Melissa-Ann L. Scotti

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 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.

Chronic social isolation in the prairie vole induces endothelial dysfunction: implications for depression and cardiovascular disease.

Humans with depression show impaired endothelium-dependent vasodilation; one recent demonstration of which was in the form of a reduced acetylcholine (ACh)-induced relaxation of adrenergically-precontracted small arteries biopsied from older depressed patients. Results from such uses of ACh in general have been validated as the most predictive marker of endothelium-related cardiovascular diseases. Accordingly, we examined vascular reactivity to ACh in the socially isolated prairie vole, a new animal model relevant to human depression and cardiovascular disease. Thoracic aortas were carefully dissected from female prairie voles after one month of social isolation (versus pairing with a sibling). Only aortas that contracted to the adrenergic agent phenylephrine (PE) and then relaxed to ACh were evaluated. Among those, ACh-induced relaxations were significantly reduced by social isolation (p<0.05), with maximum relaxation reaching only 30% (of PE-induced precontraction) compared to 47% in aortas from paired (control) animals. Experimental removal of the endothelium from an additional set of aortic tissues abolished all ACh relaxations including that difference. In these same tissues, maximally-effective concentrations of the nitric oxide-donor nitroprusside still completely relaxed all PE-induced precontraction of the endothelial-free smooth muscle, and to the same degree in tissues from isolated versus paired animals. Finally, in the absence of PE-induced precontraction ACh did not relax but rather contracted aortic tissues, and to a significantly greater extent in tissues from socially isolated animals if the endothelium was intact (p<0.05). Thus, social isolation in the prairie vole may (1) impair normal release of protective anti-atherosclerotic factors like nitric oxide from the vascular endothelium (without altering the inherent responsiveness of the vascular smooth muscle to such factors) and (2) cause the endothelium to release contracting factors. To our knowledge this is the first demonstration of this phenomenon in an animal model of depression induced solely by social isolation. These findings have implications for understanding mechanisms involved in depression and cardiovascular disease.

Behavioral and pharmacological assessment of a potential new mouse model for mania

Bipolar disorder (BPD) is a devastating long-term disease for which a significant symptom is mania. Rodent models for mania include psychostimulant-induced hyperactivity and single gene alterations, such as in the Clock or DAT genes, but there is still a pressing need for additional models. Recently, our lab isolated a line of mice, termed Madison (MSN), that exhibit behavioral characteristics that may be analogous to symptoms of mania. In this study we quantified possible traits for mania and tested the response to common anti-BPD drugs in altering the behavioral profiles observed in this strain. Relative to other mouse lines, MSN mice showed significant elevations of in-cage hyperactivity levels, significant decreases in daytime sleep, and significant increases in time swimming in the forced swim test. In terms of sexual behavior, the MSN mice showed significantly higher number of mounts and a trend toward higher time mounting. In separate studies, olanzapine and lithium (or respective controls) were administered to MSN mice for at least 2weeks and response to treatments was evaluated. Olanzapine (1mg/kg/day) significantly decreased in-cage hyperactivity and significantly increased time sleeping. Lithium (0.2-0.4% in food) significantly decreased in-cage hyperactivity. Given the behavioral phenotypes and the response to anti-BPD treatments, we propose that MSN mice may provide a possible new model for understanding the neural and genetic basis of phenotypes related to mania and for developing pharmaceutical treatments.

Social isolation disrupts innate immune responses in both male and female prairie voles and enhances agonistic behavior in female prairie voles (Microtus ochrogaster)

Psychosocial stress, specifically social isolation, is an important risk factor for the development of a variety of psychological and physiological disorders. Changes in immune function have been hypothesized to mediate this relationship. The current study used the prairie vole (Microtus ochrogaster) model of isolation-induced depressive-like behavior to test whether social isolation led to changes in innate immune function. Specifically, we used hemolytic complement (CH50) and bacteria killing assays to assess innate immunity, in paired or singly housed male and female prairie voles. Further, in a second experiment we tested whether females exposed to an additional short-term social stressor, a resident-intruder trial, would show changes in immune function as well as enhanced hypothalamic pituitary axis (HPA) activity as indicated by elevated plasma corticosterone levels. Socially isolated animals, regardless of sex, had significantly reduced CH50s and bacteria killing ability. Socially isolated females exposed to a resident-intruder stressor also showed reduced CH50s and bacteria killing ability as well as significant increases in aggressive behavior, however, they did not show elevated circulating corticosterone levels. Collectively, these data will help inform our understanding of the relationship between social isolation and physiological and psychological health.

