Glucocorticoid response to naturalistic interactions between children and dogs.

Although research has shown that pets appear to provide certain types of social support to children, little is known about the physiological bases of these effects, especially in naturalistic contexts. In this study, we investigated the effect of free-form interactions between children (ages 8-10 years) and dogs on salivary cortisol concentrations in both species. We further investigated the role of the child-dog relationship by comparing interactions with the child's pet dog to interactions with an unfamiliar dog or a nonsocial control condition, and modeled associations between survey measures of the human-animal bond and children's physiological responses. In both children and dogs, salivary cortisol decreased from pre- to post-interaction; the effect was strongest for children interacting with an unfamiliar dog (compared to their pet dog) and for the pet dogs (compared to the unfamiliar dog). We found minimal evidence for associations between cortisol output and behaviors coded from video, but children scoring higher on survey measures of the human-animal bond exhibited the greatest reductions in cortisol when interacting with dogs. Self-reported loneliness was not related to cortisol or the human-animal bond, but measures of both loneliness and the human-animal bond were higher among children who participated after the onset of the COVID-19 pandemic, relative to those who participated before the pandemic. This study builds on previous work that investigated potential stress-buffering effects of human-animal interaction during explicit stressors and demonstrates important physiological correlates of naturalistic interactions between children and dogs, similar to those that occur in daily life.

The effects of service dogs for children with autism spectrum disorder and their caregivers: a cross-sectional study.

Introduction: Service dogs are an increasingly popular complementary intervention for children with autism spectrum disorder. However, despite increasing demand, there remains a lack of empirical research on their potential benefits. The purpose of this study was to evaluate the effects of service dogs on children with autism and their caregivers. Methods: A total of N = 75 families of children with autism were recruited from a non-profit service dog provider in the US, including n = 39 families previously placed with a service dog and n = 36 families engaging in usual care while on the waitlist. Caregivers completed an online survey containing both self- and proxy-report standardized measures of child, caregiver, and family functioning. Linear regressions modeled the relationship between service dog presence and survey outcomes, controlling for relevant child and caregiver covariates. Results: Results indicated that having a service dog was associated with significantly better child sleep behaviors, including better sleep initiation and duration and less sleep anxiety/co-sleeping with medium effect sizes. However, service dog presence was not significantly related to child withdrawal, negative emotionality, emotional self-control, hyperactivity, irritability, and lethargy with small effect sizes. For caregivers, having a service dog was not significantly related to standardized measures of caregiver strain, sleep disturbance, depression, or the impact of the child's condition on family functioning with small effect sizes. Supplemental matched case-control analyses confirmed these findings. Discussion: In conclusion, service dogs were found to positively impact sleep behaviors among children with autism, but may not uniformly relate to other areas of child and caregiver wellbeing. Prospective longitudinal designs, larger sample sizes able to detect small effects, and studies that measure sleep using objective methods are needed to build on these findings.

Neurophysin I is an analytically robust surrogate biomarker for oxytocin.

Oxytocin is a pleiotropic neuropeptide that plays roles in biological processes ranging from birth, lactation, and social bonding to immune function, cardiovascular repair, and regulation of appetite. Although measurements of endogenous oxytocin concentrations have been performed for more than 50 years, the ability to measure oxytocin accurately poses notable challenges. One potential solution for overcoming these challenges involves measurement of oxytocin's carrier molecule - neurophysin I (NP-1) - as a surrogate biomarker. NP-1 is secreted in equimolar concentrations with oxytocin but has a longer half-life, circulates in higher concentrations, and can be measured using a sandwich immunoassay. We report experiments that 1) analytically validate a commercially available NP-1 sandwich immunoassay for use with human plasma and urine samples, 2) confirm the specificity of this assay, based on detection of NP-1 in plasma from wild-type but not oxytocin knockout mice, 3) demonstrate that NP-1 concentrations are markedly elevated in late pregnancy, consistent with studies showing substantial increases in plasma oxytocin throughout gestation, and 4) establish strong correlation between NP-1 and plasma oxytocin concentrations when oxytocin is measured in extracted (but not non-extracted) plasma. The NP-1 assay used in this study has strong analytical properties, does not require time-intensive extraction protocols, and the assay itself can be completed in < 2 h (compared to 16-24 h for a competitive oxytocin immunoassay). Our findings suggest that much like copeptin has become a useful surrogate biomarker in studies of vasopressin, measurements of NP-1 have similar potential to advance oxytocin research.

