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Pair housing reverses post-stroke depressive behavior in mice.

ABSTRACT: Social isolation (SI) has been linked epidemiologically to high rates of morbidity and mortality following stroke. In contrast, strong social support enhances recovery and lowers stroke recurrence. However, the mechanism by which social support influences stroke recovery has not been adequately explored. The goal of this study was to examine the effect of post-stroke pair housing and SI on behavioral phenotypes and chronic functional recovery in mice. Young male mice were paired for 14 days before a 60 min transient middle cerebral artery occlusion (MCAO) or sham surgery and assigned to various housing environments immediately after stroke. Post-stroke mice paired with either a sham or stroke partner showed significantly higher (P<0.05) sociability after MCAO than isolated littermates. Sociability deficits worsened over time in isolated animals. Pair-housed mice showed restored sucrose consumption (P<0.05) and reduced immobility in the tail suspension test compared to isolated cohorts. Pair-housed stroked mice demonstrated significantly reduced cerebral atrophy after 6 weeks (17.5 ± 1.5% in PH versus 40.8 ± 1.3% in SI; P<0.001). Surprisingly, total brain arginase-1, a marker of a M2 "alternatively activated" myeloid cells was higher in isolated mice. However, a more detailed assessment of cellular expression showed a significant increase in the number of microglia that co-labeled with arginase-1 in the peri-infarct region in PH stroke mice compared to SI mice. Pair housing enhances sociability and reduces avolitional and anhedonic behavior. Pair housing reduced serum IL-6 and enhanced peri-infarct microglia arginase-1 expression. Social interaction reduces post-stroke depression and improves functional recovery.

SUBMITTER: Verma R

PROVIDER: S-EPMC4114771 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Pair housing reverses post-stroke depressive behavior in mice.

Verma Rajkumar R Friedler Brett D BD Harris Nia M NM McCullough Louise D LD

Behavioural brain research 20140502

Social isolation (SI) has been linked epidemiologically to high rates of morbidity and mortality following stroke. In contrast, strong social support enhances recovery and lowers stroke recurrence. However, the mechanism by which social support influences stroke recovery has not been adequately explored. The goal of this study was to examine the effect of post-stroke pair housing and SI on behavioral phenotypes and chronic functional recovery in mice. Young male mice were paired for 14 days befo ...[more]

PMID: 24793492

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Project description:Background and Purpose: Stroke induces immediate profound alterations of the peripheral immune system rendering patients more susceptible to post-stroke infections. The precise mechanisms maintaining stroke-induced immune alterations (SIIA) remain unknown. High-Mobility-Group-Protein B1 (HMGB-1) is elevated for at least 7 days post-stroke and has been suggested to mediate SIIA. Patients with rapid clinical recovery of neurological deficits rarely develop severe infections. We therefore investigated whether rapid neurological recovery (either spontaneous or secondary to neurovascular recanalization therapy) alters the course of SIIA. National Institutes of Health Stroke Scale (NIHSS) served as surrogate marker for neurological improvement. Methods: Fluorescence-activated cell sorting was used to define leukocyte subpopulations. C-reactive protein (CRP), procalcitonin (PCT), HMGB-1, GM-CSF; IFN-?, IFN-?, IL-1?, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-17, IL-17F, IL-18, TNF-?, MIF, IL-8, MCP-1, MCP-4, MIP-3?, MIP-3?, Eotaxin, soluble IL-6 receptor, E-selectin, and P-selectin were analyzed by ELISA or Multiplex Assays. Serum miRNA expression changes were analyzed by qPCR. Results: Cellular parameters were similar in the improved and non-improved cohort on admission. In patients with rapid clinical recovery absolute and relative leukocyte, neutrophil, and lymphocyte numbers normalized promptly overnight. In contrast, HMGB-1 serum levels did not differ between the two groups. Nine miRNA were found to be differentially expressed between improved and non-improved patients. Conclusions: SIIA are detectable on admission of acute stroke patients. While it was assumed that post-stroke immunosuppression is rapidly reversed with improvement this is the first data set that shows that improvement actually is associated with a rapid reversal of SIIA demonstrating that SIIA require a constant signal to persist. The observation that HMGB-1 serum concentrations were similar in improved and non-improved cohorts argues against a role for this pro-inflammatory mediator in the maintenance of SIIA. Serum miRNA observed to be regulated in stroke in other publications was counter regulated with improvement in our cohort.

