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Objective: One proposed mechanism to subclassify depressive illness relates oxytocinergic dysregulation, via its effect on social behavior and Hypothalamic-pituitary-adrenal (HPA) axis inhibition. To further investigate the role of oxytocin in Major Depressive Disorder (MDD), we compared plasma oxytocin levels in patients with MDD to healthy controls. Methods: Plasma samples from 12 healthy controls and 33 MDD patients were collected at baseline, 8 weeks, and 12 weeks of treatment and oxytocin was measured by enzyme-immunoassay. Depression and anxiety scales were administered at screening, baseline, and at weeks 2, 4, 8, and 12 of treatment. Additionally, we investigated possible associations between blood concentrations of inflammatory biomarkers and oxytocin. Results: The average baseline oxytocin level was 429 pg/ml in MDD patients and 392 pg/ml in healthy control subjects. A significant negative correlation was found between baseline oxytocin and BMI. Treatment responders had significantly lower baseline oxytocin levels than non-responders. After stratifying patients into low and high oxytocin groups based on a median split, within the high oxytocin group, patients with no prior depressive episodes had significantly higher baseline oxytocin levels. A Chi-square distribution test revealed that African American patients were more likely to belong to the high baseline oxytocin group while Caucasian and Hispanic patients were more likely to belong to the low baseline oxytocin group. We found significant correlations between oxytocin and Von-Willebrand Factor (VWF) and Epidermal Growth Factor (EGF), only within the high oxytocin subgroup. There were no other significant correlations between baseline oxytocin and any other biomarkers. Conclusion: Within our limited patient cohort, our data adds to the mixed literature regarding the role of oxytocin in MDD. Oxytocinergic dysregulation and confounding factors may play a role for a subset of depressed patients.

ObjectiveEarly life trauma (ELT) and HIV are associated with social processing deficits. In people with HIV (PWH), we examined whether facial emotion identification accuracy differs by ELT and whether neuroendocrine factors including cortisol, oxytocin (OT), and arginine vasopressin, and/or immune system measures play a role in the ELT-performance association.MethodsWe used secondary data from the placebo condition of a pharmacologic challenge study in PWH. Presence of ELT was measured with the Childhood Trauma Questionnaire (at least moderate experiences of sexual, physical, and/or emotional abuse). Social processing was measured with the Facial Emotion Perception Test (FEPT). Salivary immune system measures and cortisol were sampled across a 5-hour study session. Blood was collected at study session start (12 pm ) to measure OT and arginine vasopressin. We examined the association of ELT with FEPT and five biological moderators (from principal components analysis of 12 biomarkers) of ELT-FEPT associations.ResultsOf 58 PWH (42 men; mean [standard deviation] age = 33.7 [8.9] years), 50% endorsed ELT. ELT-exposed PWH demonstrated lower identification accuracy across all emotional expressions (unstandardized β [ B ] = 0.13; standard error [SE] = 0.05; p = .021, d = 0.63) and had higher OT levels compared with ELT-unexposed PWH ( t(1,56) = 2.12, p = .039; d = 0.57). For total accuracy, an OT/C-reactive protein factor moderated the ELT-FEPT association ( B = 0.14; SE = 0.05; p = .014); accuracy was lower in ELT-exposed PWH versus ELT-unexposed PWH when the factor was low but not when high. Similar results were obtained for fearful, neutral, and happy faces ( p values < .05). Regardless of ELT, a myeloid migration (MCP-1/MMP-9) factor was associated with reduced accuracy ( p values < .05).ConclusionsOur pilot findings suggest that ELT may alter social processing in PWH, and OT and C-reactive protein may be a target for improving social processing in ELT-exposed PWH, and myeloid migration markers may be a target in PWH more generally.

Oxytocin (OT) and the OT receptor occupy essential roles in our current understanding of mammalian evolution, survival, sociality and reproduction. This narrative review examines the hypothesis that many functions attributed to OT can be traced back to conditions on early Earth, including challenges associated with managing life in the presence of oxygen and other basic elements, including sulfur. OT regulates oxidative stress and inflammation especially through effects on the mitochondria. A related nonapeptide, vasopressin, as well as molecules in the hypothalamic–pituitary–adrenal axis, including the corticotropin-releasing hormone family of molecules, have a broad set of functions that interact with OT. Interactions among these molecules have roles in the causes and consequence of social behaviour and the management of threat, fear and stress. Here, we discuss emerging evidence suggesting that unique properties of the OT system allowed vertebrates, and especially mammals, to manage over-reactivity to the ‘side effects’ of oxygen, including inflammation, oxidation and free radicals, while also supporting high levels of sociality and a perception of safety. This article is part of the theme issue ‘Interplays between oxytocin and other neuromodulators in shaping complex social behaviours’.

