Environmentally Induced Alterations In Neuron And Glia Development and Aging

神经炎基本上与所有神经疾病、神经退行性疾病和神经发育障碍有关。在大脑中，炎症反应的调节是在被称为小胶质细胞的特定细胞的控制下进行的，它们通过与其他内在细胞成分的复杂通讯网络来协调中枢神经系统的炎症反应，以形成炎症反应。脑巨噬细胞在损伤组织中以不同的激活状态存在，并保持在炎症反应的特定阶段改变其功能表型的能力。与其他组织巨噬细胞一样，小胶质细胞提供了抵御入侵微生物的第一道防线；然而，在检测神经元活动和健康的关键变化方面，小胶质细胞仍然是独一无二的。它们能够主动监测和控制细胞外环境，将中枢神经系统区域与非中枢神经系统组织隔开，并移除死亡或受损的细胞。此外，小胶质细胞在维持脑内稳态以及促进突触形成和重塑方面发挥着关键作用。小胶质细胞正常功能的改变可能会对大脑发育和大脑维持正常功能和可塑性的能力产生不利影响。我们研究了小胶质细胞随着发育、衰老以及精神分裂症等疾病状态和环境因素的变化而发生变化的过程。我们感兴趣的是确定影响小胶质细胞反应的调节因素，以及这种反应是否会被环境因素改变。我们的大部分工作都与识别小胶质细胞激活状态/极化的标志物以及了解每种状态的功能关联(吞噬、趋化、线粒体生物能量学的变化)有关。我们正在研究各种环境因素(三甲基锡、砷)改变小胶质细胞正常功能的能力。在研究砷的神经毒性潜力时，我们研究了急性和长期砷暴露对小胶质细胞对炎症事件建立正常宿主反应的能力的影响。我们已经证实，砷可以改变小胶质细胞对内毒素的正常反应，以产生促炎反应，并改变对白介素4/白介素13的正常反应，以诱导抗炎反应。我们还表征了在这些条件下小胶质细胞的生物能量能力的动态，以及它们如何随着启动刺激的变化而变化。利用这一系统作为小胶质细胞反应受阻的模型，我们正在研究对小胶质细胞功能的影响，如迁移和吞噬能力，并开发方法来评估这种变化对脑发育和损伤后修复能力的影响。 为了评估促炎细胞因子对脑修复反应的影响，我们开发了一个模型系统来检测不同年龄段海马体颗粒下区的祖细胞数量。利用该系统和体内模型，我们正在研究小胶质细胞和促炎细胞因子对神经前体细胞增殖和分化的影响，以及药物或毒物暴露如何影响这一过程以促进或阻碍修复。我们已经确定了一个可能的转折点，在炎症小体的白介素1激活过程中，区分对青春期小鼠海马区神经前体细胞的有益和有害影响。 对于这些研究，我们继续使用许多方法来检测暴露于环境因素后发育中的神经系统的变化，包括免疫组织化学、共聚焦成像、流式细胞术、海马线粒体生物能量学、检测mRNA水平的分子技术如qRT-PCR、微阵列、核糖核酸酶保护分析、神经前体细胞培养、成人来源的神经干细胞/前体细胞以及神经行为功能的评估。

Neuroinflammation is associated with essentially every neurological disorder, neurodegenerative disease, and neurodevelopmental disorder. In the brain, regulation of an inflammatory response is under the control of specific cells known as microglia, They coordinate CNS inflammation by an intricate communication network with other intrinsic cellular components to shape inflammatory responses. Brain macrophages exist in various states of activation within injured tissue and retain the capability to shift their functional phenotype within specific stages of the inflammatory response. Like other tissue macrophages, microglia provide the first line of defense against invading microbes; yet, remain unique in their ability to detect critical changes in neuronal activity and health. They are capable of actively monitoring and controlling the extracellular environment, walling off areas of the CNS from non-CNS tissue, and removing dead or damaged cells. In addition, microglia play a critical role in maintaining brain homeostasis and in facilitating synapse formation and remodeling. Alterations in the normal functions of microglia can have detrimental effects on brain development and in the ability of the brain to maintain normal functioning and plasticity. We have examined the process by which the microglia can be altered as a function of development, aging, and in disease states such as schizophrenia and as a function of environmental factors. We are interested in determining the regulatory factors that influence the microglia response and whether this can be altered by environmental factors. Much of our work has been associated with identifying markers of microglia activation state/polarization and understanding the functional associations with each state (phagocytosis, chemotaxis, shifts in mitochondrial bioenergetics). We are examining the ability of various environmental agents (trimethyltin, arsenic) to modify the normal functional ability of microglia. In examining the neurotoxic potential of arsenic, we have examined the effect of acute and prolonged arsenic exposure to modify the ability of microglia to mount a normal host-response to an inflammatory event. We have identified that arsenic can shift the normal response of microglia to lipopolysaccharide for a pro-inflammatory response and to interleukin 4/ interleukin 13 to induce an anti-inflammatory response. We have also characterized the dynamics of the bioenergetic capacity of microglia under these conditions and how they shift depending on the initiating stimulus. Using this system as a model of hindered microglia response we are examining the impact on functions of microglia such as migration and phagocytic capability and developing methods to assess what impact this shift may have in brain development and ability to repair following injury. To evaluate the impact of pro-inflammatory cytokines on the brain repair response we have developed a model system to examine the progenitor cell population from the subgranular zone of the hippocampus at different ages. Using this system as well as the in vivo model we are examining the influence of microglia and pro-inflammatory cytokines on the proliferation and differentiation of neural progenitor cells and how drug or toxicant exposure can influence this process to enhance or hinder repair. We have identified a possible pivot point distinguishing beneficial versus detrimental effects on neural progenitor cells in the hippocampus of adolescent mice in the interleukin 1 activation of the inflammasome. For these studies we continue to use a number of methods to examine alterations in the developing nervous system following exposure to environmental agents including immunohistochemistry, con-focal imaging, flow cytometry, seahorse mitochondrial bioenergetics, molecular techniques to examine mRNA level such as qRT-PCR, microarray, RNase protection assays, neuroprogenitor cell cultures, adult derived neural stem/progenitor cells, as well as assessment of neurobehavioral functioning.