Evaluation of hemostatic devices in a randomized porcine model of junctional hemorrhage and 72-hour prolonged field care.

BACKGROUND: Hemorrhage control in prolonged field care (PFC) presents unique challenges that drive the need for enhanced point of injury treatment capabilities to maintain patient stability beyond the Golden Hour. To address this, two hemostatic agents, Combat Gauze (CG) and XSTAT, were evaluated in a porcine model of uncontrolled junctional hemorrhage for speed of deployment and hemostatic efficacy over 72 hours. METHODS: The left subclavian artery and subscapular vein were isolated in anesthetized male Yorkshire swine (70-85 kg) and injured via 50% transection, followed by 30 seconds of hemorrhage. Combat Gauze (n = 6) or XSTAT (n = 6) was administered until bleeding stopped and remained within subjects for observation over 72 hours. Physiologic monitoring, hemostatic efficacy, and hematological parameters were measured throughout the protocol. Gross necropsy and histology were performed following humane euthanasia. RESULTS: Both CG and XSTAT maintained hemostasis throughout the full duration of the protocol. There were no significant differences between groups in hemorrhage volume (CG: 1021.0 ± 183.7 mL vs. XSTAT: 968.2 ± 243.3 mL), total blood loss (CG: 20.8 ± 2.7% vs. XSTAT: 20.1 ± 5.1%), or devices used (CG: 3.8 ± 1.2 vs. XSTAT: 5.3 ± 1.4). XSTAT absorbed significantly more blood than CG (CG: 199.5 ± 50.3 mL vs. XSTAT: 327.6 ± 71.4 mL) and was significantly faster to administer (CG: 3.4 ± 1.6 minutes vs. XSTAT: 1.4 ± 0.5 minutes). There were no significant changes in activated clot time, prothrombin time, or international normalized ratio between groups or compared with baseline throughout the 72-hour protocol. Histopathology revealed no evidence of microthromboemboli or disseminated coagulopathies across evaluated tissues in either group. CONCLUSION: Combat Gauze and XSTAT demonstrated equivalent hemostatic ability through 72 hours, with no overt evidence of coagulopathies from prolonged indwelling. In addition, XSTAT offered significantly faster administration and the ability to absorb more blood. Taken together, XSTAT offers logistical and efficiency advantages over CG for immediate control of junctional noncompressible hemorrhage, particularly in a tactical environment. In addition, extension of indicated timelines to 72 hours allows translation to PFC.

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.

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.

Morphological changes in the basolateral amygdala and behavioral disruptions associated with social isolation.

Social isolation and the disruption of established social bonds contribute to several physical and psychological health issues. Animal models are a useful tool for investigating consequences of social stress, including social isolation. The current study examined morphological changes in the basolateral amygdala (BLA) and affect-related behavioral and endocrine changes due to prolonged social isolation, using the translational prairie vole model (Microtus ochrogaster). Adult male prairie voles were either socially paired (control) or isolated from a same-sex sibling for 4 weeks. Following this 4-week period, a subset of animals (n = 6 per condition) underwent a series of behavioral tasks to assess affective, social, and stress-coping behaviors. Plasma was collected following the last behavioral task for stressor-induced endocrine assays. Brains were collected from a separate subset of animals (n = 10 per condition) following the 4-week social housing period for dendritic structure analyses in the BLA. Social isolation was associated with depressive- and anxiety-like behaviors, as well as elevated oxytocin reactivity following a social stressor. Social isolation was also associated with altered amount of dendritic material in the BLA, with an increase in spine density. These results provide further evidence that social isolation may lead to the development of affective disorders. Dysfunction in the oxytocin system and BLA remodeling may mediate these behavioral changes. Further research will promote an understanding of the connections between oxytocin function and structural changes in the BLA in the context of social stress. This research can facilitate novel treatments for alleviating or preventing behavioral and physiological consequences of social stressors 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.

Noninvasive Cerebral Perfusion and Oxygenation Monitoring Augment Prolonged Field Care in a Non-Human Primate Model of Decompensated Hemorrhage and Resuscitation.

