Hypothalamic oxytocin mediates social buffering of the stress response

Abstract

Background: While 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.

Methods: Female 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).

Results: We 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.

Conclusions: Together, 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.

Keywords: Corticosterone; HPA axis; elevated plus maze; immobilization stress; pair-bond; social buffering.

Figure 1

Social support attenuated the behavioral and hormonal stress response 30 min post-immobilization. (A,B) Immobilized females recovering alone (Alone) displayed a substantial increase in EPM anxiety-like behaviors, including delayed open arm latency, fewer open arms entries, and reduced open arm duration. By contrast, females recovering with their social partner (Partner) displayed low anxiety-like behavior similar to the handle controls (HAN). (C) These effects seemed to be behavior-specific as total arm entries, a locomotor measure, did not vary between groups. (D) In addition to elevated EPM anxiety-like behavior, immobilized females recovering alone displayed a rise in circulating corticosterone concentrations, but females recovering with their male social partner had corticosterone levels similar to HAN controls. Social controls (SC) are non-immobilized females removed from their social partner for 30 min prior to the EPM test. Bars labeled with different letters differ significantly by post hoc SNK test in which a significant main effect was detected in the ANOVA (p < 0.05). Data are expressed as mean ± SEM.

Figure 2

During the initial 30 min of recovery after immobilization, social support reduced female stress-related behavior, but only males increased social behavior following immobilization. (A,B) Immobilized females recovering alone displayed significant increases in stress-related behavior, including rearing, self-grooming, and route tracing as well as a composite score that accounts for all stress-related behaviors (i.e., stress index), values represent a raw change score in female stress-related behaviors (post-stress minus pre-stress values). (C,D) Females did not change their social behavior after being immobilized, values represent a raw change score in female social behaviors. (E,F) Males increased their display of social behaviors when their female partners returned after experiencing immobilization, values represent a raw change score in male social behaviors. Bars labeled with asterisks indicate a significant change between pre- and post-stress values as determined by a one-sample or paired t-test (p < 0.05). Data are expressed as mean ± SEM.

Figure 3

Neurochemical changes occurred as a result of immobilization and social support in the PVN. (A) Immobilized females had significantly lower optical density (OD) of oxytocin receptor (OTR) in the PVN. (B) V1aR expression was also lower in the PVN following immobilization. Social controls (SC) are non-immobilized females removed from their social partner for 30 min prior to sacrifice and tissue collection. (C) Recovering from immobilization with a social partner induced a reduction in the oxytocin (OT) content in the PVN. (D,E) No changes were observed in vasopressin (AVP) or CRH content. Bars labeled with different letters differ significantly by post hoc SNK test in which a significant main effect was detected in the ANOVA (p < 0.05). Data are expressed as mean ± SEM.

Figure 4

Social support promotes oxytocin release in the PVN. (A) Schematic drawing (left, adapted from (50)) and representative photomicrograph of vole brain section (right) illustrates location of microdialysis probe placement in the PVN. (B) Microdialysis was used to measure extracellular oxytocin concentrations when immobilized females recovered alone or with their social partner. Immobilization significantly increased oxytocin outflow in the PVN in all females as compared to baseline. However, during the recovery period, extracellular oxytocin concentrations only increased above baseline levels when immobilized females recovered with their social partner. Asterisks indicate differences from baseline while plus signs indicate group differences at a specific time point, determined by post hoc SNK test in which a significant main effect or interaction was detected in the ANOVA (p < 0.05). Data are expressed as mean ± SEM.

Figure 5

Oxytocin is sufficient to reduce the stress response and necessary for the social buffering effect. (A) Schematic illustrations (left, adapted from (50)) and representative photomicrograph of vole brain section (right) demonstrating location of micro-injections in the PVN. All females received bilateral implantation of guide cannulae in the PVN. Females were then immobilized, injected with a vehicle (artificial cerebrospinal fluid; CSF), oxytocin (OT; 10 ng or 100 ng/200nl/side), or a selective oxytocin receptor antagonist (OTRa; 10 ng or 100 ng/200nl/side), and recovered alone or with their male partner. (B–D) Females recovering alone displayed elevated EPM anxiety-like behavior unless they received an intra-PVN oxytocin injection. By contrast, females recovering with their partner displayed reduced EPM anxiety-like behavior compared to females recovering alone. When females recovering with their partner received an intra-PVN injection of a selective oxytocin receptor antagonist, no social buffering effects were observed on behavior. (E) No group differences were observed in total arm entries. (F) Social support and oxytocin injections reduced circulating corticosterone concentrations as compared to females recovering alone. However, when females recovering with their social partner receiving an intra-PVN selective oxytocin receptor antagonist injection, corticosterone levels were elevated, similar to females recovering alone. Bars labeled with different letters differ significantly by post hoc SNK test in which a significant main effect or interaction was detected in the ANOVA (p < 0.05). Data are expressed as mean ± SEM.