The roles of oxytocin (OT) and arginine-vasopressin (AVP) as crucial modulators of social cognition and related behaviours have been extensively addressed in the literature. The involvement of these neuropeptides in social cognition in ageing, however, and a potential mediating effect of basic cognitive capacities on this link, are not well understood. To fill these research gaps, this study assessed associations of plasma OT and AVP levels with dynamic emotion identification accuracy in generally healthy older men (aged 55–95 years) and probed the underlying roles of crystallized and fluid cognition in these associations. Higher plasma OT levels were associated with lower accuracy in dynamic emotion identification, with this negative relationship fully mediated by cognition. For plasma AVP levels, in contrast, there was no association with dynamic emotion identification accuracy. Integrated within existing theoretical accounts, results from this study advance understanding of the neuropeptide–social cognition link in ageing and support basic cognitive capacities as mediators in this association. This article is part of the theme issue ‘Interplays between oxytocin and other neuromodulators in shaping complex social behaviours’.

Oxytocin is a pleiotropic, peptide hormone with broad implications for general health, adaptation, development, reproduction, and social behavior. Endogenous oxytocin and stimulation of the oxytocin receptor support patterns of growth, resilience, and healing. Oxytocin can function as a stress-coping molecule, an anti-inflammatory, and an antioxidant, with protective effects especially in the face of adversity or trauma. Oxytocin influences the autonomic nervous system and the immune system. These properties of oxytocin may help explain the benefits of positive social experiences and have drawn attention to this molecule as a possible therapeutic in a host of disorders. However, as detailed here, the unique chemical properties of oxytocin, including active disulfide bonds, and its capacity to shift chemical forms and bind to other molecules make this molecule difficult to work with and to measure. The effects of oxytocin also are context-dependent, sexually dimorphic, and altered by experience. In part, this is because many of the actions of oxytocin rely on its capacity to interact with the more ancient peptide molecule, vasopressin, and the vasopressin receptors. In addition, oxytocin receptor(s) are epigenetically tuned by experience, especially in early life. Stimulation of G-protein-coupled receptors triggers subcellular cascades allowing these neuropeptides to have multiple functions. The adaptive properties of oxytocin make this ancient molecule of special importance to human evolution as well as modern medicine and health; these same characteristics also present challenges to the use of oxytocin-like molecules as drugs that are only now being recognized. SIGNIFICANCE STATEMENT: Oxytocin is an ancient molecule with a major role in mammalian behavior and health. Although oxytocin has the capacity to act as a "natural medicine" protecting against stress and illness, the unique characteristics of the oxytocin molecule and its receptors and its relationship to a related hormone, vasopressin, have created challenges for its use as a therapeutic drug.

We are presenting this document to medical providers as a systematic approach to improve outcomes of patients with COVID-19. The following variables are considered: Autonomic nervous system viewed from the perspective of the Polyvagal Theory; Timing of interventions in terms of phase of the body’s defense ( Fight, Flight, Freeze, Faint ); The nervous system considered the context of a “ One System ” perspective; Protein/Enzyme function; Immune system; Cytokine load - activity, inflammation and metabolic response; Viral load; Angiotensin 2 load. The ARDS and multi-system organ failure of the COVID-19 is a complex problem. This approach acknowledges the complexity and presents a structure where the variables are systematically addressed. 1. The common risk factors for death are associated with baseline elevations of pro-inflammatory cytokines. Measures can be taken to lower them before being exposed to the virus–Plan A. 2. Strategies to optimize the body’s defenses should be assessed and optimized. These include nutrition, vitamins, and trace elements, sleep, exercise, and minimizing threat. 3. The body’s own resources are utilized through recruiting the autonomic nervous system to counteract elevated pro-inflammatory cytokines. The interventions are implemented in the context of what stage of defense the body is in–fight, flight, freeze, or faint. 4. Progressive pharmacological interventions are considered with the early interventions being those with minimal risk. We are asking the following: This approach is viewed as the foundation for clinical interventions. They should be implemented in a systematic and stepwise manner. Most of the treatments are already medically proven with minimal or no risk. All basic treatments are in place before more aggressive interventions are implemented. That this process be considered a framework to test clinical protocols and novel therapies. Much work needs to be done regarding dosing and timing. We are particularly interested in the potential of the following interventions, which do need to be looked at in a protocol. o Allowing ketosis in the Mid and Late Phases of the illness. o Considering the use of ketone bodies instead of glucose for fuel in Mid and Late Phases of illness. o Eliminating glucocorticosteroids in the Early and Mid-Phases the use of steroids. o Utilizing the anti-inflammatory cholinergic nervous system (vagal stimulation, nicotine patches, etc.). o Closer monitoring of IL-6 to in real time deliver the most appropriate interventions. Doi: 10.28991/SciMedJ-2020-02-SI-2 Full Text: PDF