Transposons in the Williams-Beuren Syndrome Critical Region are Associated with Social Behavior in Assistance Dogs.

A strong signature of selection in the domestic dog genome is found in a five-megabase region of chromosome six in which four structural variants derived from transposons have previously been associated with human-oriented social behavior, such as attentional bias to social stimuli and social interest in strangers. To explore these genetic associations in more phenotypic detail-as well as their role in training success in a specialized assistance dog program-we genotyped 1001 assistance dogs from Canine Companions for Independence®, including both successful graduates and dogs released from the training program for behaviors incompatible with their working role. We collected phenotypes on each dog using puppy-raiser questionnaires, trainer questionnaires, and both cognitive and behavioral tests. Using Bayesian mixed models, we found strong associations (95% credibility intervals excluding zero) between genotypes and certain behavioral measures, including separation-related problems, aggression when challenged or corrected, and reactivity to other dogs. Furthermore, we found moderate differences in the genotypes of dogs who graduated versus those who did not; insertions in GTF2I showed the strongest association with training success (ß = 0.23, CI95% = - 0.04, 0.49), translating to an odds-ratio of 1.25 for one insertion. Our results provide insight into the role of each of these four transposons in canine sociability and may inform breeding and training practices for working dog organizations. Furthermore, the observed importance of the gene GTF2I supports the emerging consensus that variation in GTF2I genotypes and expression have important consequences for social behavior broadly.

Response to Hansen Wheat et al.: Additional analysis further supports the early emergence of cooperative communication in dogs compared to wolves raised with more human exposure.

Here, we address Hansen Wheat et al.'s commentary in this journal in response to Salomons et al. Current Biology, 31(14), 3137-3144.E11, (2021). We conduct additional analyses in response to Hansen Wheat et al.'s two main questions. First, we examine the claim that it was the move to a human home environment which enabled the dog puppies to outperform the wolf puppies in gesture comprehension tasks. We show that the youngest dog puppies who had not yet been individually placed in raisers' homes were still highly skilled, and outperformed similar-aged wolf puppies who had higher levels of human interaction. Second, we address the claim that willingness to approach a stranger can explain the difference between dog and wolf pups' ability to succeed in gesture comprehension tasks. We explain the various controls in the original study that render this explanation insufficient, and demonstrate via model comparison that the covariance of species and temperament also make this parsing impossible. Overall, our additional analyses and considerations support the domestication hypothesis as laid out by Salomons et al. Current Biology, 31(14), 3137-3144.E11, (2021).

Associations between physical activity and cognitive dysfunction in older companion dogs: results from the Dog Aging Project.

Canine cognitive dysfunction (CCD) is a form of dementia that shares many similarities with Alzheimer's disease. Given that physical activity is believed to reduce risk of Alzheimer's disease in humans, we explored the association between physical activity and cognitive health in a cohort of companion dogs, aged 6-18 years. We hypothesized that higher levels of physical activity would be associated with lower (i.e., better) scores on a cognitive dysfunction rating instrument and lower prevalence of dementia, and that this association would be robust when controlling for age, comorbidities, and other potential confounders. Our sample included 11,574 companion dogs enrolled through the Dog Aging Project, of whom 287 had scores over the clinical threshold for CCD. In this observational, cross-sectional study, we used owner-reported questionnaire data to quantify dog cognitive health (via a validated scale), physical activity levels, health conditions, training history, and dietary supplements. We fit regression models with measures of cognitive health as the outcome, and physical activity-with several important covariates-as predictors. We found a significant negative relationship between physical activity and current severity of cognitive dysfunction symptoms (estimate = - 0.10, 95% CI: - 0.11 to - 0.08, p < 0.001), extent of symptom worsening over a 6-month interval (estimate = - 0.07, 95% CI: - 0.09 to - 0.05, p < 0.001), and whether a dog reached a clinical level of CCD (odds ratio = 0.53, 95% CI: 0.45 to 0.63, p < 0.001). Physical activity was robustly associated with better cognitive outcomes in dogs. Our findings illustrate the value of companion dogs as a model for investigating relationships between physical activity and cognitive aging, including aspects of dementia that may have translational potential for Alzheimer's disease. While the current study represents an important first step in identifying a relationship between physical activity and cognitive function, it cannot determine causality. Future studies are needed to rule out reverse causation by following the same dogs prospectively over time, and to evaluate causality by administering physical activity interventions.

