V1aR (p < 0.001). These results offer for exploration new partnerships in metabolic networks, tissue-resident immunity, and labor, notably for HC that predominantly express MDMX.

Exogenous oxytocin increases gaze to humans in male cats.

Although oxytocin (OT) plays a role in bonding between heterospecifics and conspecifics, the effects of OT on the formation of such interspecific social behavior have only been investigated between humans and dogs (Canis familiaris). In this study, for comparative evaluation of the effects of OT between dog-human and cat-human social interaction, we investigated the effects of exogenous OT on the behavior of domestic cats (Felis silvestris catus) toward humans. We intranasally administered OT or saline to 30 cats using a nebulizer and recorded their behavior (gaze, touch, vocalization, and proximity). The results showed an interaction between the administration condition and sex for gaze duration. Post hoc analyses revealed a significant increase in gaze in the OT condition in male cats but not in females. There were no significant differences in gaze toward owners and strangers in any condition or sex. The male-specific OT-mediated increase in gaze toward humans observed in this study differs from previous research on dogs wherein such effects were observed only in females. These findings suggest an overall effect of exogenous OT on cats' social relationship with humans as well as the possibility of different mechanisms between cat-human and dog-human relationships.

Binding Affinity, Selectivity, and Pharmacokinetics of the Oxytocin Receptor Antagonist L-368,899 in the Coyote (Canis latrans).

L-368,899 is a selective small-molecule oxytocin receptor (OXTR) antagonist originally developed in the 1990s to prevent preterm labor. Although its utility for that purpose was limited, L-368,899 is now one of the most commonly used drugs in animal research for the selective blockade of neural OXTR after peripheral delivery. A growing number of rodent and primate studies have used L-368,899 to evaluate whether certain behaviors are oxytocin dependent. These studies have improved our understanding of oxytocin's function in the brains of rodents and monkeys, but very little work has been done in other mammals, and only a single paper in macaques has provided any evidence that L-368,899 can be detected in the CNS after peripheral delivery. The current study sought to extend those findings in a novel species: coyotes ( Canis latrans ). Coyotes are ubiquitous North American canids that form long-term monogamous pair-bonds. Although monogamy is rare in rodents and primates, all wild canid species studied to date exhibit social monogamy. Coyotes are therefore an excellent model organism for the study of oxytocin and social bonds. Our goal was to determine whether L-368,899 is a viable candidate for future use in behavioral studies in coyotes. We used captive coyotes at the USDA National Wildlife Research Center's Predator Research Facility to evaluate the pharmacokinetics of L-368,899 in blood and CSF during a 90-min time course after intramuscular injection. We then characterized the binding affinity and selectivity of L-368,899 to coyote OXTR and the structurally similar vasopressin 1a receptor. We found that L-368,899 peaked in CSF at 15 to 30 min after intramuscular injection and slowly accumulated in blood. L-368,899 was 40 times more selective for OXTR than vasopressin 1a receptors and bound to the coyote OXTR with an affinity of 12 nM. These features of L-368,899 support its utility in future studies to probe the oxytocin system of coyotes.

Maternal oxytocin treatment at birth increases epigenetic age in male offspring.

Exogenous oxytocin (OT) is widely used to induce or augment labor with little understanding of the impact on offspring development. In rodent models, including the prairie vole (Microtus ochrogaster), it has been shown that oxytocin administered to mothers can affect the nervous system of the offspring with long lasting behavioral effects especially on sociality. Here, we examined the hypothesis that perinatal oxytocin exposure could have epigenetic and transcriptomic consequences. Prairie voles were exposed to exogenous oxytocin, through injections given to the mother just prior to birth, and were studied at the time of weaning. The outcome of this study revealed increased epigenetic age in oxytocin-exposed animals compared to the saline-exposed group. Oxytocin exposure led to 900 differentially methylated CpG sites (annotated to 589 genes), and 2 CpG sites (2 genes) remained significantly different after correction for multiple comparisons. Differentially methylated CpG sites were enriched in genes known to be involved in regulation of gene expression and neurodevelopment. Using RNA-sequencing we also found 217 nominally differentially expressed genes (p<0.05) in nucleus accumbens, a brain region involved in reward circuitry and social behavior; after corrections for multiple comparisons 6 genes remained significantly differentially expressed. Finally, we found that maternal oxytocin administration led to widespread alternative splicing in the nucleus accumbens. These results indicate that oxytocin exposure during birth may have long lasting epigenetic consequences. A need for further investigation of how oxytocin administration impacts development and behavior throughout the lifespan is supported by these outcomes.

