Adam S. Smith

Manipulation of the oxytocin system alters social behavior and attraction in pair-bonding primates, Callithrix penicillata

The establishment and maintenance of stable, long-term male-female relationships, or pair-bonds, are marked by high levels of mutual attraction, selective preference for the partner, and high rates of sociosexual behavior. Central oxytocin (OT) affects social preference and partner-directed social behavior in rodents, but the role of this neuropeptide has yet to be studied in heterosexual primate relationships. The present study evaluated whether the OT system plays a role in the dynamics of social behavior and partner preference during the first 3 weeks of cohabitation in male and female marmosets, Callithrix penicillata. OT activity was stimulated by intranasal administration of OT, and inhibited by oral administration of a non-peptide OT-receptor antagonist (L-368,899; Merck). Social behavior throughout the pairing varied as a function of OT treatment. Compared to controls, marmosets initiated huddling with their social partner more often after OT treatments but reduced proximity and huddling after OT antagonist treatments. OT antagonist treatment also eliminated food sharing between partners. During the 24-h preference test, all marmosets interacted more with an opposite-sex stranger than with the partner. By the third-week preference test, marmosets interacted with the partner and stranger equally with the exception that intranasal-OT treatments facilitated initial partner-seeking behavior over initial contact with the stranger. Our findings demonstrate that pharmacological manipulations of OT activity alter partner-directed social behavior during pair interactions, suggesting that central OT may facilitate the process of pair-bond formation and social relationships in marmoset monkeys.

Hypothalamic Oxytocin Mediates Social Buffering of the Stress Response

BACKGROUNDnWhile stressful life events can enhance the risk of mental disorders, positive social interactions can propagate good mental health and normal behavioral routines. Still, the neural systems that promote these benefits are undetermined. Oxytocin is a hormone involved in social behavior and stress; thus, we focus on the impact that social buffering has on the stress response and the governing effects of oxytocin.nnnMETHODSnFemale prairie voles (Microtus ochrogaster) were exposed to 1 hour immobilization stress and then recovered alone or with their male partner to characterize the effect of social contact on the behavioral, physiological, and neuroendocrine stress response. In addition, we treated immobilized female voles recovering alone with oxytocin or vehicle and female voles recovering with their male partner with a selective oxytocin receptor antagonist or vehicle. Group sizes varied from 6 to 8 voles (N = 98 total).nnnRESULTSnWe found that 1 hour immobilization increased anxiety-like behaviors and circulating levels of corticosterone, a stress hormone, in female prairie voles recovering alone but not the female prairie voles recovering with their male partner. This social buffering by the male partner on biobehavioral responses to stress was accompanied by increased oxytocin release in the paraventricular nucleus of the hypothalamus. Intra-paraventricular nucleus oxytocin injections reduced behavioral and corticosterone responses to immobilization, whereas injections of an oxytocin receptor antagonist blocked the effects of the social buffering.nnnCONCLUSIONSnTogether, our data demonstrate that paraventricular nucleus oxytocin mediates the social buffering effects on the stress response and thus may be a target for treatment of stress-related disorders.

Salubrious effects of oxytocin on social stress-induced deficits

Social relationships are a fundamental aspect of life, affecting social, psychological, physiological, and behavioral functions. While positive social interactions can attenuate stress and promote health, the social environment can also be a major source of stress when it includes social disruption, confrontation, isolation, or neglect. Social stress can impair the basal function and stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis, impairing function of multiple biological systems and posing a risk to mental and physical health. In contrast, social support can ameliorate stress-induced physiological and immunological deficits, reducing the risk of subsequent psychological distress and improving an individuals overall well-being. For better clinical treatment of these physiological and mental pathologies, it is necessary to understand the regulatory mechanisms of stress-induced pathologies as well as determine the underlying biological mechanisms that regulate social buffering of the stress system. A number of ethologically relevant animal models of social stress and species that form strong adult social bonds have been utilized to study the etiology, treatment, and prevention of stress-related disorders. While undoubtedly a number of biological pathways contribute to the social buffering of the stress response, the convergence of evidence denotes the regulatory effects of oxytocin in facilitating social bond-promoting behaviors and their effect on the stress response. Thus, oxytocin may be perceived as a common regulatory element of the social environment, stress response, and stress-induced risks on mental and physical health. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.

Breaking bonds in male prairie vole: long-term effects on emotional and social behavior, physiology, and neurochemistry.