Characterizing veteran and PTSD service dog teams: Exploring potential mechanisms of symptom change and canine predictors of efficacy.

Psychiatric service dogs are an emerging complementary intervention for posttraumatic stress disorder (PTSD). Initial evidence suggests that partnership with a service dog may be related to less PTSD symptom severity. However, it remains unclear how or why this might occur. To address this gap, we conducted a longitudinal investigation of 82 post-9/11 military members or veterans and their PTSD service dogs to (1) evaluate service dog characteristics as potential predictors of efficacy, (2) assess dog and human characteristics as potential predictors of veteran-dog bond, and (3) explore potential mechanisms for mental health outcomes. Aim 1 results demonstrated that most service dog characteristics did not predict veterans' mental health outcomes, but lower service dog excitability was associated with less PTSD symptom severity at follow-up. Aim 2 results showed that closer dog-veteran relationships were associated with less excitable dog temperament. Aim 3 results indicated that worse mental health at follow-up was associated with greater use of the specifically trained PTSD service dog task to initiate a social greeting ("make a friend"), whereas better mental health was related to less use of dominance-based training methods, lower perceived emotional/logistical costs of service dog partnership, and closer veteran-dog relationships. More frequent use of the trained service dog task to signal when someone approaches from behind (cover/watch back) was associated with greater anxiety, but less PTSD symptom severity. Overall, veterans spent an average of 82% of their time with service dogs (assessed via Bluetooth proximity between dog collar and veteran smartphone), and most frequently asked their service dogs to perform the trained task for calming their anxiety (calm/comfort anxiety). The present study provides subjective and objective metrics of the heterogeneity among veteran-service dog dyads while also suggesting which of the assessed metrics might be potential mechanisms involved in the intervention.

Fear, love, and the origins of canid domestication: An oxytocin hypothesis.

The process of dog domestication likely involved at least two functional stages. The initial stage occurred when subpopulations of wolves became synanthropes, benefiting from life nearby or in human environments. The second phase was characterized by the evolution of novel forms of interspecific cooperation and social relationships between humans and dogs. Here, we discuss possible roles of the oxytocin system across these functional stages of domestication. We hypothesize that in early domestication, oxytocin played important roles in attenuating fear and stress associated with human contact. In later domestication, we hypothesize that oxytocin's most critical functions were those associated with affiliative social behavior, social engagement, and cooperation with humans. We outline possible neurobiological changes associated with these processes and present a Siberian fox model of canid domestication in which these predictions can be tested. Lastly, we identify limitations of current studies on the neuroendocrinology of domestication and discuss challenges and opportunities for future research.

What are oxytocin assays measuring? Epitope mapping, metabolites, and comparisons of wildtype & knockout mouse urine.

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.

The evolution of quantitative sensitivity.

The ability to represent approximate quantities appears to be phylogenetically widespread, but the selective pressures and proximate mechanisms favouring this ability remain unknown. We analysed quantity discrimination data from 672 subjects across 33 bird and mammal species, using a novel Bayesian model that combined phylogenetic regression with a model of number psychophysics and random effect components. This allowed us to combine data from 49 studies and calculate the Weber fraction (a measure of quantity representation precision) for each species. We then examined which cognitive, socioecological and biological factors were related to variance in Weber fraction. We found contributions of phylogeny to quantity discrimination performance across taxa. Of the neural, socioecological and general cognitive factors we tested, cortical neuron density and domain-general cognition were the strongest predictors of Weber fraction, controlling for phylogeny. Our study is a new demonstration of evolutionary constraints on cognition, as well as of a relation between species-specific neuron density and a particular cognitive ability. This article is part of the theme issue 'Systems neuroscience through the lens of evolutionary theory'.

Love, fear, and the human-animal bond: On adversity and multispecies relationships.