Patterns of neural activity in response to threatening faces are predictive of autistic traits: modulatory effects of oxytocin receptor genotype.

Autistic individuals generally demonstrate impaired emotion recognition but it is unclear whether effects are emotion-specific or influenced by oxytocin receptor (OXTR) genotype. Here we implemented a dimensional approach using an implicit emotion recognition task together with functional MRI in a large cohort of neurotypical adult participants (N = 255, male = 131, aged 17-29 years) to establish associations between autistic traits and neural and behavioral responses to specific face emotions, together with modulatory effects of OXTR genotype. A searchlight-based multivariate pattern analysis (MVPA) revealed an extensive network of frontal, basal ganglia, cingulate and limbic regions exhibiting significant predictability for autistic traits from patterns of responses to angry relative to neutral expression faces. Functional connectivity analyses revealed a genotype interaction (OXTR SNPs rs2254298, rs2268491) for coupling between the orbitofrontal cortex and mid-cingulate during angry expression processing, with a negative association between coupling and autistic traits in the risk-allele group and a positive one in the non-risk allele group. Overall, results indicate extensive emotion-specific associations primarily between patterns of neural responses to angry faces and autistic traits in regions processing motivation, reward and salience but not in early visual processing. Functional connections between these identified regions were not only associated with autistic traits but also influenced by OXTR genotype. Thus, altered patterns of neural responses to threatening faces may be a potential biomarker for autistic symptoms although modulatory influences of OXTR genotype need to be taken into account.

A single administration of carbetocin before electroejaculation increases the insemination doses produced from each ejaculate in rams.

The aim of the study was to determine the effect of carbetocin administration (a long-acting analog of oxytocin) 20 or 10 min before electroejaculation (EE) on the duration of semen collection procedure, quantitative and qualitative characteristics of the ejaculate, and stress biomarkers in rams. Semen was collected from 12 Corriedale rams (age, 2.5-5.5 years old) with EE, in a Latin-square design, administrating carbetocin (0.2 mg/100 kg of body weight i.v.) 20 or 10 min before EE, or without carbetocin administration (CB-20, CB-10, and CON treatments, respectively). Each treatment was applied to different rams every 3-4 days, allowing all the rams to receive all three treatments. Carbetocin administered 20 or 10 min before EE increased the number of sperm ejaculated (P = 0.01), the semen concentration (P = 0.02), the number of insemination doses collected in a single collection (P = 0.01), and the number of insemination doses collected/electrical pulses administered (P = 0.05) compared to control rams. Carbetocin administered 20 or 10 min before semen collection prolonged the time required for EE and the number of pulses administered during EE compared to CON rams (P < 0.03 for both). The CB-10 rams required the administration of more electrical pulses during ejaculation than CON rams (P = 0.001), and CB-20 treatment tended to require more electrical pulses than CON rams (P = 0.06). The volume of the ejaculate was greater in CB-10 than in CON rams (P = 0.01), and that of CB-20 treatment tended to be greater than CON rams (P = 0.08). The percentage of sperm with intact membrane was greater in CB-20 than in CON rams (P = 0.01). Total protein, albumin, and globulin concentrations were lower immediately after carbetocin administration 20 or 10 min before EE. The treatments did not affect cortisol concentration, glycemia, rectal and surface temperatures, heart rate, and facial expressions. Carbetocin administration before EE of rams improved the quantitative and qualitative characteristics of the ejaculate, duplicating the number of insemination doses collected. It can be a promising treatment to obtain a greater quantity of doses to inseminate with a lower frequency of semen collections, reducing the negative impacts of EE on animal welfare.

Analysis of gene and protein expression in the endometrium for validation of an ex vivo model of the equine uterus using PCR, digital and visual histopathology.

