ESTROGEN REGULATES CYTOKINE EXPRESSION IN THE CEREBELLUM

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。我们建议研究雌激素与衰老雌性大鼠小脑中的脑巨噬细胞(小胶质细胞)的关系。运动能力随着年龄的增长而下降，这表明小脑细胞的早熟退化对运动结构有长期影响。小胶质细胞是炎性细胞因子的丰富来源，当被激活时，已被证明在病理条件下。然而，雌激素和一些细胞因子，如IL-6，对大脑的作用一直是它们增强突触可塑性和记忆巩固。虽然小脑传统上不被认为是雌激素反应区，但最近的研究揭示了雌激素受体的存在。在这项研究中，我们的目标是阐明与年龄相关的雌激素丢失、细胞因子的产生以及它们对阳性细胞密度和分布的综合影响之间的关系。通过单/双标记免疫细胞化学和光学显微镜，我们将使用小胶质细胞标志物OX-42和IL-α、-β、IL-6和TNF-α的细胞因子标志物来鉴定免疫阳性细胞的密度和分布。这些特定的细胞因子被认为与衰老有关。我们将确定与年龄相关的雌激素丢失是否会导致小脑小胶质细胞迁移和/或增殖能力的下降，以及它是否调节老年大鼠小胶质细胞中细胞因子阳性细胞的表达。其基本原理是，由于我们知道雌激素可以作为免疫保护剂，与年龄相关的雌激素丢失可能导致小脑小胶质细胞中细胞因子受体的上调，从而启动一种可能影响小脑功能的反应。更重要的是，我们的目标是对标记的小胶质细胞以及那些可能表达细胞因子的细胞的数量和形态计量特性进行有效、准确、公正和可靠的估计。神经生物学和计算机的结合将使我们能够将收集到的关于老化小脑的信息存储到共享数据库中，这将证明对计算神经科学领域有用。

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.