BACKGROUND: Decompensated hemorrhagic shock (DHS) is the leading cause of preventable death in combat casualties. "Golden hour" resuscitation effects on cerebral blood flow and perfusion following DHS in prolonged field care (PFC) are not well investigated. Using an established non-human primate model of DHS, we hypothesized noninvasive regional tissue oxygenation (rSO2) and Transcranial Doppler (TCD) would correlate to the invasive measurement of partial pressure of oxygen (PtO2) and mean arterial pressure (MAP) in guiding hypotensive resuscitation in a PFC setting. METHODS: Ten rhesus macaques underwent DHS followed by a 2 h PFC phase (T0-T120), and subsequent 4 h hospital resuscitation phase (T120-T360). Invasive monitoring (PtO2, MAP) was compared against noninvasive monitoring systems (rSO2, TCD). Results were analyzed using t tests and one-way repeated measures ANOVA. Linear correlation was determined via Pearson r. Significance = P < 0.05. RESULTS: MAP, PtO2, rSO2, and mean flow velocity (MFV) significantly decreased from baseline at T0. MAP and PtO2 were restored to baseline by T15, while rSO2 was delayed through T30. At T120, MFV returned to baseline, while the Pulsatility Index significantly elevated by T120 (1.50 ±â€Š0.31). PtO2 versus rSO2 (R2 = 0.2099) and MAP versus MFV (R2 = 0.2891) shared very weak effect sizes, MAP versus rSO2 (R2 = 0.4636) displayed a low effect size, and PtO2 versus MFV displayed a moderate effect size (R2 = 0.5540). CONCLUSIONS: Though noninvasive monitoring methods assessed here did not correlate strongly enough against invasive methods to warrant a surrogate in the field, they do effectively augment and direct resuscitation, while potentially serving as a substitute in the absence of invasive capabilities.

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.

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.

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.

Making waves: Comparing Morris water task performance in rats and prairie voles.

Spatial processing is a critical component for survival. This domain of information processing has been extensively studied in rats and mice. Limited work has examined the capacity of other rodent species, like the prairie vole (Microtus ochrogaster), to process spatial information. The Morris water task (MWT) is a classic spatial task that has been used to examine spatial cognition in rodents. This task involves an animal developing configural relationships between extra-maze cues and the location of a hidden platform to successfully escape from a pool of water. The current study compared performance in the MWT between rats and prairie voles. Rats were observed to outperform prairie voles in key aspects of the task including latency to find the platform, directness of swim paths to the platform, and degrees of heading error. These results may be attributed to potential interspecies differences in spatial cognition, stress reactivity, physiology, or motivation. This study provides the foundation for future work investigating the spatial cognition of prairie voles and the factors that contribute to water task performance in rodents.

Cardiac and behavioral effects of social isolation and experimental manipulation of autonomic balance.

Improved understanding of how depression and social isolation interact to increase cardiac morbidity and mortality will improve public health. This experiment evaluated the effect of pharmacological autonomic blockade on cardiac and behavioral reactivity following social isolation in prairie voles. Experiment 1 validated the dose and time course of pharmacological autonomic antagonism of peripheral ß-adrenergic (atenolol) and muscarinic cholinergic receptors (atropine methyl nitrate), and Experiment 2 used a novel protocol to investigate behavioral responses in the tail suspension test during pharmacological autonomic blockade as a function of social isolation (vs. paired control). Prairie voles isolated for 4 weeks (vs. paired) displayed significantly elevated heart rate and reduced heart rate variability. Autonomic receptor antagonism by atenolol led to exaggerated reductions in heart rate and standard deviation of normal-to-normal intervals, and lower amplitude of respiratory sinus arrhythmia in the isolated group (vs. paired). Administration of atropine led to an attenuated increase in heart rate in the isolated group (vs. paired), and similar near-zero levels of respiratory sinus arrhythmia amplitude in both groups. During the tail suspension test, isolated animals (vs. paired) displayed significantly greater immobility. In paired animals, atenolol administration did not influence immobility; atropine administration increased the duration of immobility (vs. vehicle). In isolated animals, atenolol administration increased the duration of immobility; atropine did not influence immobility duration (vs. vehicle). The current study contributes to our understanding of differential effects of social isolation and autonomic imbalance on cardiac and behavioral reactivity.

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.

Social isolation alters central nervous system monoamine content in prairie voles following acute restraint.

