Abstract TMP29: Type II Diabetes Induces an Early Decline of Neurogenesis with Increased Morphological Alteration in Neuroblasts

Introduction: Diabetes increases the severity of stroke outcome and impairs the capacity for neuroplasticity. Evidence suggests that neurogenesis, a mechanism of neuroplasticity, is induced after experimental stroke, although how it is confounded by type 2 diabetes mellitus (T2DM) or aging remains to be clarified. Hypothesis: We hypothesize that T2DM exacerbates age-associated reduction in neurogenesis. Methods: Experimental stroke was induced by distal middle cerebral artery occlusion (dMCAO) in young (11-13 weeks-old, n=12) and middle-aged (53-75 weeks-old, n=50) db/+ or db/db mice, as well as in db/+ mice of old age (99-124 weeks-old, n=30). Thymidine analog 5-bromo-2′-deoxyuridine-5′(BrdU) was administered i.p. at 50 mg/kg twice daily from days 4-7 after dMCAO to label proliferating cells. Mice were euthanized 28 days after dMCAO and their brain tissue was processed for immunohistochemistry for BrdU and markers of neuronal or glial lineages. Results: A significant reduction in the number of DG neuroblasts was found in the db/db compared to db/+ mice in both young and middle-aged groups at baseline and after dMCAO. There was a further decline of neurogenesis in the old db/+ mice compared to the middle-aged db/+ mice by 6.2 and 3 folds at baseline and after dMCAO, respectively. dMCAO induces an increase of DCX(+) neuroblasts in all age groups of db/+ mice but not in db/db mice, suggesting that T2DM elicited an early decline of neurogenesis, leading to a failed regeneration after stroke. Large DCX(+) cells without processes were found in the DG of old db/+ and middle-aged db/db mice. Neuroblasts with aberrant morphology do not express markers of astrocytes or oligodendrocytes, although their identity and nature remains unclear. Conclusions: Our data suggest that T2DM accelerates the decline of neurogenesis induced by aging, which may potentially affect the functional outcome of regeneration and post stroke neuroplasticity impacted by this comorbidity. Ongoing investigation will further characterize the functional change of the neuroblasts with altered morphology and determine the effect on differentiation and survival of newborn neurons in the DG of db/db mice.