Love and strong social bonds are known buffers in the experience of adversity. Humans often form strong bonds with non-human animals. The human-animal bond refers to a mutually beneficial and dynamic relationship between humans and non-human animals. Previous research suggests that strong bonds with pets may promote resilience in the experience of adversity, but a strong bond with a pet can also complicate this very experience of adversity, particularly among low-resourced and disadvantaged populations. What is the role of the human-animal bond in adversity, and what is the role of adversity in the bond between a human and a non-human animal? In this article we outline the state of research on the role of various types and sources of adversities in multispecies households (i.e., families, relationships) to consider this overarching question. We focus specifically on intimate partner violence, housing discrimination, LGBTQ+ identity-based discrimination, racism, neighborhood disadvantage, and economic inequality. We then outline an agenda for future research about love, adversity, and multispecies relationships, and discuss implications for public policy and community-based interventions.

The New Era of Canine Science: Reshaping Our Relationships With Dogs.

Canine science is rapidly maturing into an interdisciplinary and highly impactful field with great potential for both basic and translational research. The articles in this Frontiers Research Topic, Our Canine Connection: The History, Benefits and Future of Human-Dog Interactions, arise from two meetings sponsored by the Wallis Annenberg PetSpace Leadership Institute, which convened experts from diverse areas of canine science to assess the state of the field and challenges and opportunities for its future. In this final Perspective paper, we identify a set of overarching themes that will be critical for a productive and sustainable future in canine science. We explore the roles of dog welfare, science communication, and research funding, with an emphasis on developing approaches that benefit people and dogs, alike.

Specificity of plasma oxytocin immunoassays: A comparison of commercial assays and sample preparation techniques using oxytocin knockout and wildtype mice.

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 = 468 pg/ml; extracted mean = 381 pg/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.

Working Dog Training for the Twenty-First Century.

Dogs are trained for a variety of working roles including assistance, protection, and detection work. Many canine working roles, in their modern iterations, were developed at the turn of the 20th century and training practices have since largely been passed down from trainer to trainer. In parallel, research in psychology has advanced our understanding of animal behavior, and specifically canine learning and cognition, over the last 20 years; however, this field has had little focus or practical impact on working dog training. The aims of this narrative review are to (1) orient the reader to key advances in animal behavior that we view as having important implications for working dog training, (2) highlight where such information is already implemented, and (3) indicate areas for future collaborative research bridging the gap between research and practice. Through a selective review of research on canine learning and behavior and training of working dogs, we hope to combine advances from scientists and practitioners to lead to better, more targeted, and functional research for working dogs.

Cooperative Communication with Humans Evolved to Emerge Early in Domestic Dogs.

Although we know that dogs evolved from wolves, it remains unclear how domestication affected dog cognition. One hypothesis suggests dog domestication altered social maturation by a process of selecting for an attraction to humans.1-3 Under this account, dogs became more flexible in using inherited skills to cooperatively communicate with a new social partner that was previously feared and expressed these unusual social skills early in development.4-6 Here, we comparedog (n = 44) and wolf (n = 37) puppies, 5-18 weeks old, on a battery of temperament and cognition tasks. We find that dog puppies are more attracted to humans, read human gestures more skillfully, and make more eye contact with humans than wolf puppies. The two species are similarly attracted to familiar objects and perform similarly on non-social measures of memory and inhibitory control. These results are consistent with the idea that domestication enhanced the cooperative-communicative abilities of dogs as selection for attraction to humans altered social maturation.

Early-emerging and highly heritable sensitivity to human communication in dogs.

Human cognition is believed to be unique in part because of early-emerging social skills for cooperative communication.1 Comparative studies show that at 2.5 years old, children reason about the physical world similarly to other great apes, yet already possess cognitive skills for cooperative communication far exceeding those in our closest primate relatives.2,3 A growing body of research indicates that domestic dogs exhibit functional similarities to human children in their sensitivity to cooperative-communicative acts. From early in development, dogs flexibly respond to diverse forms of cooperative gestures.4,5 Like human children, dogs are sensitive to ostensive signals marking gestures as communicative, as well as contextual factors needed for inferences about these communicative acts.6-8 However, key questions about potential biological bases for these abilities remain untested. To investigate their developmental and genetic origins, we tested 375 8-week-old dog puppies on a battery of social-cognitive measures. We hypothesized that if dogs' skills for cooperating with humans are biologically prepared, then they should emerge robustly in early development, not require extensive socialization or learning, and exhibit heritable variation. Puppies were highly skillful at using diverse human gestures, and we found no evidence that their performance required learning. Critically, over 40% of the variation in dogs' point-following abilities and attention to human faces was attributable to genetic factors. Our results suggest that these social skills in dogs emerge early in development and are under strong genetic control.

