Most neurons in the adult CNS are terminally differentiated, and are thus not replaced after injury or disease related neuronal cell death. However, neural stem cells with multilineage potential are present in the adult CNS, and many factors including age and injury affect proliferation and differentiation of resident stem cells. Further, studies in young animals suggest that grafting of embryonic neural stem cells is useful for repairing the injured CNS. Nonetheless, it is unknown whether: (i) the responses of resident neural stem cells to injury change as a function of the age of the organism; and (ii) the stem cells grafted to the lesioned aging CNS are capable of integrating with the host tissue to produce both structural and functional recovery. Using a lesion model of the hippocampus, this project will elucidate how the post-injury responses of adult neural stem cells change during aging, and the efficacy of grafted embryonic neural stem cells for repair of the lesioned brain of different ages. There are three major hypotheses underlying the proposed experiments. (1) The number of resident stem cells that exhibit proliferation in response to a lesion in the hippocampus undergoes a significant decline as a function of the age of the organism (2) Sequential exogenous applications of a mitogen the fibroblast growth factor (FGF-2) and a differentiation factor the brain-derived neurotrophic factor (BDNF), enhance proliferation response of resident stem cells in the lesioned aging hippocampus. (3) Embryonic hippocampal CA3 region stem cells pre-treated and grafted with BDNF into the lesioned CA3 region of the hippocampus differentiate into CA3 pyramidal neurons and integrate into the host brain, independent of the age of the host at the time of the lesion. These hypotheses will be evaluated using the following measurements in young adult, middle-aged and aged Fischer 344 rats. (1) Stem cell proliferation and differentiation within the dentate gyrus of the hippocampus in both intact and lesioned conditions, and in the lesioned condition with sequential exogenous applications of FGF-2 and BDNF. (2) Analyses of the survival, differentiation, and integration of hippocampal CA3 region stem cells pre-treated and grafted with BDNF into the lesioned hippocampus. Understanding of age-related alterations in the post-lesion plasticity of resident stem cells, and the integration of grafted embryonic stem cells into the lesioned brain of different ages, is of significant relevance for developing treatment modalities for aged individuals with neurodegenerative diseases.
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