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.

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.

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.

Lymph node status combined with lymphovascular invasion creates a more powerful tool for predicting outcome in patients with invasive breast cancer.

BACKGROUND: Multiple clinical, biologic, and pathologic factors are known to correlate with outcome in patients with invasive breast cancer. The utility of lymphovascular invasion as an additional useful prognostic indicator has been heretofore ill defined. The purpose of the current study was to determine whether the presence or absence of peritumoral lymphovascular invasion (LVI) contribute further significant information in assessing survival. METHODS: Using a prospective database of 1,258 patients with invasive breast cancer followed up for as long as 12 years, eight factors were evaluated for their impact on patient survival: lymph node status, LVI, age at diagnosis, tumor size, tumor palpability, estrogen and progesterone receptor status, and nuclear grade. RESULTS: Multivariate analysis revealed that both lymph node status and the presence or absence of LVI were highly significant independent predictors of outcome. CONCLUSIONS: Knowledge of both lymph node status and the presence or absence of LVI can be used to predict which subset of patients will do extremely well (node negative + LVI absent) or extremely poorly (node positive + LVI present). The combination of the two factors is most meaningful in patients with 1 to 3 positive nodes.