Social isolation and oxytocin antagonism increase emotion-related behaviors and heart rate in female prairie voles.

Social isolation influences depression- and anxiety-related disorders and cardiac function. Oxytocin may mediate these conditions through interactions with social behavior, emotion, and cardiovascular function, via central and/or peripheral mechanisms. The present study investigated the influence of oxytocin antagonism using L-368,899, a selective oxytocin receptor antagonist that crosses the blood-brain barrier, on depression- and anxiety-related behaviors and heart rate in prairie voles. This rodent species has translational value for investigating interactions of social stress, behavior, cardiac responses, and oxytocin function. Adult female prairie voles were socially isolated or co-housed with a sibling for 4 weeks. A subset of animals in each housing condition was subjected to 4 sessions of acute L-368,899 (20 mg/kg, ip) or saline administration followed by a depression- or anxiety-related behavioral assessment. A subset of co-housed animals was evaluated for cardiac function following acute administration of L-368,899 (20 mg/kg, ip) and during behavioral assessments. Social isolation (vs. co-housing) increased depression- and anxiety-related behaviors. In isolated animals, L-368,899 (vs. vehicle) did not influence anxiety-related behaviors but exacerbated depression-related behaviors. In co-housed animals, L-368,899 exacerbated depression-related behaviors and increased heart rate at baseline and during behavioral tests. Social isolation produces emotion-related behaviors in prairie voles; central and/or peripheral oxytocin antagonism exacerbates these behavioral signs. Oxytocin antagonism induces depression-relevant behaviors and increases basal and stressor-reactive heart rate in co-housed prairie voles, similar to the consequences of social isolation demonstrated in this model. These results provide translational value for humans who experience behavioral and cardiac consequences of loneliness or social stress.

Differential paraventricular nucleus activation and behavioral responses to social isolation in prairie voles following environmental enrichment with and without physical exercise.

Social stressors produce neurobiological and emotional consequences in social species. Environmental interventions, such as environmental enrichment and exercise, may modulate physiological and behavioral stress responses. The present study investigated the benefits of environmental enrichment and exercise against social stress in the socially monogamous prairie vole. Female prairie voles remained paired with a sibling (control) or were isolated from a sibling for 4 weeks. The isolated groups were assigned to isolated sedentary, isolated with environmental enrichment, or isolated with both enrichment and exercise conditions. Behaviors related to depression, anxiety, and sociality were investigated using the forced swim test (FST), elevated plus maze (EPM), and a social crowding stressor (SCS), respectively. cFos expression was evaluated in stress-related circuitry following the SCS. Both enrichment and enrichment with exercise protected against depression-relevant behaviors in the FST and social behavioral disruptions in the SCS, but only enrichment with exercise protected against anxiety-related behaviors in the EPM and altered cFos expression in the hypothalamic paraventricular nucleus in isolated prairie voles. Enrichment may improve emotion-related and social behaviors, however physical exercise may be an important component of environmental strategies for protecting against anxiety-related behaviors and reducing neural activation as a function of social stress.

Physiological and behavioral responses to observing a sibling experience a direct stressor in prairie voles.

Uncontrollable stress precipitates negative mental and physical health outcomes. Furthermore, the vicarious experience of stress (e.g. observing another individual experience a direct stressor) can mimic the effects of directly experiencing the stressor. The current experiment examined the behavioral and physiological effects of the vicarious experience of stress using the socially monogamous prairie vole. Male prairie voles were exposed to either an empty open field chamber, or a chamber in which the animal observed a sibling undergoing a concurrent direct physical stressor (tail suspension test) for five minutes. Exploratory and anxiety-like behaviors were recorded in all observers during the test session. Cardiac indices of heart rate and heart rate variability were recorded in a subset of observers prior to, during, and following the test session. Corticosterone levels were measured in all observers and siblings following the test session. When compared to animals exposed to an empty open field chamber, animals that observed a sibling undergo a direct physical stressor exhibited increased heart rate and circulating corticosterone, and decreased heart rate variability. These physiological stress indicators were supported by behavioral changes, including increased freezing followed immediately by orienting of the head toward the center of the apparatus, and decreased locomotion, grooming, and rearing. These preliminary results suggest that prairie voles experience stress vicariously, and provide a foundation for additional studies focused on the underlying mechanisms of vicarious stress. The use of this model may inform our understanding of the social transmission of stress among social species, including humans.LAY SUMMARYThe experience of stress, including observing stress in a loved one, has negative consequences on mental and physical health. This study used a social rodent (prairie voles) to demonstrate that stress transfers among social individuals, consequently producing an increased physiological and behavioral stress response in prairie voles observing their siblings experience stress. This research informs our understanding of the interactions of social experiences and stress in humans.