Social relationships are essential for many fundamental aspects of life while bond disruption can be detrimental to mental and physical health. Male prairie voles form enduring social bonds with their female partners, allowing the evaluation of partner loss on behavior, physiology, and neurochemistry. Males were evaluated for partner preference formation induced by 24h of mating, and half were separated from their partner for 4 wk. In Experiment 1, partner loss significantly increased anxiety-like behaviors in the elevated plus maze and light-dark box tests and marginally increased depressive-like behaviors in the forced swim test. In addition, while intruder-directed aggression is common in pair bonded prairie voles, separated males were affiliative and lacked aggression toward an unfamiliar female and an intruding male conspecific. Partner loss increased the density of oxytocin-immunoreactivity (-ir), vasopressin-ir, and corticotrophin-releasing hormone-ir cells in the paraventricular nucleus of the hypothalamus and oxytocin-ir cells in the supraoptic nucleus. Tyrosine hydroxylase-ir was not affected. In Experiment 2, partner preference was observed after 2 wk of partner loss but eliminated after 4 wk partner loss. Body weight gain and plasma corticosterone concentrations were elevated throughout the 4 wk. No effects were observed for plasma oxytocin or vasopressin. Together, partner loss elicits anxiety-like and depression-like behaviors, disrupts bond-related behaviors, and alters neuropeptide systems that regulate such behaviors. Thus, partner loss in male prairie voles may provide a model to better understand the behavior, pathology, and neurobiology underlying partner loss and grief.

Local oxytocin tempers anxiety by activating GABAA receptors in the hypothalamic paraventricular nucleus

Oxytocin (Oxt) is released in various hypothalamic and extrahypothalamic brain areas in response to anxiogenic stimuli to regulate aspects of emotionality and stress coping. We examined the anxiolytic action of Oxt in the hypothalamic paraventricular nucleus (PVN) while appraising if Oxt recruits GABA neurons to inhibit the behavioral, hormonal, and neuronal response to stress in female prairie voles (Microtus ochrogaster). Voles received an injection of Oxt in the PVN either before or after an elevated platform stress to determine a time-course for the effects of Oxt on the hormonal stress response. Subsequently, we evaluated if ante-stress injections of Oxt affected anxiety-like behaviors as well as neuronal activity in the PVN, using real-time in-vivo retrodialysis and immunohistochemistry with c-Fos expression as a biomarker of neural activity. In addition, we exposed voles to Oxt and a GABAA receptor antagonist, concurrently, to evaluate the impact of pharmacological blockade of GABAA receptors on the anxiolytic effects of Oxt. Elevated platform stress amplified anxiety-like behaviors and hypothalamic-pituitary-adrenal (HPA) axis activity-catalyzing corticotrophin-releasing hormone (CRH) neuronal activity and augmenting corticosterone release in circulation. Ante-stress Oxt injections in the PVN blocked these stress effects while promoting PVN GABA activity and release. Post-stress Oxt treatments were ineffective. The anxiolytic effects of Oxt were hindered by concurrent pharmacological blockade of GABAA receptors. Together, our data demonstrate ante-stress treatments of Oxt in the PVN inhibit stress activation of the HPA axis through recruitment of GABAergic neurons, providing insights to the local circuitry and potential therapeutically-relevant mechanisms.

Social isolation affects partner-directed social behavior and cortisol during pair formation in marmosets, Callithrix geoffroyi

Pair-bonded relationships form during periods of close spatial proximity and high sociosexual contact. Like other monogamous species, marmosets form new social pairs after emigration or ejection from their natal group resulting in periods of social isolation. Thus, pair formation often occurs following a period of social instability and a concomitant elevation in stress physiology. Research is needed to assess the effects that prolonged social isolation has on the behavioral and cortisol response to the formation of a new social pair. We examined the sociosexual behavior and cortisol during the first 90-days of cohabitation in male and female Geoffroys tufted-ear marmosets (Callithrix geoffroyi) paired either directly from their natal group (Natal-P) or after a prolonged period of social isolation (ISO-P). Social isolation prior to pairing seemed to influence cortisol levels, social contact, and grooming behavior; however, sexual behavior was not affected. Cortisol levels were transiently elevated in all paired marmosets compared to natal-housed marmosets. However, ISO-P marmosets had higher cortisol levels throughout the observed pairing period compared to Natal-P marmoset. This suggests that the social instability of pair formation may lead to a transient increase in hypothalamic-pituitary-adrenal (HPA) axis activity while isolation results in a prolonged HPA axis dysregulation. In addition, female social contact behavior was associated with higher cortisol levels at the onset of pairing; however, this was not observed in males. Thus, isolation-induced social contact with a new social partner may be enhanced by HPA axis activation, or a moderating factor.

Maternal gestational androgen levels in female marmosets (Callithrix geoffroyi) vary across trimesters but do not vary with the sex ratio of litters.