In the past, most research in equine reproduction has been performed in vivo but the use of in vitro and ex vivo models has recently increased. This study aimed to evaluate the functional stability of an ex vivo hemoperfused model for equine uteri with molecular characterization of marker genes and their proteins. In addition, the study validated the respective protein expression and the aptness of the software QuPath for identifying and scoring immunohistochemically stained equine endometrium. After collection, uteri (n = 12) were flushed with preservation solution, transported to the laboratory on ice, and perfused with autologous blood for 6 h. Cycle stage was determined by examination of the ovaries for presence of Graafian follicles or corpora lutea and analysis of plasma progesterone concentration (estrus: n = 4; diestrus: n = 4; anestrus: n = 4). Samples were obtained directly after slaughter, after transportation, and during perfusion (240, 300, 360 min). mRNA expression levels of progesterone (PGR), estrogen (ESR1) and oxytocin (OXTR) receptor as well as of MKI67 (marker of cell growth) and CASP3 (marker of apoptosis) were analyzed by RT-qPCR, and correlation to protein abundance was validated by immunohistochemical staining. Endometrial samples were analyzed by visual and computer-assisted evaluation of stained antigens via QuPath. For PGR, effects of the perfusion and cycle stage on expression were found (P < 0.05), while ESR1 was affected only by cycle stage (P < 0.05) and OXTR was unaffected by perfusion and cycle stage. MKI67 was lower after 360 min of perfusion as compared to samples collected before perfusion (P < 0.05). For CASP3, differences in gene expression were found after transport and samples taken after 240 min (P < 0.05). Immunohistochemical staining revealed effects of perfusion on stromal and glandular cells for steroid hormone receptors, but not for Ki-67 and active Caspase 3. OXTR was visualized in all layers of the endometrium and was unaffected by perfusion. Comparison of QuPath and visual analysis resulted in similar results. For most cell types and stained antigens, the correlation coefficient was r > 0.5. In conclusion, the isolated hemoperfused model of the equine uterus was successfully validated at the molecular level, demonstrating stability of key marker gene expression. The utility of computer-assisted immunohistochemical analysis of equine endometrial samples was also confirmed.

Oxytocin-induced increases in cytokines and clinical effect on the core social features of autism: Analyses of RCT datasets.

Although oxytocin may provide a novel therapeutics for the core features of autism spectrum disorder (ASD), previous results regarding the efficacy of repeated or higher dose oxytocin are controversial, and the underlying mechanisms remain unclear. The current study is aimed to clarify whether repeated oxytocin alter plasma cytokine levels in relation to clinical changes of autism social core feature. Here we analyzed cytokine concentrations using comprehensive proteomics of plasmas of 207 adult males with high-functioning ASD collected from two independent multi-center large-scale randomized controlled trials (RCTs): Testing effects of 4-week intranasal administrations of TTA-121 (A novel oxytocin spray with enhanced bioavailability: 3U, 6U, 10U, or 20U/day) and placebo in the crossover discovery RCT; 48U/day Syntocinon or placebo in the parallel-group verification RCT. Among the successfully quantified 17 cytokines, 4 weeks TTA-121 6U (the peak dose for clinical effects) significantly elevated IL-7 (9.74, 95 % confidence interval [CI] 3.59 to 15.90, False discovery rate corrected P (PFDR) < 0.001), IL-9 (56.64, 20.46 to 92.82, PFDR < 0.001) and MIP-1b (18.27, 4.96 to 31.57, PFDR < 0.001) compared with placebo. Inverted U-shape dose-response relationships peaking at TTA-121 6U were consistently observed for all these cytokines (IL-7: P < 0.001; IL-9: P < 0.001; MIP-1b: P = 0.002). Increased IL-7 and IL-9 in participants with ASD after 4 weeks TTA-121 6U administration compared with placebo was verified in the confirmatory analyses in the dataset before crossover (PFDR < 0.001). Furthermore, the changes in all these cytokines during 4 weeks of TTA-121 10U administration revealed associations with changes in reciprocity score, the original primary outcome, observed during the same period (IL-7: Coefficient = -0.05, -0.10 to 0.003, P = 0.067; IL-9: -0.01, -0.02 to -0.003, P = 0.005; MIP-1b: -0.02, -0.04 to -0.007, P = 0.005). These findings provide the first evidence for a role of interaction between oxytocin and neuroinflammation in the change of ASD core social features, and support the potential role of this interaction as a novel therapeutic seed. Trial registration: UMIN000015264, NCT03466671/UMIN000031412.

Are there sex differences in oxytocin and vasopressin V1a receptors ligand binding affinities?