Researchers have endeavored to subclassify depressive illness based on pathophysiological mechanism. One model relates to hypothalamic-pituitary-adrenal (HPA) axis overactivation with a shift from corticotropin-releasing hormone (CRH) driven regulation to arginine vasopressin (AVP) driven regulation. Given the mixed literature, we compared plasma AVP levels in healthy controls to patients with major depressive disorder (MDD). Plasma samples from 33 patients and 12 controls were collected at baseline, 8 weeks, and 12 weeks of treatment and measured by immunochemical assay. Patients who were treatment responders trended toward lower AVP levels than non-responders. Patients were stratified into low and high AVP groups based on median split. Within the low AVP group, patients whose current episode lasted longer than a year had significantly higher baseline AVP levels than patients whose current episode was less than 6 months. Female patients in the low AVP group had significantly higher baseline AVP levels than male patients. Given the association between stress, HPA axis activation, immune dysregulation, and depression, we also measured concentrations of inflammatory biomarkers. We found a significant negative correlation between IL-10 and baseline AVP levels, within the low AVP subgroup. Given inconsistent data, HPA axis overactivation may be present within a subset of depressed patients.

Positive social experiences may induce oxytocin release. However, previous studies of moral elevation have generally utilized cross-sectional and simple modeling approaches to establish the relationship between oxytocin and emotional stimuli. Utilizing a cohort of 30 non-lactating women (aged 23.6±5.7 years), we tested whether exposure to a video identified as capable of eliciting moral elevation could change plasma oxytocin levels. Uniquely, we utilized a high-frequency longitudinal sampling approach and multilevel growth curve modeling with landmark registration to test physiological responses. The moral elevation stimulus, versus a control video, elicited significantly greater reports of being "touched/inspired" and "happy/joyful". However, the measured plasma oxytocin response was found to be markedly heterogeneous. While the moral elevation stimulus elicited increased plasma oxytocin as expected, this increase was only modestly larger than that seen following the control video. This increase was also only present in some individuals. We found no relationship between plasma oxytocin and self-report responses to the stimulus. From these data, we argue that future studies of the relationship between oxytocin and emotion need to anticipate heterogeneous responses and thus incorporate comprehensive individual psychological data; these should include evidence-based variables known to be associated with oxytocin such as a history of trauma, and the individual's psychological and emotional state at the time of testing. Given the complexity of physiological oxytocin release, such studies also need to incorporate frequent biological sampling to properly examine the dynamics of hormonal release and response.

IntroductionHuman and nonhuman animal research suggests that greater oxytocin (OT) activity is protective against harmful substance use. Most research on this topic is preclinical, with few studies evaluating the association between substance use and individual differences in the human OT system. The present study sought to fill this gap by evaluating the relationship between alcohol use and multiple biological measures of OT activity in an overall low to moderate-drinking sample.MethodAs part of a larger study, generally healthy young (n=51) and older (n=53) adults self-reported whether they regularly used alcohol and how much alcohol they consumed per week. Participants also provided blood samples from which peripheral OT, and in an age-heterogeneous subset of participants (n=56) variation in the oxytocin receptor gene (the OXTR rs53576 polymorphism) and OXTR DNA methylation levels (at cytosine-guanine dinucleotide sites -860, -924, -934), were obtained.ResultsA-allele carriers of the OXTR rs53579 polymorphism were less likely to regularly consume alcohol. Among regular alcohol consumers, number of alcoholic drinks per week was positively associated with peripheral OT in regression models excluding observations of high influence (postdiagnostic models). Number of alcoholic drinks per week was consistently negatively associated with OXTR DNA methylation at site -860; and with OXTR DNA methylation at site -924 in postdiagnostic models.ConclusionsThe significant associations between alcohol use and individual differences in OT activity support the involvement of the OT system in alcohol use, which most likely reflect the role of OT when alcohol use is under control of its rewarding properties and/or the acute impacts of alcohol on the OT system. Additional research with markers of OT activity and alcohol use, particularly longitudinal, is needed to clarify the bidirectional effects of OT and alcohol use in moderate to harmful drinking and dependence.