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

Abstract 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.

Stress and Neuroinflammation

It has been well established that there is bidirectional communication between the immune and central nervous systems. One context in which this interaction has been extensively studied is that of the stress response. Stress, whether physical or psychological, induces alterations in immune function. Often exposure to a stressor results in pro-inflammatory responses in the brain and periphery. These responses are mediated by a variety of inflammatory molecules including neuropeptides, cytokines, and stress hormones among others. Here, we will discuss several of the more comprehensively studied of these inflammatory mediators and their role(s) in stress-induced neurogenic inflammation.

Neurotensin induced Egr-1 activity is altered in the postpartum period in mice

Neurotensin (NT) is a 13 amino acid neuropeptide that is identical in mice and humans and is released from and acts upon a number of social brain regions. Recent work indicates NT neurotransmission may be altered in postpartum females and support the onset of some maternal behaviors. In a recent study, we highlighted how virgin and postpartum brains from mice selected for high offspring protection differ in response to injected NT (0.1 μg) relative to vehicle when examining c-Fos profiles across the CNS. In this companion study we use a second marker for brain activity, Egr-1, and evaluate multiple brain regions. Common significant increased Egr-1 responses to NT (relative to vehicle) were found in both female groups only in ventromedial hypothalamus. In lateral periaqueductal gray, virgin mice showed a significant Egr-1 increase with NT (relative to vehicle), but maternal mice did not. When comparing NT injections, virgin (relative to maternal) mice had significantly higher activity in five regions, including anterior hypothalamus, lateral hypothalamus, somatosensory cortex, paraventricular nucleus, and zona incerta; no regions were higher in maternal mice. A Principal Components Analysis was also used for data mining and in virgin mice, greater changes in activity hubs were found with NT (relative to vehicle) than for maternal mice. Overall, a lower sensitivity to NT in terms of Egr-1 reactivity in the maternal state was highlighted and this is consistent with previous c-Fos results. These findings provide additional insight into the mechanisms by which NT functions in the CNS.

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

Abstract 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.

Changes in CNS response to neurotensin accompany the postpartum period in mice

Neurotensin (NT) is a highly conserved neuropeptide in mammals. Recent studies suggest that altered NT neurotransmission in postpartum females could promote the emergence of some maternal behaviors, including offspring protection. Here we evaluated how virgin and postpartum brains from mice selected for high maternal defense differ in response to NT. Virgin and postpartum mice were injected with either vehicle or 0.1 μg NT icv and brains were evaluated for c-Fos immunoreactivity, an indirect marker of neuronal activity. Using ANOVA analysis, common significant responses to NT were found in both female groups in four brain regions, including supraoptic nucleus, ventromedial nucleus, bed nucleus of stria terminalis dorsal, and a subregion of lateral septum (LS). For postpartum mice, only one additional region showed a significant response to NT relative to vehicle, whereas for virgin mice seven unique brain regions showed a significant c-Fos response: nucleus accumbens shell, paraventricular nucleus, central amygdala, and substantia nigra. Using a principal components analysis of c-Fos, we identified regions within each group with highly correlated activity. As expected, virgin and postpartum mice (vehicle conditions) showed different activity hubs and in the postpartum group the hubs matched regions linked to maternal care. The response to injected NT was different in the maternal and virgin groups with maternal mice showing a stronger coordinated activity in periaqueductal gray whereas virgin mice showed a stronger septal and amygdala linking of activity. Together, these results indicate neuronal responses of virgin and postpartum mice to NT and highlight pathways by which NT can alter maternal responses.