The deleterious effects of chronic social isolation (SI) have been recognized for several decades. Isolation is a major source of psychosocial stress and is associated with an increased prevalence of vascular and neurological diseases. In addition, isolation exacerbates morbidity and mortality following acute injuries such as stroke or myocardial infarction. In contrast, affiliative social interactions can improve organismal function and health. The molecular mechanisms underlying these effects are unknown. Recently, results from large epidemiological trials and pre-clinical studies have revealed several potential mediators of the detrimental effects of isolation. At least three major biological systems have been implicated; the neuroendocrine (HPA) axis, the immune system, and the autonomic nervous system. This review summarizes studies examining the relationship between isolation and mortality and the pathophysiological mechanisms underlying SI. Cardiovascular, cerebrovascular, and neurological diseases including atherosclerosis, myocardial infarction, ischemic stroke and Alzheimer’s disease are given special emphasis in the context of SI. Sex differences are highlighted and studies are separated into clinical and basic science for clarity.

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 behavioural phenotypes and chronic functional recovery in mice. Young male mice were paired for 14 days before a 60 minute 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 vs. 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 behaviour. Pair housing reduced serum IL-6 and enhanced peri-infarct microglia arginase-1 expression. Social interaction reduces post-stroke depression and improves functional recovery.

Social isolation (SI) increases stroke-related mortality and morbidity in clinical populations. The detrimental effects of SI have been successfully modeled in the laboratory using young animals. Mechanistically, the negative effects of SI in young animals are primarily mediated by an enhanced inflammatory response to injury and a reduction in neurotrophic factors. However, the response to brain injury differs considerably in the aged. Given that SI is more prevalent in aged populations, we hypothesized that isolation, even when initiated after stroke, would delay recovery in aged mice. We found that aged isolated male mice had significantly increased infarct volume, neurological deficits, and serum IL-6 levels three days after stroke compared to pair housed (PH) mice. Using RT2 Profiler PCR Array and real-time quantitative PCR we found several important synaptic plasticity genes were differentially expressed in post-stroke SI mice. Furthermore, paired mice showed improved memory and neurobehavioral recovery four weeks after injury. Mechanistic and histological studies showed that the beneficial effects of pair housing are partially mediated by BDNF via downstream MAPK/ERK signaling and restoration of axonal basic myelin protein levels.

Background and Purpose Aging is an important determinant of ischemic stroke outcomes. Both clinical and experimental stroke studies have shown that aging negatively correlates with infarct volumes but is associated with worsened functional recovery after stroke. This may correspond to a differing cellular and molecular response to stroke in the aged vs. young brain. It was hypothesized in this study that the smaller injury seen in the aged ischemic brain is due to structural differences in microvasculature with aging or differences in intra-ischemic tissue perfusion. Methods Both young and aged C57BL6 mice were subject to middle cerebral artery occlusion (MCAO) modeling. Laser Speckle Flowmetry (LSF) was utilized to study the functional dynamics of cerebral perfusion, and FITC-dextran staining was performed to examine the structural change in microvasculature. In separate cohorts, Cresyl violet (CV) staining and immunohistochemistry with CD31 and IgG antibodies were applied to further assess the microvascular density and blood brain barrier breakdown after stroke. Results No difference in cerebral blood flow was seen at the baseline, intra-ischemically and post-reperfusion in young vs. aged mice. FITC-dextran and CD31 staining did not show significant differences in the microvascular density between young and aged ischemic brains. More extravasation of IgG through the BBB was found in the young vs. aged cohort at both 24 and 72 hours after stroke. Conclusions Cerebrovascular dynamics and perfusion are not responsible for the different stroke phenotypes seen in the young vs. aged animals, which may be more related to different levels of BBB breakdown.

Sirtuins (Sirt) are a family of NAD+ dependent histone deacetylase (HDAC) proteins implicated in aging, cell cycle regulation, and metabolism. These proteins are involved in the epigenetic modification of neuromodulatory proteins after strokevia acetylation/deacetylation. The specific role of Sirt3, a mitochondrial sirtuin, in post-stroke injury has been relatively unexplored. Using male Sirt3 knockout (KO) mice and wild-type littermates (WT), we show that Sirt3 KO mice show significant neuroprotection at 3 days after ischemia/reperfusion (I/R) or stroke injury. The deacetylation activity of Sirt3, measured as the amount of reduced acetylated lysine, was increased after stroke. Stroke-induced increases in liver kinase 1 (LKB1) activity were also reduced in KO mice at 3 days after stroke. On further investigation, we found that the levels of Sirt1, another important member of the Sirtuin family, were increased in the brains of Sirt3 KO mice after stroke. To determine the translational relevance of these findings, we then tested the effects of pharmacological inhibition of Sirt3. We found no benefit of Sirt3 inhibition despite clear evidence of deacetylation. Overall, these data suggest that Sirt3 KO mice show neuroprotection by a compensatory rise in Sirt1 rather than the loss of Sirt3 after stroke. Further analysis reveals that the beneficial effects of Sirt1 might be mediated by a decrease in LKB1 activity after stroke. Finally, our data clearly demonstrate the importance of using both pharmacological and genetic methods in pre-clinical stroke studies.