Central oxytocin alters cortisol and behavioral responses of guinea pig pups during isolation in a novel environment.

The neuropeptide oxytocin plays key roles in social bonding and stress reduction, and thus appears to be a likely mediator of maternal buffering of infant stress responses. In the guinea pig, the presence of the mother in a threatening environment buffers cortisol elevations as well as active (vocalizing) and passive (e.g. crouching) responses typical of isolation in this species; yet, effects of OT in guinea pig pups under any conditions have not been reported. Here, we examined the ability of intracerebroventricular (ICV) OT to moderate plasma cortisol levels and behavior in guinea pig pups isolated in a brightly lit, novel environment, and the ability of a highly selective OT antagonist (OTA) to reduce buffering by the mother. We found that ICV OT moderated cortisol levels and vocalizations, but increased time spent in the crouched stance, particularly in females. In addition, OT modulated other ongoing behaviors in a sex-dependent fashion. In females, OT reduced duration of walking and rearing, and increased time spent quiet, while in males OT increased duration of rearing. OTA, however, was without effect on cortisol levels or behavior. These findings, including sex differences in response, extend results from other species to the guinea pig. Further, while demonstrating that exogenous OT is sufficient to reduce biobehavioral stress responses typical of isolated guinea pig infants, the results suggest that endogenous OT is not necessary for maternal buffering of infant responses in this species.

The negative effects of social bond disruption are partially ameliorated by sertraline administration in prairie voles.

Negative social experiences influence both depression and cardiovascular dysfunction. Many individuals who experience negative mood states or cardiovascular conditions have limited social support. Therefore, investigation of drug treatments that may protect against the consequences of social stress will aid in designing effective treatment strategies. The current study used an animal model to evaluate the protective effect of sertraline administration on behavioral and cardiovascular consequences of social stress. Specifically, male prairie voles (Microtus ochrogaster), which are socially monogamous rodents that share several behavioral and physiological characteristics with humans, were isolated from a socially-bonded female partner, and treated with sertraline (16 mg/kg/day, ip) or vehicle during isolation. Unexpectedly, sertraline did not protect against depression-relevant behaviors, and it was associated with increased short- and long-term heart rate responses. However, sertraline administration improved heart rate variability recovery following a behavioral stressor, including increased parasympathetic regulation, and altered long-term neuronal activity in brain regions that modulate autonomic control and stress reactivity. These results indicate that sertraline may partially protect against the consequences of social stressors, and suggest a mechanism through which sertraline may beneficially influence neurobiological control of cardiac function.

Protective neuroendocrine effects of environmental enrichment and voluntary exercise against social isolation: evidence for mediation by limbic structures.

Previous research indicates that loneliness and social isolation may contribute to behavioral disorders and neurobiological dysfunction. Environmental enrichment (EE), including both cognitive and physical stimulation, may prevent some behavioral, endocrine, and cardiovascular consequences of social isolation; however, specific neural mechanisms for these benefits are still unclear. Therefore, this study examined potential neuroendocrine protective effects of both EE and exercise. Adult female prairie voles were randomly assigned to one of four experimental conditions: paired control, social isolation/sedentary, social isolation/EE, and social isolation/voluntary exercise. All isolated animals were housed individually for 8 weeks, while paired animals were housed with their respective sibling for 8 weeks. Animals in the EE and voluntary exercise conditions received EE items (including a running wheel) and a running wheel only, respectively, at week 4 of the isolation period. At the end of the experiment, plasma and brains were collected from all animals for corticosterone and FosB and delta FosB (FosB/ΔFosB) - immunoreactivity in stress-related brain regions. Overall, social isolation increased neuroendocrine stress responses, as reflected by the elevation of corticosterone levels and increased FosB/ΔFosB-immunoreactivity in the basolateral amygdala (BLA) compared to paired animals; EE and voluntary exercise attenuated these increases. EE and exercise also increased FosB/ΔFosB-immunoreactivity in the medial prefrontal cortex (mPFC) compared to other conditions. Limbic structures statistically mediated hypothalamic immunoreactivity in EE and exercise animals. This research has translational value for socially isolated individuals by informing our understanding of neural mechanisms underlying responses to social stressors. Highlights Prolonged social isolation increased basal corticosterone levels and basolateral amygdala immunoreactivity. Environmental enrichment and exercise buffered corticosterone elevations and basolateral amygdala hyperactivity. Protective effects of environmental enrichment and exercise may be mediated by medial prefrontal cortex and limbic structures.

Wheel access has opposing effects on stress physiology depending on social environment in female prairie voles (Microtus ochrogaster).

