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 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.

Aging alters the immunological response to ischemic stroke

“…The tail suspension test (TST) was performed as described previously [90] with minor modifications. Briefly, the mice were individually suspended from the tail suspension apparatus, 60 cm above the surface of the table.…”

Deletion of the P2X4 receptor is neuroprotective acutely, but induces a depressive phenotype during recovery from ischemic stroke

“…We selected the three-day outcome because the infarct matures completely and shows minimal variation in its volume by that time. The 15- and 30-day time points represent sub-acute and chronic recovery as discussed previously (Verma et al, 2014, 2016). Briefly, we performed a midline ventral neck incision and unilateral right MCAo by advancing a 6.0 silicone rubber-coated monofilament (Doccol Corporation, CA) 10–11 mm from the internal carotid artery bifurcation via an external carotid artery stump.…”

“…Finally, P2X4R activation drives the release of brain-derived neurotrophic factor (BDNF) from microglial cells (Trang et al, 2009). BDNF is necessary for the maintenance of synaptic plasticity, enhances post-stroke recovery, and has an anti-depressant effect (Verma et al, 2014, 2016). Thus, microglial-induced neuroinflammation may be responsible for the depressive phenotype observed after stroke; this especially could be the case in immunocompromised animals, in which virus can rapidly gain access to the brain, infect microglia (but not neurons), and induce their activation (Kaul et al, 2001).…”

Inflammation and the Silent Sequelae of Stroke

“…Epigenetics are invoked as a link between psychosocial stressors and the biology that mediates disease onset or outcome [65]. In animal studies, social isolation after stroke leads to behaviors consistent with PSD and is associated with increased serum IL-6 [66].…”