BACKGROUND: There is substantial evidence for sex differences in the functioning of one of the most common receptor systems; G protein-coupled receptors (GPCRs). There are many points along the GPCR-mediated molecular signaling pathway at which males and females may differ, one of the first of which, chronologically, is in the stability of the interaction between the ligand and the receptor, or its binding affinity. Here we investigate the binding affinities of oxytocin (OT) and vasopressin (AVP) at the oxytocin receptor (OTR) and the vasopressin V1a receptor (V1aR), both of which are present in numerous in brain regions associated with social behavior. METHOD: In order to investigate sex- and estrous cycle-dependent differences in ligand-receptor binding affinity, male (n = 6) Syrian hamsters (Mesocricetus auratus), females on the day of estrus (E females, n = 6), and females on the second day of diestrus (D2 females n = 6) were chosen for study. Brains from hamsters were mounted on slides and competition and saturation binding assays were conducted. RESULTS: We report a remarkable similarity in the binding affinities of OT and AVP in males and females. Small differences were detected, however, in receptor and ligand specificity in females depending on whether they were in the estrous or diestrous stage of their ovulatory cycle. CONCLUSION: These data suggest that sex differences in binding affinity are not a likely source of the many sex differences that have been observed in the effects of OT and AVP in hamsters and other species.

Group differences in OXT methylation between patients with Major Depressive Disorder and healthy controls: A pre-registered replication study.

Depression is linked to stress which leaves traces in the epigenetic signature of genes. The oxytocin system is implicated in allostatic processes promoting adaption to environmental stressors. Interactions of the oxytocin system with the environment, e.g., methylation of the gene coding for oxytocin (OXT), are candidates for the investigation of the biological underpinnings of depression. Recently, we found hypomethylation of OXT in patients with Major Depressive Disorder (MDD) compared to healthy controls (HC). Since the replicability of findings is a key point of criticism in (epi­)genetic research, we aimed to confirm our previous findings in a pre-registered study (data was stored in a database prior to pre-registration) within a new sample of n = 85 patients with MDD and n = 85 HC. We investigated OXT DNA-methylation in peripheral blood samples, stressful life events and depression severity. In accordance with our previous study, we found hypomethylation of OXT in patients with MDD compared to HC. Methylation was not associated with stressful life events. Patients reported significantly more stressful life events compared to HC. Our study revealed that hypomethylation of OXT can be demonstrated in a reproducible fashion and provides further evidence for the involvement of the oxytocin system in depression.

A phase II randomised controlled trial of intranasal oxytocin in anorexia nervosa.

BACKGROUND: Anorexia nervosa (AN) is an eating disorder (ED) with high mortality rates and limited response to existing treatments, prompting the need to identify effective agents and adjuncts. There is evidence for an emerging role for the neuropeptide oxytocin (OT) in the pathophysiology of AN, with studies showing a perturbed oxytocinergic system in patients with AN. Preliminary evidence has demonstrated that intranasal OT (IN-OT) can produce anxiolytic effects in AN, as well as reducing concern about eating, and dysfunctional attentional biases related to the disorder. IN-OT is a non-invasive treatment option for AN that requires investigation as an adjunct to nutritional rehabilitation. METHODS: This multi-site study (Trial Registration:ACTRN1261000897460) sought to replicate and extend a previous randomised placebo-controlled pilot trial of repeated dose IN-OT in patients with AN hospitalised for nutritional rehabilitation. Patients with AN (N=61) received daily IN-OT (18 IU twice per day) or placebo for four weeks, whilst undergoing inpatient hospital treatment. Outcome measures included ED psychopathology (primary) as measured by the Eating Disorder Examination (EDE) and Body Mass Index (BMI; secondary). Participants were assessed pre- and post-treatment, and at six months following the intervention. The effects of the first and last doses of IN-OT on responses (anxiety ratings and salivary cortisol) to a high-energy snack were also examined. RESULTS: Sixty-one female inpatients (Mage=24.36,SD=7.87) with an average BMI of 16.24 (range: 11.43-18.55), were recruited into the study. No significant differences were found between placebo and OT groups at any of the time points on the outcomes of interest, but significant improvements in almost all psychological parameters in both groups were evident over time. IN-OT did not significantly reduce anxiety nor salivary cortisol in response to a high-calorie snack. CONCLUSION: This is the largest randomised placebo-controlled trial of repeated dose intranasal OT in people with AN, during refeeding. The therapeutically promising findings of the pilot study were not replicated. Limitations and reasons for the non-replication included relatively large variance, baseline psychopathology scores being higher in this patient group, potential ceiling effects in BMI and ED psychopathology as well as differing comorbidities.

Oxytocin and social learning in socially anxious men and women.

