Gut microbiota is necessary for pair-housing to protect against post-stroke depression in mice.

The goal of this study is to investigate the role of microbiota-gut-brain axis involved in the protective effect of pair-housing on post-stroke depression (PSD). PSD model was induced by occluding the middle cerebral artery (MCAO) plus restraint stress for four weeks. At three days after MCAO, the mice were restrained 2 h per day. For pair-housing (PH), each mouse was pair housed with a healthy isosexual cohabitor for four weeks. While in the other PH group, their drinking water was replaced with antibiotic water. On day 35 to day 40, anxiety- and depression-like behaviors (sucrose consumption, open field test, forced swim test, and tail-suspension test) were conducted. Results showed pair-housed mice had better performance on anxiety- and depression-like behaviors than the PSD mice, and the richness and diversity of intestinal flora were also improved. However, drinking antibiotic water reversed the effects of pair-housing. Furthermore, pair-housing had an obvious improvement in gut barrier disorder and inflammation caused by PSD. Particularly, they showed significant decreases in CD8 lymphocytes and mRNA levels of pro-inflammatory cytokines (TNF-a, IL-1ß and IL-6), while IL-10 mRNA was upregulated. In addition, pair-housing significantly reduced activated microglia and increased Nissl's body in the hippocampus of PSD mice. However, all these improvements were worse in the pair-housed mice administrated with antibiotic water. We conclude that pair-housing significantly improves PSD in association with enhanced functions of microbiota-gut-brain axis, and homeostasis of gut microbiota is indispensable for the protective effect of pair-housing on PSD.

The oxytocin receptor is essential for the protective effect of pair housing on post-stroke depression in mice.

The beneficial effect of social interaction in mitigating the incidence of post-stroke depression (PSD) and ameliorating depressive symptoms has been consistently demonstrated through preclinical and clinical studies. However, the underlying relationship with oxytocin requires further investigation. In light of this, the present study aimed to explore the protective effect of pair housing on the development of PSD and the potential relationship with oxytocin receptors. The PSD model was induced by middle cerebral artery occlusion (MCAO) for 50 min, followed by 4-week isolated housing and restrained stress. Subsequently, each mouse in the pair-housing group (PH) was pair-housed with an isosexual healthy partner. Another group was continuously administrated fluoxetine (10 mg/Kg, i.p, once a day) for 3 weeks. To elucidate the potential role of oxytocin, we subjected pair-housed PSD mice to treatment with an oxytocin receptor (OXTR) antagonist (L368,889) (5 mg/Kg, i.p, once a day) for 3 weeks. At 31 to 32 days after MCAO, anxiety- and depressive-like behaviors were assessed using sucrose consumption, forced swim test, and tail-suspension test. The results showed that pair housing significantly improved post-stroke depression to an extent comparable to that of fluoxetine treatment. Furthermore, pair housing significantly decreased corticosterone in serum, increasing OXT mRNA expression in the hypothalamus. Treatment with L368,889 essentially reversed the effect of pair housing, with no discernible sex differences apart from changes in body weight. Pair housing increased hippocampal serotonin (5-HT), but treatment with L368,889 had no significant impact. Additionally, pair housing effectively reduced the number of reactive astrocytes and increased Nissl's body in the cortex and hippocampal CA3 regions. Correspondingly, treatment with L368,889 significantly reversed the changes in the Nissl's body and reactive astrocytes. Moreover, pair housing downregulated mRNA levels of TNF-α, IL-1ß, and IL-6 in the cortex caused by PSD, which was also reversed by treatment with L368,889. In conclusion, pair housing protects against the development of PSD depending on OXT and OXTR in the brain, with no significant divergence based on sex. These findings provide valuable insights into the potential of social interaction and oxytocin as therapeutic targets for PSD. Further research into the underlying mechanisms of these effects may contribute to the development of novel treatments for PSD.