Animal models have shown that social isolation and other forms of social stress lead to depressive- and anxiety-relevant behaviors, as well as neuroendocrine and physiological dysfunction. The goal of this study was to investigate the effects of prior social isolation on neurotransmitter content following acute restraint in prairie voles. Animals were either paired with a same-sex sibling or isolated for 4 weeks. Plasma adrenal hormones and ex vivo tissue concentrations of monoamine neurotransmitters and their metabolites were measured following an acute restraint stressor in all animals. Isolated prairie voles displayed significantly increased circulating adrenocorticotropic hormone levels, as well as elevated serotonin and dopamine levels in the hypothalamus, and potentially decreased levels of serotonin in the frontal cortex. However, no group differences in monoamine levels were observed in the hippocampus or raphe. The results suggest that social stress may bias monoamine neurotransmission and stress hormone function to subsequent acute stressors, such as restraint. These findings improve our understanding of the neurobiological mechanisms underlying the consequences of social stress.

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.

The protective effects of social bonding on behavioral and pituitary-adrenal axis reactivity to chronic mild stress in prairie voles.

Positive social interactions may protect against stress. This study investigated the beneficial effects of pairing with a social partner on behaviors and neuroendocrine function in response to chronic mild stress (CMS) in 13 prairie vole pairs. Following 5 days of social bonding, male and female prairie voles were exposed to 10 days of CMS (mild, unpredictable stressors of varying durations, for instance, strobe light, white noise, and damp bedding), housed with either the social partner (paired group) or individually (isolated group). Active and passive behavioral responses to the forced swim test (FST) and tail-suspension test (TST), and plasma concentrations of adrenocorticotropic hormone (ACTH) and corticosterone, were measured in all prairie voles following the CMS period. Both female and male prairie voles housed with a social partner displayed lower durations of passive behavioral responses (immobility, a maladaptive behavioral response) in the FST (mean ± SEM; females: 17.3 ± 5.4 s; males: 9.3 ± 4.6 s) and TST (females: 56.8 ± 16.4 s; males: 40.2 ± 11.3 s), versus both sexes housed individually (females, FST: 98.6 ± 12.9 s; females, TST: 155.1 ± 19.3 s; males, FST: 92.4 ± 14.1 s; males, TST: 158.9 ± 22.0 s). Female (but not male) prairie voles displayed attenuated plasma stress hormones when housed with a male partner (ACTH: 945 ± 24.7 pg/ml; corticosterone: 624 ± 139.5 ng/ml), versus females housed individually (ACTH: 1100 ± 23.2 pg/ml; corticosterone: 1064 ± 121.7 ng/ml). These results may inform understanding of the benefits of social interactions on stress resilience. Lay Summary: Social stress can lead to depression. The study of social bonding and stress using an animal model will inform understanding of the protective effects of social bonds. This study showed that social bonding in a rodent model can protect against behavioral responses to stress, and may also be protective against the elevation of stress hormones. This study provides evidence that bonding and social support are valuable for protecting against stress in humans.

Altered Connexin 43 and Connexin 45 protein expression in the heart as a function of social and environmental stress in the prairie vole.

Exposure to social and environmental stressors may influence behavior as well as autonomic and cardiovascular regulation, potentially leading to depressive disorders and cardiac dysfunction including elevated sympathetic drive, reduced parasympathetic function, and ventricular arrhythmias. The cellular mechanisms that underlie these interactions are not well understood. One mechanism may involve alterations in the expression of Connexin43 (Cx43) and Connexin45 (Cx45), gap junction proteins in the heart that play an important role in ensuring efficient cell-to-cell coupling and the maintenance of cardiac rhythmicity. The present study investigated the hypothesis that long-term social isolation, combined with mild environmental stressors, would produce both depressive behaviors and altered Cx43 and Cx45 expression in the left ventricle of prairie voles - a socially monogamous rodent model. Adult, female prairie voles were exposed to either social isolation (n = 22) or control (paired, n = 23) conditions (4 weeks), alone or in combination with chronic mild stress (CMS) (1 week). Social isolation, versus paired control conditions, produced significantly (p < 0.05) increased depressive behaviors in a 5-min forced swim test, and CMS exacerbated (p < 0.05) these behaviors. Social isolation (alone) reduced (p < 0.05) total Cx43 expression in the left ventricle; whereas CMS (but not isolation) increased (p < 0.05) total Cx45 expression and reduced (p < 0.05) the Cx43/Cx45 ratio, measured via Western blot analysis. The present findings provide insight into potential cellular mechanisms underlying altered cardiac rhythmicity associated with social and environmental stress in the prairie vole.

The effects of environmental enrichment on depressive and anxiety-relevant behaviors in socially isolated prairie voles.

