Environmentally Induced Alterations In Neuron And Glia Development and Aging

神经炎症基本上与每种神经系统疾病、神经退行性疾病和神经发育障碍相关。在大脑中，炎症反应的调节是在称为小胶质细胞的特定细胞的控制下，它们通过与其他内在细胞组分的复杂通信网络协调CNS炎症以形成炎症反应。脑巨噬细胞以各种激活状态存在于受损组织中，并保留在炎症反应的特定阶段内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，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CNS区域与非CNS组织隔开，并清除死亡或受损细胞。 此外，小胶质细胞在维持脑内环境稳定和促进突触形成和重塑中起关键作用。 小胶质细胞正常功能的改变可能对大脑发育以及大脑维持正常功能和可塑性的能力产生有害影响。 我们已经研究了小胶质细胞作为发育、衰老和疾病状态（如精神分裂症）的函数以及作为环境因素的函数而改变的过程。 我们感兴趣的是确定影响小胶质细胞反应的调节因素，以及环境因素是否可以改变这一点。 我们的大部分工作都与识别小胶质细胞激活状态/极化的标志物和理解与每个状态的功能关联（吞噬作用，趋化性，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，我们已经研究了急性和长期砷暴露的影响，以修改小胶质细胞的能力，安装一个正常的主机响应炎症事件。 我们已经确定，砷可以改变小胶质细胞的正常反应，脂多糖的促炎反应和白细胞介素4/白细胞介素13诱导抗炎反应。 我们还发现，在这些暴露条件下，巨噬细胞的吞噬能力减弱。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根据起始刺激而转变。我们已经扩大了这项研究，以检查环境因素作为炎症调节过程的炎症体激活触发因素的能力。 使用这些系统作为巨噬细胞反应受阻的模型，我们正在研究对生物功能的影响，如迁移和吞噬能力，并开发方法来评估这种转变不仅对成人对疾病或损伤的反应，而且对大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查不同年龄海马颗粒下区的祖细胞群。 使用该系统以及体内模型，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以增强或阻碍修复。 我们已经确定了一个可能的支点区分有益的和有害的影响，在海马神经祖细胞的青春期小鼠在白细胞介素1激活的炎性小体。 对于这些研究，我们继续使用许多方法来检查暴露于环境因子后发育中的神经系统的改变，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、检查mRNA水平的分子技术如qRT-PCR、微阵列、RNA酶保护测定、神经祖细胞培养物、成体来源的神经干/祖细胞、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 identified that under these exposure conditions the phagocytic capability of the macrophage is blunted. We have also characterized the dynamics of the bioenergetic capacity of microglia under these conditions and how they shift depending on the initiating stimulus. We have expanded this research to examine the ability of environmental agents to act as a trigger for inflammasome activation as a regulatory process for inflammation. Using these systems as models of hindered macrophage response we are examining the impact on biological functions such as migration and phagocytic capability and developing methods to assess what impact this shift may have not only on adult response to disease or injury but also 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.