Sex differences in heart rate variability measures that predict alcohol drinking in rats.

Problem alcohol drinking continues to be a substantial cost and burden. In addition, alcohol consumption in women has increased in recent decades, and women can have greater alcohol problems and comorbidities. Thus, there is a significant need for novel therapeutics to enhance sex-specific, individualized treatment. Heart rate (HR) and HR variability (HRV) are of broad interest because they may be both biomarkers for and drivers of pathological states. HRV reflects the dynamic balance between sympathetic (SNS, 'fight or flight') and parasympathetic (PNS, 'rest and digest') systems. Evidence from human studies suggest PNS predominance in women and SNS in men during autonomic regulation, indicating the possibility of sex differences in risk factors and physiological drivers of problem drinking. To better understand the association between HRV sex differences and alcohol drinking, we examined whether alcohol consumption levels correlated with time domain HRV measures (SDNN and rMSSD) at baseline, at alcohol drinking onset, and across 10 min of drinking, in adult female and male Wistar rats. In particular, we compared both HRV and HR measures under alcohol-only and compulsion-like conditions (alcohol + 10 mg/L quinine), because compulsion can often be a significant barrier to treatment of alcohol misuse. Importantly, previous work supports the possibility that different HRV measures could be interpreted to reflect PNS versus SNS influences. Here, we show that females with higher putative PNS indicators at baseline and at drinking onset had greater alcohol consumption. In contrast, male intake levels related to increased potential SNS measures at drinking onset. Once alcohol was consumed, HR predicted intake level in females, perhaps a pharmacological effect of alcohol. However, HRV changes were greater during compulsion-like intake versus alcohol-only, suggesting HRV changes (reduced SNS in females, reduced PNS and increased HR in males) specifically related to aversion-resistant intake. We find novel and likely clinically relevant autonomic differences associated with biological sex and alcohol drinking, suggesting that different autonomic mechanisms may promote differing aspects of female and male alcohol consumption.

Maladaptive cardiac and behavioral reactivity to repeated vicarious stress exposure in socially bonded male prairie vole siblings.

Behaviors, emotions, and cardiovascular functions are influenced by stress. But these detrimental effects are not exclusive to an individual that directly experiences stress. Stress is also experienced vicariously through observation of another individual undergoing stress. The current study used the strong social bonds in socially monogamous prairie voles to determine effects of repeated vicarious stress on cardiac and behavioral outcomes. Male prairie voles were exposed to either a 5-minute open field chamber alone [separate (control)] or while concurrently witnessing their sibling undergo a tail-suspension stressor [concurrent (experimental)], repeated across 4 sessions. Cardiac responses in animals in the open field were evaluated for heart rate and heart rate variability prior to, during, and after each test session, and behaviors were evaluated for motion, exploration, stress reactivity, and anxiety-relevant behaviors during each test session. The concurrent condition (versus separate) displayed increased heart rate and reduced heart rate variability during repeated test sessions, and impaired recovery of these parameters following the test sessions. The pattern of disturbances suggests that both increased sympathetic and reduced parasympathetic influence contributed to the cardiac responses. Animals in the concurrent condition (versus separate) displayed disrupted rearing, grooming, and motion; reduced duration of center section exploration; and increased freezing responses across repeated test sessions. Collectively, cardiac and behavioral stress reactivity are increased as a function of vicarious stress in prairie voles, which are evident across repeated experiences of stress. These results inform our understanding of the experience of vicarious stress in social species, including humans.

Heart rate variability measures indicating sex differences in autonomic regulation during anxiety-like behavior in rats.