OBJECTIVES: Social isolation is associated with depression, anxiety, and negative health outcomes. Environmental enrichment, including environmental and cognitive stimulation with inanimate objects and opportunities for physical exercise, may be an effective strategy to include in treatment paradigms for affective disorders as a function of social isolation. In a rodent model-the socially monogamous prairie vole-we investigated the hypothesis that depression- and anxiety-related behaviors after social isolation would be prevented and remediated with environmental enrichment. METHODS: Experiment 1 investigated the preventive effects of environmental enrichment on negative affective behaviors when administered concurrently with social isolation. Experiment 2 investigated the remediating effects of enrichment on negative affective behaviors when administered after a period of isolation. Behaviors were measured in three operational tests: open field, forced swim test (FST), and elevated plus maze. RESULTS: In isolated prairie voles, enrichment prevented depression-relevant (immobility in FST, group × housing interaction, p = .049) and anxiety-relevant behaviors (exploration in open field, group × housing interaction, p = .036; exploration in elevated plus maze, group × housing interaction, p = .049). Delayed enrichment also remediated these behaviors in isolated animals (immobility in FST, main effect of housing, p = .001; exploration in open field, main effect of housing, p = .047; exploration in elevated plus maze, main effect of housing, p = .001) and was slightly more effective than physical exercise alone in remediating anxiety-relevant behaviors. CONCLUSIONS: These findings provide insight into the beneficial effects of an enriched environment on depression- and anxiety-relevant behaviors using a translational rodent model of social isolation.

Disruption of social bonds induces behavioral and physiological dysregulation in male and female prairie voles.

The social disruption of losing a partner may have particularly strong adverse effects on psychological and physiological functioning. More specifically, social stressors may play a mediating role in the association between mood disorders and cardiovascular dysfunction. This study investigated the hypothesis that the disruption of established social bonds between male and female prairie voles would produce depressive behaviors and cardiac dysregulation, coupled with endocrine and autonomic nervous system dysfunction. In Experiment 1, behaviors related to depression, cardiac function, and autonomic nervous system regulation were monitored in male prairie voles during social bonding with a female partner, social isolation from the bonded partner, and a behavioral stressor. Social isolation produced depressive behaviors, increased heart rate, heart rhythm dysregulation, and autonomic imbalance characterized by increased sympathetic and decreased parasympathetic drive to the heart. In Experiment 2, behaviors related to depression and endocrine function were measured following social bonding and social isolation in both male and female prairie voles. Social isolation produced similar levels of depressive behaviors in both sexes, as well as significant elevations of adrenocorticotropic hormone and corticosterone. These alterations in behavioral and physiological functioning provide insight into the mechanisms by which social stressors negatively influence emotional and cardiovascular health in humans.

The integration of depressive behaviors and cardiac dysfunction during an operational measure of depression: investigating the role of negative social experiences in an animal model.

OBJECTIVE: There is a bidirectional association between depression and cardiovascular disease. The neurobiological mechanisms underlying this association may involve an inability to cope with disrupted social bonds. This study investigated in an animal model the integration of depressive behaviors and cardiac dysfunction after a disrupted social bond and during an operational measure of depression, relative to the protective effects of intact social bonds. METHODS: Depressive behaviors in the forced swim test and continuous electrocardiographic parameters were measured in 14 adult, female socially monogamous prairie voles (rodents), after 4 weeks of social pairing or isolation. RESULTS: After social isolation, animals exhibited (all values are mean ± standard error of the mean; isolated versus paired, respectively) increased heart rate (416 ± 14 versus 370 ± 14 bpm, p < .05) and reduced heart rate variability (3.3 ± 0.2 versus 3.9 ± 0.2 ln(ms(2))). During the forced swim test, isolated animals exhibited greater helpless behavior (immobility = 106 ± 11 versus 63 ± 11 seconds, p < .05), increased heart rate (530 ± 22 versus 447 ± 15 bpm, p < .05), reduced heart rate variability (1.8 ± 0.4 versus 2.7 ± 0.2 ln(ms(2)), p < .05), and increased arrhythmias (arrhythmic burden score = 181 ± 46 versus 28 ± 12, p < .05). CONCLUSIONS: The display of depressive behaviors during an operational measure of depression is coupled with increased heart rate, reduced heart rate variability, and increased arrhythmias, indicative of dysfunctional behavioral and physiological stress coping abilities as a function of social isolation. In contrast, social pairing with a sibling is behaviorally protective and cardioprotective. The present results can provide insight into a possible social mechanism underlying the association between depression and cardiovascular disease in humans.