This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We propose to investigate estrogens association with brain macrophages (microglial cells) in the cerebellum of aging female rats. Motor abilities decrease with age, suggesting that precocious degeneration of cerebellar cells have long-term effects on motor structures. Microglia are rich sources for inflammatory cytokines, and when activated, have been documented in pathological conditions. However, the actions of estrogens, as well as some cytokines, e.g., IL-6, on the brain have been their enhancement of synaptic plasticity and memory consolidation. Although the cerebellum has not traditionally been considered an estrogen responsive region, recent studies reveal the presence of estrogen receptors. In this study, our goal is to elucidate the relationship between age-related loss of estrogen, the production of cytokines, and their integrative affects on positive cell density and distribution. Using single-/double-labeling immunocytochemistry and light microscopy, we will identify, using the microglial marker OX-42 and the cytokine markers for IL-alpha, -beta, IL-6, and TNF alpha, the density and distribution of immunopositive cells. These specific cytokines are known to be associated with aging. We will determine if age-related loss in estrogen causes a decrease in the migratory and/or proliferative potential of microglia in the cerebellum, and if it regulates the expression of cytokine-positive cells that are identified in microglia of aged rats. The rationale is since we know that estrogen may serve as an immunoprotective agent, age-related loss of estrogen may result in up-regulation of cytokine receptors in cerebellar microglia, thus initiating a response that may affect cerebellar function. More importantly, it is our goal to obtain efficient, precise, unbiased, and reliable estimates of the number and morphometric properties of labeled microglial cells, and those that may express cytokines. Integration of neurobiology and computers will enable us to store information gathered about aging cerebella into shared databases proving useful to the field of computational neuroscience.
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