Oxytocin has become a popular analyte in behavioral endocrinology in recent years, due in part to its roles in social behavior, stress physiology, and cognition. Urine samples have the advantage of being non-invasive and minimally disruptive to collect, allowing for oxytocin measurements even in some wild populations. However, methods for urinary oxytocin immunoassay have not been sufficiently optimized and rigorously assessed for their potential limitations. Using samples from oxytocin knockout (KO) and wildtype (WT) mice, we find evidence of considerable interference in unextracted urine samples, with similar distributions of measured oxytocin in both genotypes. Importantly, although this interference can be reduced by a reversed-phase solid-phase extraction (SPE), this common approach is not sufficient for eliminating false-positive signal on three immunoassay kits. To better understand the source of the observed interference, we conducted epitope mapping of the Arbor Assays antibody and assessed its cross-reactivity with known, biologically active fragments of oxytocin. We found considerable cross-reactivity (0.5-52% by-molarity) for three fragments of oxytocin that share the core epitope, with more cross-reactivity for longer fragments. Given the presence of some cross-reactivity for even the tripeptide MIF-1, it is likely that many small protein metabolites might be sufficiently similar to the epitope that at high concentrations they interfere with immunoassays. We present a new mixed-mode cation-exchange SPE method that minimizes interference-with knockout samples measuring below the assay's limit of detection-while effectively retaining oxytocin from the urine of wildtype mice. This method demonstrates good parallelism and spike recovery across multiple species (mice, dogs, sifakas, humans). Our results suggest that immunoassays of urine samples may be particularly susceptible to interference, even when using common extraction protocols, but that this interference can be successfully managed using a novel mixed-mode cation exchange extraction. These findings imply that previous conclusions based on urinary oxytocin measurements-especially those involving unextracted samples-may need to be reassessed.

Despite evidence supporting a role for oxytocin (OT) in regulating social behavior, surprisingly little is known about how this neuropeptide is calibrated during development. We systematically reviewed empirical studies in humans (k = 86 publications reporting on 66 independent samples; N = 7319) that examined associations between early-life stress and three OT system components: endogenous OT, methylation of the OT receptor gene (OXTRm), and biological and behavioral responses to intranasally administered OT. In a series of meta-analyses, we found some evidence that people who grew up under more adverse conditions tend to have lower endogenous OT (children: r =.12; adults: r =.09), that early adversity is associated with higher levels of OXTRm (r =.02), and that adults who report lower levels of childhood adversity tend to show more positive responses to intranasally administered OT (r =.12). These results were found in typical populations, and were in most cases absent in clinical samples. We discuss these findings in terms of both the prevailing medical model (focusing on the harmful effects of early-life stress) and the adaptive calibration model (focusing on developmental adaptation of biobehavioral systems to early conditions) and suggest that an adaptation-based approach could meaningfully advance research and intervention on the sequelae of early adversity.

Since its discovery more than a century ago, oxytocin has become one of the most intensively studied molecules in behavioral biology. In the last five years, Psychoneuroendocrinology has published more than 500 articles with oxytocin in the title, with many of these articles including measures of endogenous oxytocin concentrations. Despite longstanding interest, methods of measuring endogenous oxytocin are still in active development. The widely varying oxytocin concentrations detected by different approaches to measurement - and lack of correlation among these techniques - has led to controversy and confusion. We identify features of oxytocin that may help to explain why various approaches may be differentially sensitive to diverse conformational states of the oxytocin molecule. We propose that discrepancies in data generated by different methods of measurement are not necessarily an indicator that some methods are valid whereas others are not. Rather, we propose that current challenges in the measurement of oxytocin may be analogous to the parable of the blind men and the elephant, with different methods of sample preparation and measurement being sensitive to different states in which the oxytocin molecule can exist.

Background: Maternal milk production requires the neuropeptide oxytocin. Individual variation in oxytocin function is a compelling target for understanding low milk production, a leading cause of breastfeeding attrition. Complicating the understanding of oxytocin pathways is that vasopressin may interact with oxytocin receptors, yet little is known about the role of vasopressin in lactation. Research aims: The aims of this study were (1) to describe maternal plasma oxytocin, vasopressin, and prolactin patterns during breastfeeding following low-risk spontaneous labor and birth in healthy first-time mothers and (2) to relate hormone patterns to maternal characteristics and breastfeeding measures. Methods: Eligible women were recruited before hospital discharge. Forty-six participants enrolled and 35 attended the study visit. Participants kept a journal of breastfeeding frequency, symptoms of lactogenesis, and infant weight. Plasma samples were obtained at breastfeeding onset on Day 4–5 postpartum, and repeated after 20 min. Hormones were measured with immunoassays. Infant weight change, milk transfer, and onset of lactogenesis were also measured. Results: Baseline oxytocin and vasopressin were inversely related to one another. Oxytocin and prolactin increased significantly across the 20-min sampling period while vasopressin decreased. Higher oxytocin was associated with higher maternal age, lower BMI, shorter active labor, physiologic labor progression, and less weight loss in the newborn. Higher vasopressin correlated with younger maternal age, higher BMI, and greater newborn weight loss. Conclusions: Oxytocin and vasopressin have contrasting relationships with maternal clinical characteristics and newborn weight gain in early breastfeeding infants. Further study is needed to understand how oxytocin and vasopressin influence lactation outcomes.

