Venugopal R Venna

Social interaction plays a critical role in neurogenesis and recovery after stroke

Stroke survivors often experience social isolation. Social interaction improves quality of life and decreases mortality after stroke. Male mice (20–25u2009g; C57BL/6N), all initially pair housed, were subjected to middle cerebral artery occlusion (MCAO). Mice were subsequently assigned into one of three housing conditions: (1) Isolated (SI); (2) Paired with their original cage mate who was also subjected to stroke (stroke partner (PH-SP)); or (3) Paired with their original cage mate who underwent sham surgery (healthy partner (PH-HP)). Infarct analysis was performed 72u2009h after stroke and chronic survival was assessed at day 30. Immediate post-stroke isolation led to a significant increase in infarct size and mortality. Interestingly, mice paired with a healthy partner had significantly lower mortality than mice paired with a stroke partner, despite equivalent infarct damage. To control for changes in infarct size induced by immediate post-stroke isolation, additional cohorts were assessed that remained pair housed for three days after stroke prior to randomization. Levels of brain-derived neurotrophic factor (BDNF) were assessed at 90 days and cell proliferation (in cohorts injected with 5-bromo-2′-deoxyuridine, BrdU) was evaluated at 8 and 90 days after stroke. All mice in the delayed housing protocol had equivalent infarct volumes (SI, PH-HP and PH-SP). Mice paired with a healthy partner showed enhanced behavioral recovery compared with either isolated mice or mice paired with a stroke partner. Behavioral improvements paralleled changes in BDNF levels and neurogenesis. These findings suggest that the social environment has an important role in recovery after ischemic brain injury.

Ischemic stroke induces gut permeability and enhances bacterial translocation leading to sepsis in aged mice.

Aging is an important risk factor for post-stroke infection, which accounts for a large proportion of stroke-associated mortality. Despite this, studies evaluating post-stroke infection rates in aged animal models are limited. In addition, few studies have assessed gut microbes as a potential source of infection following stroke. Therefore we investigated the effects of age and the role of bacterial translocation from the gut in post-stroke infection in young (8-12 weeks) and aged (18-20 months) C57Bl/6 male mice following transient middle cerebral artery occlusion (MCAO) or sham surgery. Gut permeability was examined and peripheral organs were assessed for the presence of gut-derived bacteria following stroke. Furthermore, sickness parameters and components of innate and adaptive immunity were examined. We found that while stroke induced gut permeability and bacterial translocation in both young and aged mice, only young mice were able to resolve infection. Bacterial species seeding peripheral organs also differed between young (Escherichia) and aged (Enterobacter) mice. Consequently, aged mice developed a septic response marked by persistent and exacerbated hypothermia, weight loss, and immune dysfunction compared to young mice following stroke.

Reversal of the Detrimental Effects of Post-Stroke Social Isolation by Pair-Housing is Mediated by Activation of BDNF-MAPK/ERK in Aged Mice.

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.

“Won't You Be My Neighbor?”: Deciphering the Mechanisms of Neuroprotection Induced by Social Interaction

See related article, pages 3606–3611.nnAccumulating evidence from numerous epidemiological and preclinical studies has suggested that social factors can have a profound influence on physical and mental health.1–7 People with high levels of social support or large social networks exhibit lower all-cause mortality and more rapid and extensive functional and cognitive recovery after a wide variety of pathological insults, including stroke.1–6 In contrast, social isolation is associated with increased mortality and morbidity in patients with established vascular disease.2,4 Individuals who report lack of social support or isolation have an increased incidence of recurrent stroke, poorer recovery, and greater functional decline over the 5 years following a stroke compared with individuals with social support.3 Low social support is associated with increased vascular risk even after controlling for common risk factors such as age, education, obesity, exercise, smoking, and drinking.2,3 Attesting to the importance of behavioral factors in stroke outcome is that these same effects can be modeled in animals.5 Social interaction improves behavioral deficits and reduces histological damage after experimental stroke, whereas isolation, even for as little as a week, enhances ischemic damage.1,5 The work by Karelina et al in this issue of Stroke moves us closer to understanding the basic mechanisms involved in the protective effects of social interaction.nnSocial isolation has been defined in a myriad of ways in the literature. In general, in population-based studies, social isolation represents people who had poor (less than 3 people well enough to visit home) or limited primary informal social networks that include friend, family, or friend-neighbors.2–4,6 In animal studies, pair-housing …

Inhibition of Mitochondrial P53 Abolishes the Detrimental Effects of Social Isolation on Ischemic Brain Injury

Background and Purpose— Social isolation (SI) increases stroke incidence and delays poststroke recovery. Women may be at greater risk from the negative consequences of SI, but few studies have examined both sexes in experimental models, and none have evaluated the effects of isolation initiated after stroke. The effects of poststroke SI in men and women were examined, and the role of mitochondrial P53 was evaluated. Methods— C57Bl6 mice were pair-housed (PH; male and ovariectomized female) for 2 weeks, subjected to stroke and then assigned to a housing condition (isolated or PH). The effects of housing on infarct volume and recovery were examined. Changes in Bcl-2 and mitochondrial p53 were assessed by Western blot. A mitochondrial p53 inhibitor (pifithrin-&mgr;) was given to mice of both sexes. Results— Compared with pair-housed mice, poststroke SI significantly increased infarct size in both sexes; SI mice also had worse neurological deficits. The detrimental effects of SI paralleled increases in mitochondrial p53 levels. Pharmacological inhibition of mitochondrial p53 using pifithrin-&mgr; abolished the detrimental effects of SI and reduced cell death. Conclusions— Poststroke SI results in increased ischemic injury in both sexes. The effect of housing on infarct was more pronounced in women. Targeting the mitochondrial P53 pathway could minimize the detrimental effects of isolation after stroke.