New neurons are constantly added to the granule cell layer of the dentate gyrus (DG) in rats and humans throughout adulthood. New neurons that are formed in the dentate may be increased by at least 3 mechanisms: a) increased precursor cell proliferation, b) increased precursor cell survival, or c) increased precursor cell differentiation to a neuronal form. It is controversial whether DG precursor cell neurogenesis that is decreased in aged animals underlies cognitive deficits seen with aging, as traditional methods to detect neurogenesis have employed low doses of the marker BrdU (30-50 mg/kg), which is now known to identify only a fraction of newly dividing cells. Thus, existing assesments of neurogenesis in aged animals may be largely underestimated. We will employ high doses of BrdU (300 mg/kg), which are non-toxic, specific for newly dividing cells, and can more accurately reveal the total number of new precursor cells. Whether granule cell proliferation or survival can be induced in aged animals by environmental or experiential challenges is unknown.
In Specific Aim 1, experiments will investigate whether aging is associated with deficits in either the basal rate of proliferation or survival of newly formed DG granule cells.
In Specific aim 2, experiments will investigate whether aged rats show reduced neuronal survival that normally is increased with mossy fiber stimulation, or reduced proliferation which normally is increased by brief exposure to novel objects.
In Specific Aim 3, experiments will investigate whether impaired proliferation or survival is paralleled by deficits in novel object recognition working memory in aged rats. Subsequent experiments will determine whether caloric restriction can ameliorate deficits in basal or induced proliferation or survival observed in aged rats. These studies will provide a more thorough understanding of age deficits in basal and inducible neurogenesis. The identification of age deficits in neurogenesis, and their amelioration by caloric restriction will provide insights with therapeutic potential for age-related neurological disorders.