Love and fear were forged by the same fundamental evolutionary processes that permitted life on Earth. Both love and fear are deeply interwoven with the adaptive management of stress and disease. Love and fear share common roots and both can play a role in reproduction, survival, perceived safety and wellbeing. This special issue of

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

Background The neuropeptide oxytocin regulates mammalian social behavior. Disruptions in oxytocin signaling are a feature of many psychopathologies. One commonly studied biomarker for oxytocin involvement in psychiatric diseases is DNA methylation at the oxytocin receptor gene (OXTR). Such studies focus on DNA methylation in two regions of OXTR, exon 3 and a region termed MT2 which overlaps exon 1 and intron 1. However, the relative contribution of exon 3 and MT2 in regulating OXTR gene expression in the brain is currently unknown. Results Here, we use the prairie vole as a translational animal model to investigate genetic, epigenetic, and environmental factors affecting Oxtr gene expression in a region of the brain that has been shown to drive Oxtr related behavior in the vole, the nucleus accumbens. We show that the genetic structure of Oxtr in prairie voles resembles human OXTR. We then studied the effects of early life experience on DNA methylation in two regions of a CpG island surrounding the Oxtr promoter: MT2 and exon 3. We show that early nurture in the form of parental care results in DNA hypomethylation of Oxtr in both MT2 and exon 3, but only DNA methylation in MT2 is associated with Oxtr gene expression. Network analyses indicate that CpG sites in the 3′ portion of MT2 are most highly associated with Oxtr gene expression. We also identify two novel SNPs in exon 3 of Oxtr in prairie voles and a novel alternative transcript originating from the third intron of the gene. Expression of the novel alternative transcript is associated with genotype at SNP KLW2. Conclusions These results identify putative regulatory features of Oxtr in prairie voles which inform future studies examining OXTR in human social behaviors and disorders. These studies indicate that in prairie voles, DNA methylation in MT2, particularly in the 3′ portion, is more predictive of Oxtr gene expression than DNA methylation in exon 3. Similarly, in human temporal cortex, we find that DNA methylation in the 3′ portion of MT2 is associated with OXTR expression. Together, these results suggest that among the CpG sites studied, DNA methylation of MT2 may be the most reliable indicator of OXTR gene expression. We also identify novel features of prairie vole Oxtr, including SNPs and an alternative transcript, which further develop the prairie vole as a translational model for studies of OXTR.

Oxytocin has garnered much interest due to its role in affective states, social behaviors, and diverse physiological functions. However, approaches for measuring endogenous oxytocin concentrations have generated considerable controversy and debate. Common procedures for measuring oxytocin often produce uncorrelated results, and the detected concentrations frequently vary across two orders of magnitude. These findings have led some researchers to argue that immunoassays of plasma oxytocin may be unreliable and nonspecific, particularly when samples are not first processed using an extraction procedure. Here, we assess the specificity of oxytocin immunoassays using plasma samples from wildtype (WT) and oxytocin knockout (KO) mice. Plasma samples from both genotypes were measured using immunoassay and were measured with or without a solid-phase extraction. Using a commercially available kit from Arbor Assays, we demonstrate that both techniques generate a clear contrast between genotypes, with wildtype samples containing high concentrations of oxytocin (unextracted mean = 468pg/ml; extracted mean = 381pg/ml), while knockout samples measured below the lower limit of detection. Analytical validations demonstrated good parallelism and spike recovery for both methods. Furthermore, the same wildtype samples measured with both procedures were highly correlated (r=0.95), although unextracted samples measured at significantly higher concentrations (p=2.0×10-7, Cohen's d = 2.65). To test the generalizability of these results across immunoassay kits, we performed additional assays with kits from Cayman Chemical and Enzo Life Sciences. The Cayman Chemical kit produced results similar to Arbor Assays with a clean signal differentiating WT and KO plasma, both with and without an extraction step. The Enzo kit also differentiated the genotypes, with correlation between extracted and unextracted samples, but was considerably more susceptible to interference without the extraction, as evidenced by false positive signal in KO plasma samples. The extent to which these results generalize to other species remains unknown and challenging to assess.