Introduction: Mental health conditions remain a substantial and costly challenge to society, especially in women since they have nearly twice the prevalence of anxiety disorders. However, critical mechanisms underlying sex differences remain incompletely understood. Measures of cardiac function, including heart rate (HR) and HR variability (HRV), reflect balance between sympathetic (SNS) and parasympathetic (PNS) systems and are potential biomarkers for pathological states. Methods: To better understand sex differences in anxiety-related autonomic mechanisms, we examined HR/HRV telemetry in food-restricted adult rats during novelty suppression of feeding (NSF), with conflict between food under bright light in the arena center. To assess HRV, we calculated the SDNN (reflective of both SNS and PNS contribution) and rMSSD (reflective of PNS contribution) and compared these metrics to behaviors within the anxiety task. Results: Females had greater HR and lower SNS indicators at baseline, as in humans. Further, females (but not males) with higher basal HR carried this state into NSF, delaying first approach to center. In contrast, males with lower SNS measures approached and spent more time in the brightly-lit center. Further, females with lower SNS indicators consumed significantly more food. In males, a high-SNS subpopulation consumed no food. Among consumers, males with greater SNS ate more food. Discussion: Together, these are congruent with human findings suggesting women engage PNS more, and men SNS more. Our previous behavior-only work also observed female differences from males during initial movement and food intake. Thus, high basal SNS in females reduced behavior early in NSF, while subsequent reduced SNS allowed greater food intake. In males, lower SNS increased engagement with arena center, but greater SNS predicted higher consumption. Our findings show novel and likely clinically relevant sex differences in HRV-behavior relationships.

Microbiome and Metabolome Variation as Indicator of Social Stress in Female Prairie Voles.

Social isolation is detrimental to the health of social mammals inducing neurochemical and hormonal changes related to depression and anxiety, as well as impairments of cardiovascular and immune functioning. Likewise, perceptions of loneliness are increasingly recognized as detrimental to human psychological well-being, cognitive functioning, and physical health. Few studies, however, have examined the impact of social isolation on the intestinal microbiome and metabolome. To better understand the impact of social isolation on these systems, intestinal microbiota, and the systemic impact via the gut-brain axis, we employed prairie voles. Physiological stress on female prairie voles (n = 22) either with a same-sex sibling (n = 11) or in isolation (n = 11) for four weeks demonstrated behavioral indicators of increased anxiety and depression in isolated voles (p ≤ 0.01). Bacterial DNA from fecal and colon samples, collected at five time points (T0-4), were sequenced for all nine hypervariable regions of the 16S rRNA gene. Microbiome analyses revealed several differences in gut communities of paired and isolated voles with greater differences at T4. Notably, several taxa associated with host health including Anaerostipes and Lactobacillaceae were more prevalent in paired voles, whereas several taxa associated with known pathogens (e.g., Staphylococcaceae and Enterococcus) or disease were elevated in isolated animals. Similarly, metabolome analyses suggested isolated voles, when compared to paired animals, exhibited differences in metabolites associated with diabetes and colitis. These findings further contribute to our understanding of the harmful effects of social isolation, which cause perturbations in the gut microbiome and serum metabolites.

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.

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.

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.

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.

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.

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.

Social anxiety and employment interviews: does nonverbal feedback differentially predict cortisol and performance?

BACKGROUND & OBJECTIVES: Interviewers often provide positive nonverbal feedback to reduce interviewees' anxiety. Socially anxious individuals typically harbor negative self-views discrepant with positive feedback. We examined whether nonverbal feedback and social anxiety jointly influence cortisol responses to, and performance during, interviews. DESIGN: An experimental between-subjects design randomly assigned participants to feedback condition. METHODS: Undergraduate students (N = 130) provided saliva and completed social anxiety, interview anxiety, and affective measures before a simulated interview. Following a standardized script, a confederate interviewer provided positive, ambiguous, or negative nonverbal feedback. Participants then provided saliva and completed self-focused attention and self-awareness measures. Confederate interviewers and an external rater evaluated participants' anxiety displays, assertive behavior, and performance. RESULTS: Positive feedback decreased cortisol and improved performance for low social anxiety participants. Socially anxious participants exhibited higher cortisol but did not exhibit significant differences in performance after positive compared to negative feedback. CONCLUSIONS: Consistent with previous findings, positive feedback did not benefit socially anxious interviewees. Positive feedback increased physiological arousal relative to negative feedback but did not hinder performance among people high in social anxiety. These results provide novel information about the interactive influence of social anxiety and nonverbal interviewer feedback on arousal, self-focus, and interview performance.

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.

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.