Abstract TMP31: Mir363 Treatment Improves Depressive-Like Behavioral Phenotype and Rescues Retrograde Degeneration of Meso-Striatal Projections in Middle-Aged Female Rats

Abstract

Introduction: Stroke survivors suffer from long-term physical, cognitive and affective disabilities. Post-stroke depression (PSD), which develops in over one-third of the survivors, disproportionately affects women. Conventional anti-depressant therapies are not as effective in this population of PSD patients. Hypothesis: Mir363-3p treatment after stroke will preserve the meso-striatal ‘reward’ pathway in the ischemic hemisphere, and consequently improve chronic development of PSD. Methods: Middle-aged SD female rats (12 months) were subjected to ischemic stroke using a vasoconstrictor, Endothelin-1, and randomly assigned to one of two treatment groups: scrambled oligos or mir363-3p mimic. T Maze cost/benefit task (TMCBT), Social Interaction (SI) and Forced Swim Test (FST) were performed up to 100 days after stroke to assess depressive-like behavior. Thereafter, rats were injected with Fluorogold (Flg) into the left and right striatum. Four days later, rats were overdosed with anesthetic, perfused with saline and formaldehyde and the brain removed for cryosectioning. Flg-labeled cells in the VTA and SNc were counted in both hemispheres, using fluorescent illumination. Results: After stroke, there was a reduction of high-reward choice (anhedonia) at 98d in the TMCBT in the scrambled group as compared to the mir363-3p group (p=0.0343). SI at 100d decreased 3 fold from the baseline for scrambled group (p=0.0002), but not the mir363-3p group. Similarly, FST at 100d showed significant increase in immobility (helplessness) from baseline for the scrambled group (p=0.0030), but not the mir363-3p group. Neurotrophin levels measured at 3+ months after stroke indicated that circulating BDNF were lower in the scrambled group as compared to Mir363-3p group (p=0.0170). This decrease in BNDF was also accompanied by a reduction in the number of retrogradely-labeled cells in the SNc and VTA in scrambled group. (p=0.022; ischemic Vs non ischemic hemisphere). Conclusions: Our previous work shows that mir363-3p treatment given 4h after stroke reduces infarct volume in the acute phase (5days). The current studies show that post-stroke mir363-3p treatment improves long-term stroke disability (3+ months) by improving depressive-like behavior.