The role of oxytocin (OT) in close relationships is complex, as both positive and negative associations have been found between OT and relationship processes. Also, with most research focusing on the effects of exogenous OT administration on communication and couple behaviors, our knowledge about the association between endogenous OT and couple dynamics remains limited. This study is the first to assess the link between peripheral OT levels and observed communication behaviors during sexual and nonsexual conflict discussions in romantic relationships. A sample of 126 young, heterosexual couples (Mean age=23.3, SD=2.4; average relationship duration=1.9 years, SD=0.9) participated in videotaped sexual and nonsexual couple conflict discussions of 7min each. Communication behaviors were coded using an adaptation of the Specific Affect Coding System (SPAFF) and the System for Coding Interactions and Family Functioning (SCIFF). Blood samples were collected prior to the couple discussions, during a separate lab visit, and OT plasma levels were determined using enzyme-linked immunosorbent assays (ELISA). Plasma OT levels were positively associated with validating behaviors during sexual discussions in both women (r=+.24, p=.008) and men (r=+.18, p=.052). No significant associations were found between OT levels and validating behaviors during nonsexual discussions and between OT and affectionate and negative behaviors during either sexual or nonsexual discussions. Analyses revealed significant associations between OT levels and one's own validating behaviors during sexual discussions (b =47.82, t(201.16)=3.81, p&nbsp

A series of vasopressin receptor V 1a ligands have been synthesized for positron emission tomography (PET) imaging. The lead compound (1 S, 5 R )- 1 ( (4-(1H-indol-3-yl)-3-methoxyphenyl) ((1 S ,5R)-1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-yl)methanone ) and its F-ethyl analog 6c exhibited the best combination of high binding affinity and optimal lipophilicity within the series. (1 S, 5 R )- 1 was radiolabeled with 11 C for PET studies. [ 11 CH 3 ](1 S, 5 R )- 1 readily entered the mouse (4.7% ID/g tissue) and prairie vole brains (∼2% ID/g tissue) and specifically (30–34%) labeled V 1a receptor. The common animal anesthetic Propofol significantly blocked the brain uptake of [ 11 CH 3 ](1 S, 5 R )- 1 in the mouse brain, whereas anesthetics Ketamine and Saffan increased the uptake variability. Future PET imaging studies with V 1a radiotracers in non-human primates should be performed in awake animals or using anesthetics that do not affect the V 1a receptor.

Background Negative outcomes related to prematurity may lead to maternal distress. Mothers of premature/low birth-weight infants report increased posttraumatic stress (50%) and depressive symptoms (63%) compared with mothers of full-term infants. Low-income, minority mothers with greater posttraumatic stress and depression have an increased risk for premature/low birth-weight delivery compared with their white counterparts. Variations in the neuropeptide oxytocin are implicated in lactation, perinatal depression, and maternal behavior. Purpose To examine the associations among posttraumatic stress, depressive symptoms, and oxytocin in a pilot sample of minority mothers with premature/low birth-weight infants in the neonatal intensive care unit (NICU). Methods This study employed a descriptive, correlational pilot design of 8 minority, low-income mothers with premature/low birth-weight infants. Participants answered questionnaires pertaining to posttraumatic stress, depression, lactation, and demographics and oxytocin was measured. This is a substudy that added oxytocin values. Results Four participants had elevated depressive symptoms and 5 supplied their own milk. Women who provided their own milk had lower depressive (t = 3.03, P = .023) and posttraumatic stress (t = 3.39, P = .015) symptoms compared with women not supplying their own milk. Women with elevated posttraumatic stress had higher levels of depressive symptoms (r(8) = 0.8, P = .006) and lower levels of oxytocin (r(8) = 0.77, P = .026). Implications for practice These results are congruent with previous literature on providing human milk and maternal mental health. In addition, we found a possible relationship between postpartum posttraumatic stress and oxytocin in minority women with premature/low birth-weight infants. NICU nurses should encourage lactation and assess mothers for posttraumatic stress and depressive symptoms. Implications for research Research is needed to identify the biologic milieu associated with posttraumatic stress and depression in at-risk mothers.

A growing literature associates the neuropeptides oxytocin (OT) and arginine vasopressin (AVP) with affiliative and cognitive outcomes. The majority of this work in humans, however, considers these neuropeptides separately. Also, despite evidence that OT and AVP interact with gonadal hormones, still warranted is an examination of sex and age variations in endogenous neuropeptide levels, their interrelations, and their functional relationships with attachment and cognition in humans. This study measured endogenous plasma OT and AVP levels in generally healthy young (18-31 years) and older (63-81 years) men and women to (i) determine levels of and interrelations between OT and AVP; (ii) explore functional relationships with self-reported attachment (attachment anxiety and avoidance) and performance-based cognition (processing speed, verbal memory); and (iii) identify variations in these effects by sex and age. We observed sex- and age-differential patterns of results: Women had higher plasma OT levels than men and older adults had higher plasma AVP levels than young adults. The two neuropeptides were highly negatively intercorrelated across all groups. Functionally, higher AVP levels were associated with greater attachment anxiety and higher OT and lower AVP levels were associated with faster sensorimotor processing speed, with sex and age moderating these effects. This integrated approach identifies variations in endogenous peripheral neuropeptide levels in humans, supporting their sex- and age-specific role as "difference makers" in attachment and cognition.

