| dc.description.abstract | Menopause not only signifies the end of the reproductive age for women, but also marks the time period of higher risk for cardiovascular disease such as stroke. In older females, stroke leads to greater disabilities in physical, communicative, emotional and cognitive functions. About a third of stroke survivors develop depression or cognitive impairment over time and there is no specific drug approved for these behavior impairment. This dissertation focused on testing therapeutic affects of small non-coding (micro)RNA for post stroke depression and cognitive impairment. Middle-aged female rats were used to best resemble the post-menopausal female population. In the experiments included in this dissertation we tested the therapeutic effects of a microRNA, mir363-3p in long-term stroke outcome such as depression and cognitive decline. In experiment 1, we found that a depressive-like phenotype develops in middle-aged female rats 1-3 months after stroke and is accompanied by transient increases in pro-inflammatory cytokines and decrease in the circulating levels of Brain Derived Neurotrophic Factor (BDNF). The mesostriatal dopaminergic pathway, a part of the reward pathway, showed retrograde degeneration in the ischemic hemisphere. Mir363-3p treatment improved the depressive-like phenotype as well as normalized the cytokines and growth factors in the blood. In addition to this, the mesostriatal pathway was preserved in the mir363-3p treated group. Cognitive impairment did not occur up to 3 months in experiment 1. Experiment 3 found that cognitive impairment develops by 6 months after stroke, and the impairment was in the spatial as well as non-spatial memory. Mir363-3p improved both aspects of memory. In experiment 2, we tested if the depressive phenotype displayed by rats from experiment 1 was associated with changes in the gut microbiome. We found that stroke animals had lower circulating level of tryptophan, a metabolite from the gut. Furthermore, gut dysbiosis was also evident in this group in the form of an increased ratio of Firmicutes: Bacteroidetes (F:B) ratio and reduced expression of specific bacterial families associated with the depressive phenotype. Collectively, these data show that mir363-3p has a therapeutic role for not only acute sensorimotor deficit after stroke, but also long-term depression and delayed cognitive impairment. | en |