Maternal hormones can dramatically modify offspring phenotypes via organizational actions on morphological and behavioral development. In placental mammals, there is the possibility that some portion of hormones in maternal circulation may be derived from fetal origin. We tested the possibility that maternal androgens in pregnant female marmosets reflected, in part, contributions from male fetuses by comparing levels of urinary androgens across pregnancy in females carrying varying numbers of male offspring. We monitored urinary androgen excretion in 18 pregnancies from five female white-faced marmosets (Callithrix geoffroyi). Androgen levels rose significantly in the first trimester of pregnancy, reached a peak in the middle of the second trimester, and then declined gradually until parturition. At no point in pregnancy were levels of urinary androgens higher in females carrying litters that had 50% or more males than in females carrying litters that were less than 50% male. Levels of maternal androgens were not associated with litter size, the number of males in the litter, or with the proportion of the litter that was male. The high levels of androgen in pregnant females are therefore likely of strictly maternal origin, and any modification of fetal growth and development can be considered a maternal effect.

Maternal androgen levels during pregnancy are associated with early-life growth in Geoffroy's marmosets, Callithrix geoffroyi

Fetal development is a critical period of physical development, and factors in the intrauterine environment can cause lasting effects on the growth and development of offspring. There is little research evaluating organizational effects of early androgen exposure of endogenous maternal origins on the prenatal and postnatal growth of offspring. We evaluated the association between maternal androgen levels during gestation and pre- and postnatal growth of offspring. Maternal androgen levels in marmoset females were measured using enzyme immunoassays of urine samples acquired during 18 pregnancies. Somatic measurements of the resulting 25 viable offspring were taken on postnatal days (PND) 2, 30, 60, 120, 180, 240, and 300. Maternal androgen levels during the first trimester were negatively associated with weight, body length, and several girth measurements (i.e., torso, head, chest, and arm circumference) of offspring on PND 2. First trimester maternal androgen was also negatively associated with physical growth during early and late infancy but seemed to be positively associated with a rebound in juvenile growth. Exposure to maternal androgen during early gestation led to both a reduction in birth weight and postnatal catch-up for both males and females, equally. Fetal growth retardation and the reprogramming of metabolic tissues by exposure to prenatal androgen could be mediating factors of suppressed postnatal growth.

Behavioral and physiological responses of female prairie voles (Microtus ochrogaster) to various stressful conditions

Abstract Stressful life events elicit hypothalamic–pituitary–adrenal (HPA) axis activation, which may alter psychological states or behavioral routines. Therefore, the current study focused on the HPA axis response to better understand such manifestations in female prairie voles (Microtus ochrogaster). In Experiment 1, females were stressed for 1u2009h via one of the four stressors: exposure to a novel environment, immobilization (“plastic mesh”), brief social defeat, or prolonged social defeat. Following a 30-min recovery, the females received a 5-min elevated plus maze (EPM) test and, subsequently, blood was collected to measure plasma corticosterone concentrations. Only immobilization stress induced an anxiety-like behavioral response in the EPM test and elevated plasma corticosterone levels compared to the control groups. Corticosterone concentrations were also significantly elevated following exposure to prolonged social defeat compared to the control conditions, but not after novel environment stress or short social defeat. In Experiment 2, females were exposed to immobilization stress over 1, 3, or 7 days in a daily (predictable; pIMO) or irregular (unpredictable; uIMO) schedule. The biobehavioral stress response in females exposed to pIMO for 3 or 7 days did not differ significantly from controls, suggesting these females habituated. By comparison, females exposed to uIMO over 3 or 7 days did not habituate behaviorally or physiologically, even producing augmented corticosterone levels. In both experiments, positive correlations were found between corticosterone levels and anxiety-like behaviors in the EPM test. Together, our data suggest that the stress response by female prairie voles is dependent on stress intensity, source, previous experience, and predictability. Furthermore, the HPA axis response, as evident by corticosterone levels, is associated with the impact that these factors have on behavioral routine.

Prenatal Androgens Affect Development and Behavior in Primates

Maturation and differentiation persists throughout childhood, adolescence, and adult life into senescence; however, the foundation for normal postnatal development is established during fetal ontogeny. The organizational hypothesis proposes that nongenomic, environmental factors within the intrauterine environment attribute to prenatal programming (Phoenix et al. 1959). From the inception of this hypothesis over 50 years ago, researchers have documented the effects of exposure to prenatal steroid hormones, particularly androgens, on the behavior and growth of primate offspring. The effects of androgen within the intrauterine environment from maternal and exogenous sources can be observed in long-term changes to multiple developmental trajectories, including somatic growth, homeostatic functions of the body, and differentiation of sex-typical morphology, physiology, and behavior. Thus, the sensitivity and plasticity of the fetus during development toward androgens and other physiological cues from the mother and environment may underlie the development of diseases, a premise postulated by the Barker hypothesis (Barker 1998). In the current chapter, we discuss a number of prenatal and postnatal developmental outcomes associated with exposure to normal variations and excessive concentrations of androgens during prenatal life in human and nonhuman primates. In addition, it seems that the timing of androgen exposure during gestation and the sex of the fetus are two major factors that contribute to the concentration of androgens in the prenatal environment and the ultimate outcomes. Therefore, we also discuss the timing of androgen exposure during gestation and the sex of the fetus as modulating variables on the androgen-induced effects on development.