Alloparenting, defined as care provided by individuals other than parents, is a universal behavior among humans that has shaped our evolutionary history and remains important in contemporary society. Dysfunctions in alloparenting can have serious and sometimes fatal consequences for vulnerable infants and children. In spite of the importance of alloparenting, they still have much to learn regarding the underlying neurobiological systems governing its expression. Here, they review how a lack of alloparental behavior among traditional laboratory species has led to a blind spot in our understanding of this critical facet of human social behavior and the relevant neurobiology. Based on what is known, they draw from model systems ranging from voles to meerkats to primates to describe a conserved set of neuroendocrine mechanisms supporting the expression of alloparental care. In this review we describe the neurobiological and behavioral prerequisites, ontogeny, and consequences of alloparental care. Lastly, they identified several outstanding topics in the area of alloparental care that deserve further research efforts to better advance human health and wellbeing. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 214-232, 2017.

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.

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 Bipolar and Schizophrenia Network on Intermediate Phenotypes study completed the Penn Emotion Recognition Test, 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 magnetic resonance imaging 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. Conclusions 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.

The prairie vole has proven a valuable animal model for the neurobiological study of social monogamy and pair bonding. Previous research has focused almost exclusively on virgin prairie voles forming pair-bonds for the first time – a paradigm with limited relevance to human social behavior. In the present study, we used stud males to assess the impact of repeated pair-bond formation and dissolution on the behaviors and neurobiology relevant to subsequent pair-bond formation. Stud males were tested for behavioral and neurobiological e ffects of repeated pair-bonding after the 1st, 5th, and 10th pairing. Aged breeder males that experienced minimal pair-bond dissolution were included to control for the effects of aging. Results showed that male prairie voles readily form new pair-bonds after repeated pair-bond dissolution. In terms of social monogamy, old age was associated with males spending less time in close social contact with unfamiliar females. There were no effects of age nor number of lifetime pairings on depressive-like behavior or paternal behavior toward pups. Within the brain, the patterns of oxytocin (OTR) and vasopressin type 1a (V1aR) receptors were largely unaffected, with the following exceptions: 1) males with only a single pairing had higher OTR densities in the paraventricular thalamus and bed nucleus of the stria terminalis; 2) there was an age-related increase in the density of OTR in the caudate putamen and an age-related decline in the density of V1aR in the cortical amygdala. The present findings have translational relevance to human social behavior in the context of aging and social experience.

Sex- and species-specific patterns of estrogen receptor (ER)-α expression are established early in development, which may contribute to sexual differentiation of behavior and determine male social organization. The current study investigated the effects of ERα and ERβ activation during the second postnatal week on subsequent alloparental behavior and ERα expression in juvenile prairie voles. Male and female pups were treated daily with 17β-estradiol (E2, ERα/ERβ agonist), PPT (selective ERα agonist), DPN (selective ERβ agonist), or the oil vehicle on postnatal days (PD) 8–14. Alloparental behavior and ERα expression were examined at PD21. PPT treatment inhibited prosocial motivation in males and increased pup-directed aggression in both sexes. E2 and DPN had no apparent effect on behavior in either sex. PPT-treated males had increased ERα expression in the medial preoptic area (MPN), medial amygdala (MEApd) and bed nucleus of the stria terminalis (BSTpr). DPN treatment also increased ERα expression in males, but only in the BSTpr. Female ERα expression was unaffected by treatment. These results support the hypothesis that ERα activation in early life is associated with less prosocial patterns of central ERα expression and alloparental behavior in males. The lack of an effect of E2 on behavior suggests that ERβ may antagonize the effects of ERα on alloparental behavior. The results in DPN-treated males suggest that ERα in the MEApd, and not the BSTpr, may be a primary determinant of alloparental behavior in males.

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.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.Expected sex differences were observed on "female-dominant" and "male-dominant" tasks (p0.001), 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 (p0.05).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.