Physical exercise and chronic social stress are both known to impact general health and hypothalamic-pituitary-adrenal (HPA) axis function, albeit typically in opposing directions. Therefore, the question we investigated in this study was how these two factors - physical exercise and chronic social isolation - would interact when presented simultaneously in a female rodent model. Adult female prairie voles were separated into four experimental groups: (1) isolated without wheel access, (2) isolated with wheel access, (3) paired without wheel access, and (4) paired with wheel access. Plasma, hair, and adrenal glands were sampled to investigate changes in stress physiology. Our results indicate that, when isolated, wheel access had a mitigating effect on HPA activity. However, in paired animals, wheel access had the opposite effect, as both adrenal mass and increase in hair corticosterone concentrations were greater in paired animals with wheel access. Strong correlations were detected between change in hair corticosterone and adrenal mass, while no correlations were found between plasma corticosterone and either of the other markers. These results imply that the HPA axis is highly sensitive to both the social environment and the physical demands placed on the individual, and that when investigating the effects of chronic isolation, both hair corticosterone and adrenal mass may be more reliable markers than a single plasma corticosterone sample.

Behavioral and cardiovascular consequences of disrupted oxytocin communication in cohabitating pairs of male and female prairie voles.

Negative social experiences may influence psychological and physiological health via altered central oxytocin communication. The prairie vole is valuable for investigating the potential influence of oxytocin on responses to social experiences. Prairie voles are socially monogamous, live in pairs or family groups, and respond negatively to changes in the social environment. This study investigated the hypothesis that disruptions of oxytocin in one prairie vole of a cohabitating male-female pair would alter social behavior in that specific animal; and these behavioral changes in turn would influence the untreated partner's behavior and physiology. Pharmacological antagonism of oxytocin with the receptor antagonist L-368,899 in the male prairie vole disrupted social behaviors between the male and his untreated female partner. This manipulation also negatively influenced the behavior and cardiovascular function in the untreated female partner, including increased: (a) depression-relevant behaviors in two behavioral stressors, (b) basal mean arterial pressure and heart rate, and (c) cardiovascular reactivity to the behavioral stressors. These results suggest that disruptions of oxytocin and social behavior in one animal may produce indicators of social stress in an untreated social partner. This preliminary research provides a foundation for future studies to investigate mechanisms underlying responses to social experiences in humans.

Adult males buffer the cortisol response of young guinea pigs: Changes with age, mediation by behavior, and comparison with prefrontal activity.

In the guinea pig, the presence of the mother buffers hypothalamic-pituitary-adrenal (HPA) responses of her young during exposure to a novel environment, and can do so even if she is anesthetized. In contrast, under comparable conditions other conspecifics (siblings, other adult females) are less effective or ineffective in doing so. However, we recently observed that an unfamiliar adult male reduced plasma cortisol elevations and increased Fos in the prefrontal cortex of preweaning pups exposed to a novel enclosure for 120min. Here we found adult males buffered the adrenocortical response of preweaning pups at 60 as well as 120min and of periadolescent guinea pigs if exposure was of 120min. Further, because males vigorously engaged in social interactions with the young during exposure, we examined the effect of behavior by comparing the impact of conscious and unconscious (anesthetized) adult males. When tested with a conscious but not unconscious male, pups exhibited reduced plasma cortisol elevations. Pups, particularly females, had greater Fos induction in the prefrontal cortex when with a conscious versus unconscious adult male. Overall, we found that an unfamiliar adult male can buffer the cortisol response of guinea pigs both before and after weaning, though more-prolonged exposure appears necessary in the older animals. Further, unlike buffering by the biological mother, the effect of the male is mediated by behavioral interactions. Thus, the buffering of the infant guinea pig's cortisol response by the mother and an unfamiliar adult male involve different underlying mechanisms.

Voluntary physical exercise protects against behavioral and endocrine reactivity to social and environmental stressors in the prairie vole.

Physical activity can combat detrimental effects of stress. The current study examined the potential protective effects of exercise against a combination of social isolation and chronic mild stress (CMS) in a prairie vole model. Female voles were isolated for 4 weeks, with the addition of CMS during the final 2 weeks. Half of the voles were allowed access to a running wheel during this final 2 weeks, while the other half remained sedentary. Animals underwent behavioral tests to assess depressive- and anxiety-behaviors. In a subset of animals, plasma was collected 10 minutes after behavioral testing for corticosterone analysis. In a separate subset, brains were collected 2 hours after behavioral testing for cFos analysis in the paraventricular nucleus (PVN). Voles in the exercise group displayed significantly lower depressive- and anxiety-behaviors, and displayed significantly lower corticosterone levels, compared to animals in the sedentary group. There was no difference in PVN cFos activity between groups. Interestingly, animals that moderately exercised displayed lower levels of depressive-behavior and attenuated corticosterone reactivity compared to animals in the low and high activity subgroups. These findings suggest that physical activity can protect against a combination of social and environmental stressors.