Enhancing the Selection and Performance of Working Dogs.

Dogs perform a variety of integral roles in our society, engaging in work ranging from assistance (e.g., service dogs, guide dogs) and therapy to detection (e.g., search-and-rescue dogs, explosive detection dogs) and protection (e.g., military and law enforcement dogs). However, success in these roles, which requires dogs to meet challenging behavioral criteria and to undergo extensive training, is far from guaranteed. Therefore, enhancing the selection process is critical for the effectiveness and efficiency of working dog programs and has the potential to optimize how resources are invested in these programs, increase the number of available working dogs, and improve working dog welfare. In this paper, we review two main approaches for achieving this goal: (1) developing selection tests and criteria that can efficiently and effectively identify ideal candidates from the overall pool of candidate dogs, and (2) developing approaches to enhance performance, both at the individual and population level, via improvements in rearing, training, and breeding. We summarize key findings from the empirical literature regarding best practices for assessing, selecting, and improving working dogs, and conclude with future steps and recommendations for working dog organizations, breeders, trainers, and researchers.

How do non-human primates represent others' awareness of where objects are hidden?

Although non-human primates (NHPs) generally appear to predict how knowledgeable agents use knowledge to guide their behavior, the cognitive mechanisms that enable this remain poorly understood. We assessed the conditions under which NHPs' representations of an agent's awareness break down. Free-ranging rhesus macaques (Macaca mulatta) watched as an agent observed a target object being hidden in one of two boxes. While the agent could no longer see the boxes, the box containing the object flipped open and the object either changed in size/shape (Experiment 1) or color (Experiment 2). Monkeys looked longer when the agent searched for the object incorrectly rather than correctly following the color change (a non-geometric manipulation), but not the size/shape change (a geometric manipulation). Even though the agent maintained knowledge of the object's location in both cases, monkeys no longer expected the agent to search correctly after it had been geometrically (but not non-geometrically) manipulated. Experiment 3 confirmed that monkeys were sensitive to the color manipulation used in Experiment 2, making it unlikely that a failure to perceive the color manipulation accounted for our findings. Our results show that NHPs do not always expect that knowledgeable agents will act on their knowledge to obtain their goals, consistent with heuristic-based accounts of how NHPs represent others' mental states. These findings also suggest that geometric changes that occur outside the agent's perceptual access may disrupt attribution of awareness more so than non-geometric changes.

Dog cognitive development: a longitudinal study across the first 2 years of life.

While our understanding of adult dog cognition has grown considerably over the past 20 years, relatively little is known about the ontogeny of dog cognition. To assess the development and longitudinal stability of cognitive traits in dogs, we administered a battery of tasks to 160 candidate assistance dogs at 2 timepoints. The tasks were designed to measure diverse aspects of cognition, ranging from executive function (e.g., inhibitory control, reversal learning, memory) to sensory discrimination (e.g., vision, audition, olfaction) to social interaction with humans. Subjects first participated as 8-10-week-old puppies, and then were retested on the same tasks at ~ 21 months of age. With few exceptions, task performance improved with age, with the largest effects observed for measures of executive function and social gaze. Results also indicated that individual differences were both early emerging and enduring; for example, social attention to humans, use of human communicative signals, independent persistence at a problem, odor discrimination, and inhibitory control all exhibited moderate levels of rank-order stability between the two timepoints. Using multiple regression, we found that young adult performance on many cognitive tasks could be predicted from a set of cognitive measures collected in early development. Our findings contribute to knowledge about changes in dog cognition across early development as well as the origins and developmental stability of individual differences.

Is Oxytocin "Nature's Medicine"?

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.