Environmentally Induced Alterations In Neuron And Glia Development and Aging

神经炎症基本上与每一种神经系统疾病、神经退行性疾病和神经发育障碍有关。在大脑中，炎症反应的调节是由被称为小胶质细胞的特定细胞控制的，它们通过与其他内在细胞成分的复杂通信网络来协调中枢神经系统炎症，从而形成炎症反应。脑巨噬细胞在损伤组织中以各种激活状态存在，并在炎症反应的特定阶段保留改变其功能表型的能力。像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，它们在检测神经元活动和健康的关键变化方面仍然是独一无二的。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离开来，并移除死亡或受损的细胞。我们研究了小胶质细胞在发育、衰老、精神分裂症等疾病状态以及环境因素的作用下发生改变的过程。我们感兴趣的是确定影响小胶质细胞对脑损伤反应的调节因素，以及这种调节因素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/极化的标记物以及了解与每种状态（吞噬、趋化、线粒体生物能量转移）的功能关联有关。为了评估促炎细胞因子对大脑修复反应的影响，我们开发了一个模型系统来检查不同年龄海马亚颗粒区祖细胞群。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祖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，从而增强或阻碍修复。我们正在使用这个模型来识别新的信号因子，可以促进成人神经发生，改善大脑修复和认知功能。我们已经确定了一个可能的枢轴点，在炎症体的白细胞介素1激活中区分对青少年小鼠海马神经祖细胞的有益和有害影响。

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. 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 to brain injury 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). 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 are using this model to identify novel signaling factors that can promote adult neurogenesis and improve brain repair and cognitive functioning. 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.