The Influence of Environmental Enrichment on Affective and Neural Consequences of Social Isolation Across Development.

Social stress is associated with depression and anxiety, physiological disruptions, and altered brain morphology in central stress circuitry across development. Environmental enrichment strategies may improve responses to social stress. Socially monogamous prairie voles exhibit analogous social and emotion-related behaviors to humans, with potential translational insight into interactions of social stress, age, and environmental enrichment. This study explored the effects of social isolation and environmental enrichment on behaviors related to depression and anxiety, physiological indicators of stress, and dendritic structural changes in amygdala and hippocampal subregions in young adult and aging prairie voles. Forty-nine male prairie voles were assigned to one of six groups divided by age (young adult vs. aging), social structure (paired vs. isolated), and housing environment (enriched vs. non-enriched). Following 4 weeks of these conditions, behaviors related to depression and anxiety were investigated in the forced swim test and elevated plus maze, body and adrenal weights were evaluated, and dendritic morphology analyses were conducted in hippocampus and amygdala subregions. Environmental enrichment decreased immobility duration in the forced swim test, increased open arm exploration in the elevated plus maze, and reduced adrenal/body weight ratio in aging and young adult prairie voles. Age and social isolation influenced dendritic morphology in the basolateral amygdala. Age, but not social isolation, influenced dendritic morphology in the hippocampal dentate gyrus. Environmental enrichment did not influence dendritic morphology in either brain region. These data may inform interventions to reduce the effects of social stressors and age-related central changes associated with affective behavioral consequences in humans.

Behavioral and neuroendocrine consequences of disrupting a long-term monogamous social bond in aging prairie voles.

Social support from a spouse, long-term partner, or someone who provides emotional or instrumental support may protect against consequences of aging, including mediating behavioral stress reactivity and altering neurobiological process that underlie short-term stress responses. Therefore, long-term social bonding may have behavioral and neurobiological benefits. The socially monogamous prairie vole provides a valuable experimental model for investigating the benefits of long-term social bonds on short-term stress reactivity in aging animals, given their unique social structure of forming enduring opposite-sex bonds, living in family groups, and bi-parental rearing strategies. Male-female pairs of long-term, cohabitating prairie voles were investigated for short-term behavioral and neuroendocrine stress reactivity following either long-term social pairing (control), or a period of social isolation. In Experiment 1, social isolation was associated with altered behavioral reactivity to an acute swim stressor, and greater neural activation in the hypothalamic paraventricular nucleus, as well as specifically the parvocellular region, following the swim stressor (vs. control). In Experiment 2, social isolation was associated with greater corticosterone reactivity following an acute restraint stressor (vs. control). No sex differences were observed. Exploratory correlation and subgroup analyses revealed systematic relationships among various demographic variables (such as age of the subjects, amount of time the pair cohabitated together, and number of litters the pair reared together) and the behavioral and neuroendocrine outcome measures. These findings may inform our understanding of the benefits of long-term social bonding on modulating short-term behavioral and neuroendocrine responses to stress.LAY SUMMARYReceiving social support from a long-term spouse or partner, or having a strong support network from friends, may have important health benefits as people age. In aging monogamous prairie voles, social isolation from a long-term social partner disrupted behaviors and short-term stress responses, whereas living with a long-term partner protected against these disruptions. This research is important for our understanding of the benefits of social support on stress responses as we age.

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.

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.

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.

The Influence of Environmental Enrichment on Cardiovascular and Behavioral Responses to Social Stress.

OBJECTIVE: Stress is linked to negative cardiovascular consequences and increases in depressive behaviors. Environmental enrichment (EE) involves exposure to novel items that provide physical and cognitive stimulation. EE has behavioral, cognitive, and neurobiological effects that may improve stress responses in humans and animal models. This study investigated the potential protective effects of EE on behavior and cardiovascular function in female prairie voles after a social stressor. METHODS: Radiotelemetry transmitters were implanted into female prairie voles to measure heart rate (HR) and heart rate variability (HRV) throughout the study. All females were paired with a male partner for 5 days, followed by separation from their partner for 5 additional days, and a 10-day treatment period. Treatment consisted of continued isolation, isolation with EE, or re-pairing with the partner (n = 9 per group). After treatment, animals were observed in the forced swim test (FST) for measures of stress coping behaviors. RESULTS: Isolation elevated HR and reduced HRV relative to baseline for all groups (p < .001). HR and HRV returned to baseline in the EE and re-paired groups, but not in the continued isolation group (p < .001). Animals in the EE and re-paired groups displayed significantly lower immobility time (p < .001) and HR (p < .03) during the FST, with a shorter latency for HR to return to baseline levels after the FST, relative to the continued isolation group (p < .001). CONCLUSIONS: EE and re-pairing reversed the negative behavioral and cardiovascular consequences associated with social isolation.

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.