Project description:In laboratory animal facilities, it is a common code of practice to house female mice in groups. However, some experimental conditions require to house them individually, even though social isolation may impair their well-being. Therefore, we introduced a separated pair housing system and investigated whether it can refine single housing of adult female C57BL/6JRj mice. Individually ventilated cages (IVC) were divided by perforated transparent walls to separate two mice within a cage. The cage divider allowed visual, acoustic, and olfactory contact between the mice but prevented interindividual body-contact or food sharing. Short- and long-term effects of the separated pair housing system on the well-being of the mice were compared with single and group housing using a range of behavioral and physiological parameters: Nest building behavior was assessed based on the complexity of nests, the burrowing performance was measured by the amount of food pellets removed from a bottle, and trait anxiety-related behavior was tested in the free exploratory paradigm. For the evaluation of the ease of handling, interaction with the experimenter's hand was monitored. Social interaction with unknown conspecifics and locomotor activity were investigated in a test arena. Moreover, body weight and stress hormone (metabolites) were measured in feces and hair. After the mice spent a day under the respective housing conditions, concentrations of fecal corticosterone metabolites were higher in separated pair-housed mice, and they built nests of a higher complexity when compared to single-housed mice. The latter effect was still observable eight weeks later. In week 8, separated pair-housed mice showed less locomotor activity in the social interaction arena compared to mice from the other housing systems, i.e., single and group housing. Regardless of the time of testing, pair housing improved the burrowing performance. Separated pair-housed mice were more difficult to catch than group-housed mice. Hair corticosterone, progesterone, and dehydroepiandrosterone concentrations changed with increasing age independently of the housing system. There were no effects of the housing systems on trait anxiety-related behavior in the free exploratory paradigm, voluntary interaction with the experimenter's hand, and body weight. Overall, the transfer to the separated pair housing system caused short-term stress responses in female C57BL/6JRj mice. Long-term effects of separated pair housing were ambiguous. On one hand, separated pair housing increased nesting and burrowing behavior and may therefore be beneficial compared to single housing. But on the other hand, locomotor activity decreased. The study underlined that the effects of the housing conditions on physiological and behavioral parameters should be considered when analyzing and reporting animal experiments.

Project description:Laboratory rhesus macaques are often housed in pairs and may be temporarily or permanently separated for research, health, or management reasons. While both long-term social separations and introductions can stimulate a stress response that impacts inflammation and immune function, the effects of short-term overnight separations and whether qualities of the pair relationship mediate these effects are unknown. In this study, we investigated the effects of overnight separations on the urinary cortisol concentration of 20 differentially paired adult female rhesus macaques (Macaca mulatta) at the California National Primate Research Center. These females were initially kept in either continuous (no overnight separation) or intermittent (with overnight separation) pair-housing and then switched to the alternate pair-housing condition part way through the study. Each study subject was observed for 5 weeks, during which we collected measures of affiliative, aggressive, anxious, abnormal, and activity-state behaviors in both pair-housing conditions. Additionally, up to three urine samples were collected from each subject per week and assayed for urinary free cortisol and creatinine. Lastly, the behavioral observer scored each pair on four relationship quality attributes ("Anxious," "Tense," "Well-meshed," and "Friendly") using a seven-point scale. Data were analyzed using a generalized linear model with gamma distribution and an information theoretic approach to determine the best model set. An interaction between the intermittent pairing condition and tense pair adjective rating was in the top three models of the best model set. Dominance and rates of affiliation were also important for explaining urinary cortisol variation. Our results suggest that to prevent significant changes in HPA-axis activation in rhesus macaque females, which could have unintended effects on research outcomes, pairs with "Tense" relationships and overnight separations preventing tactile contact should be avoided.

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Pair housing reverses post-stroke depressive behavior in mice.

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Pair housing reverses post-stroke depressive behavior in mice.

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