This study examined factors associated with postpartum depressive symptoms in mothers with premature infants in the neonatal intensive care unit (NICU).A total of 113 new mothers with very low-birth-weight infants in their initial NICU admission were recruited from 2 urban hospitals servicing low-income minority communities.This study employed a cross-sectional design.Data were collected during the infants' postpartum NICU admission and included maternal demographic information (eg, age, education, race, living with the baby's father), infant illness severity (Neurobiologic Risk Score from infant's medical record), and maternal psychological measures (the Center for Epidemiologic Studies Depression Scale, the Perinatal Posttraumatic Stress Questionnaire, and the State-Trait Anxiety Inventory).The findings indicated that 47 (42%) women had elevated postpartum depressive symptoms and 33 (30%) women had elevated postpartum posttraumatic stress symptoms (PTSs). Factors associated with postpartum depressive symptoms included PTS, anxiety, maternal age, and whether the mother lived with the baby's father (F₄, ₁₀₄ = 52.27, P.001). The severity of the infants' illness, parental stress, and maternal education were not associated with depressive symptoms among low-income mothers of NICU infants.On the basis of our findings, we recommend that low-income women should be screened for symptoms of anxiety, posttraumatic stress, and postpartum depression on their infants' admission to the NICU. When this is not feasible, we advise NICU healthcare providers to assess women for familial support, maternal age, posttraumatic stress related to their infants birth, and anxiety to determine which mothers are at the greatest risk for postpartum depressive symptoms. Screening for postpartum depression in the NICU can aid in early identification and treatment, thereby decreasing negative consequences for mothers and their infants.

Aggressive behavior in dogs poses public health and animal welfare concerns, however the biological mechanisms regulating dog aggression are not well understood. We investigated the relationships between endogenous plasma oxytocin (OT) and vasopressin (AVP) – neuropeptides that have been linked to affiliative and aggressive behavior in other mammalian species – and aggression in domestic dogs. We first validated enzyme-linked immunosorbent assays (ELISAs) for the measurement of free (unbound) and total (free + bound) OT and AVP in dog plasma. In Experiment 1 we evaluated behavioral and neuroendocrine differences between a population of pet dogs with a history of chronic aggression toward conspecifics and a matched control group. Dogs with a history of aggression exhibited more aggressive behavior during simulated encounters with conspecifics, and had lower free, but higher total plasma AVP than matched controls, but there were no group differences for OT. In Experiment 2 we compared OT and AVP concentrations between pet dogs and a population of assistance dogs that have been bred for affiliative and non-aggressive temperaments, and investigated neuroendocrine predictors of individual differences in social behavior within the assistance dog population. Compared to pet dogs, assistance dogs had higher free and total OT, but there were no differences in either measure for AVP. Within the assistance dog population, dogs who behaved more aggressively toward a threatening stranger had higher total AVP than dogs who did not. Collectively these data suggest that endogenous OT and AVP may play critical roles in shaping dog social behavior, including aspects of both affiliation and aggression.

BackgroundOxytocin (OT) and Vasopressin (AVP) are phylogenetically conserved neuropeptides with effects on social behavior, cognition and stress responses. Although OT and AVP are most commonly measured in blood, urine and cerebrospinal fluid (CSF), these approaches present an array of challenges including concerns related to the invasiveness of sample collection, the potential for matrix interference in immunoassays, and whether samples can be collected at precise time points to assess event-linked endocrine responses.New MethodWe validated enzyme-linked immunosorbent assays (ELISAs) for the measurement of salivary OT and AVP in domestic dogs.ResultsBoth OT and AVP were present in dog saliva and detectable by ELISA and high performance liquid chromatography – mass spectrometry (HPLC-MS). OT concentrations in dog saliva were much higher than those typically detected in humans. OT concentrations in the same samples analyzed with and without sample extraction were highly correlated, but this was not true for AVP. ELISA validation studies revealed good accuracy and parallelism, both with and without solid phase extraction. Collection of salivary samples with different synthetic swabs, or following salivary stimulation or the consumption of food led to variance in results. However, samples collected from the same dogs using different techniques tended to be positively correlated. We detected concurrent elevations in salivary and plasma OT during nursing.Comparison with Existing MethodsThere are currently no other validated methods for measuring OT/AVP in dog saliva.ConclusionsOT and AVP are present in dog saliva, and ELISAs for their detection are methodologically valid.

A series of vasopressin receptor V(1a) ligands have been synthesized for positron emission tomography (PET) imaging. The lead compound (1S,5R)-1 ((4-(1Hindol-3-yl)-3-methoxyphenyl)((1S,5R)-1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-yl)methanone) and its F-ethyl analog 6c exhibited the best combination of high binding affinity and optimal lipophilicity within the series. (1S,5R)-1 was radiolabeled with (11)C for PET studies. [(11)CH(3)](1S,5R)-1 readily entered the mouse (4.7% ID/g tissue) and prairie vole brains (~2% ID/g tissue) and specifically (30–34%) labeled V(1a) receptor. The common animal anesthetic Propofol significantly blocked the brain uptake of [(11)CH(3)](1S,5R)-1 in the mouse brain, whereas anesthetics Ketamine and Saffan increased the uptake variability. Future PET imaging studies with V(1a) radiotracers in non-human primates should be performed in awake animals or using anesthetics that do not affect the V(1a) receptor.