OBJECTIVE: This study extended a classic self-referential learning paradigm by investigating the effects of intranasally-administered oxytocin in high and low socially anxious participants during social learning, as a function of social anxiety levels and sex. METHODS: In a randomized double-blinded design, 160 participants were either given intranasal oxytocin (24 I.U.) or placebo. Subsequently, while lying in an MR scanner, participants were shown neutral faces that were paired with positively, neutrally, or negatively valenced self-referential sentences, during which we measured self-reported arousal and sympathy of the facial stimuli, pupil dilation, and changes in the brain-oxygen-level dependent signal. Four-factor mixed analyses of variance with the between-subjects factors group (high socially anxious vs. low socially anxious), substance (oxytocin vs. placebo), and sex (male vs. female) and the within-subjects factor sentence valence (positive vs. neutral vs. negative) were conducted for each measure, respectively. RESULTS: Administration of intranasal oxytocin yielded an increase in sympathy ratings in high socially anxious compared to low socially anxious individuals and decreased arousal ratings for positively-conditioned faces in low socially anxious participants. As an objective physiological measure of arousal, pupil dilation mirrored the behavioral results. Oxytocin effects on neural activation in the insula interacted with anxiety levels and sex: low socially anxious individuals yielded lower activation under oxytocin than placebo; the converse was observed in high socially anxious individuals. This interaction also differed between sexes, as men yielded higher activation levels than women. These findings were more prominent for positively- and negatively-conditioned faces. Within the amygdala, high socially anxious men yielded higher activation than high socially anxious women in the left hemisphere, and low socially anxious men yielded higher activation than low socially anxious women from positively- and negatively-conditioned faces, though no influence of oxytocin was detected. CONCLUSION: These results suggest oxytocin-induced behavioral, physiological, and neural changes as a function of social learning in socially low and high anxious individuals. These findings challenge the amygdalocentric view of the role of emotions in social learning, instead contributing to the growing body of findings implicating the insula therein, revealing an interaction between oxytocin, sex, and emotional valence. Such discoveries raise an interesting set of questions regarding the computational goals of regions such as the insula in emotional learning and how neural activity can play a diagnostic or prognostic role in social anxiety, potentially leading to new treatment opportunities that may combine oxytocin and neurofeedback differentially for men and women.

Expression of bond-related behaviors affects titi monkey responsiveness to oxytocin and vasopressin treatments.

Social bonds influence physiology and behavior, which can shape how individuals respond to physical and affective challenges. Coppery titi monkey (Plecturocebus cupreus) offspring form selective bonds with their fathers, making them ideal for investigating how father-daughter bonds influence juveniles' responses to oxytocin (OT) and arginine-vasopressin (AVP) manipulations. We quantified the expression of father-daughter bond-related behaviors in females (n = 10) and gave acute intranasal treatments of saline, low/medium/high OT, low/high AVP, or an OT receptor antagonist (OTA) to subjects prior to a parent preference test. While females spent more time in proximity to their parents than strangers, we found a large degree of individual variation. Females with greater expression of bonding behaviors responded to OT treatments in a dose-dependent manner. Subjects also spent less time in proximity to strangers when treated with High OT (p = 0.003) and Low OT (p = 0.007), but more time when treated with High AVP (p = 0.007), Low AVP (p = 0.009), and OTA (p = 0.001). Findings from the present study suggest that variation in the expression of bond-related behaviors may alter responsiveness to OT and AVP, increasing engagement with unfamiliar social others. This enhanced sociality with strangers may promote the formation of pair bonds with partners.

Effects of chronic intranasal oxytocin on visual attention to faces vs. natural scenes in older adults.

Aging is associated with changes in face processing, including desensitization to face cues like gaze direction and an attentional preference to faces with positive over negative emotional valence. A parallel line of research has shown that acute administration of oxytocin (OT) increases visual attention to social stimuli such as human faces. The current study examined effects of chronic OT administration among older adults on fixation duration to faces that varied in emotional expression, gaze direction, age, and sex. One hundred and twelve generally healthy older adults (aged 55-95 years) underwent a randomized, placebo-controlled, double-blind, between-subject clinical trial in which they self-administered either OT or placebo (P) intranasally twice a day for 4 weeks. The behavioral task involved rating the trustworthiness of faces (i.e., social stimuli) and natural scenes (i.e., non-social control stimuli) during eye tracking and was conducted before and after the intervention. Fixation duration to both the faces and the natural scenes declined from pre- to post-intervention, however this decline was less pronounced among older adults in the OT compared to the P group for faces but not scenes. Further, face cues (emotional expression, gaze direction, age, sex) did not moderate the treatment effect. This study provides first evidence that chronic intranasal OT maintains salience of social cues over time in older adults, perhaps buffering effects of habituation. These findings enhance understanding of OT effects on social cognition among older adults, and would benefit from follow up with a young adult comparison group to directly speak to specificity of observed effects to older adults and reflection of the aging process.