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|Title:||CHARACTERIZATION OF CONTINUOUS DELIVERY OF BDNF ON DENTATE GYRUS NEUROGENESIS IN POL G MUTATOR MICE|
|Advisor:||Tarnopolsky, Mark Andrew|
|Abstract:||Polymerase gamma POL G1 mutator mice (POL G) are deficient in the mitochondrial DNA proof-reading capacity leading to an accumulation of mtDNA point mutations, resulting in accelerated aging phenotype and brain atrophy. Endurance exercise training reverses the phenotypic manifestations and rescues much of the progeroid aging phenotype, including brain atrophy. Neurogenesis is mediated by neurotrophins that stimulate cell growth and survival. One of the main neurotrophins is brain-derived neurotrophic factor (BDNF), which is secreted by muscle cells and has been shown to increase with acute exercise in brain and serum. Therefore, we investigated whether continuous delivery of BDNF by in-vivo gene therapy would improve the neurogenesis on the dentate gyrus in POL G mutator mice. Wild-type controls and POL G mutator mice were given intra-peritoneal injections of capsules containing recombinant G8 myoblasts that secreted BDNF, or vehicle (veh), over five months. Cell survival analysis at the level of the dentate gyrus in the brain was measured by BrdU analysis. By nine months of age, BDNF-injected POL G mutator mice did not exhibit improvements in neurogenesis in comparison with POL G controls. Motor assessment through rotarod performance showed no differences between wild type and POL G. CLAMS assessment demonstrated impairment of locomotor activity in POL G mice as expected; and no improvement in the POL G group treated with BDNF. Unexpectedly, wild type animals treated with BDNF exhibited decreased levels of locomotor activity similar to the POL G mutator mice. In conclusion, continuous BDNF administration did not improve neurogenesis at the level of the dentate gyrus in the POL G animal model. It is likely that the prevention of brain atrophy seen with endurance exercise is mediated by additional molecular factors, including BDNF.|
|Appears in Collections:||Open Access Dissertations and Theses|
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