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，炎症反应的调节是由被称为小胶质细胞的特定细胞控制的。除了这种经典的功能外，这些细胞对神经系统的形成、突触形成和重塑的调节以及大脑的维护也是至关重要的。它们通过复杂的通讯网络与其他固有的细胞成分协调中枢神经系统的炎症反应，以形成反应。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，将中枢神经系统与非中枢神经系统组织隔开，并清除死亡或受损的细胞。此外，小胶质细胞在中枢神经系统发育中发挥重要作用，维持脑内稳态，清除异常和过剩的蛋白，如淀粉样β蛋白和α-突触蛋白，促进突触的形成和重塑，并启动损伤/损伤后的修复。小胶质细胞正常功能的改变会改变大脑维持正常功能和可塑性的能力，从而对大脑发育和衰老产生不利影响。因此，作为一种分布于整个神经系统的重要而独特的中枢神经系统细胞，该细胞及其功能的改变可能代表着遗传或环境影响的靶点，这些影响可能会显著影响神经系统的结构和功能。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了解小胶质细胞激活状态/极化的变化以及与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。我们正在测试各种环境因素(有机锡、砷、阻燃剂，以及与神经发育中断的基因图谱相关的化学药库)改变小胶质细胞正常功能的能力。为了开发一种系统的方法来评估小胶质细胞功能障碍，我们建立了评估小胶质细胞各种功能的方法，包括炎症因子的产生、小胶质细胞活动的功能变化和能量动力学。我们已经用啮齿动物和人类小胶质细胞建立了这些方法。在我们处理化学品暴露的工作中，我们已经确定了不同类型的反应，我们可以根据这些反应生成简档。例如，我们报告了关于炎症和线粒体信号对阻燃剂的不同反应。环境中的有机金属对线粒体有毒性，使炎症反应失控，可能导致慢性炎症的能力。使用砷作为一种可以改变人类免疫系统的化学物质，我们发现小胶质细胞功能障碍，因为促炎和抗炎特性减弱，加上功能活动的改变，如清除细菌碎片。我们已经能够将这些在细胞中的发现转化为在动物身上发生的影响。此外，我们已经证明，暴露在砷中可能通过表观遗传机制产生长期影响。 为了评估小胶质细胞在脑修复反应中的作用，我们开发了一个模型系统来检测小鼠海马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轴心点，区分对海马区神经前体细胞的有益和有害影响。我们目前正在研究这种相互作用以及修复能力如何随着年龄的变化而变化。 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的变化，包括神经炎症的活体成像、免疫组织化学、共聚焦成像、流式细胞术、质量细胞术、海马线粒体生物能量学、炎症体激活的活细胞成像、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、成年神经干细胞/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. In addition to this classic function, these cells are also critical for the formation of the nervous system, regulation of synapse formation and remodelling, and maintenance of the brain. They coordinate CNS inflammation by an intricate communication network with other intrinsic cellular components to shape 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 CNS development, maintaining brain homeostasis, clearing aberrant and excess proteins such as amyloid beta, alpha synuclin, facilitating synapse formation and remodeling, and initiating repair following insult/injury. Alterations in the normal functions of microglia can have detrimental effects on brain development and aging by shifting the ability of the brain to maintain normal functioning and plasticity. Thus, as a critical and unique CNS cell that is distributed across the entire nervous system, alterations in this cell and its functions may represent a target for genetic or environmental influences that could significantly affect the structure and function of the nervous system. 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 understanding alterations in microglia activation state/polarization and the functional associations with each state (phagocytosis, chemotaxis, shifts in mitochondrial bioenergetics). We are examining the ability of various environmental agents (organotins, arsenic, flame retardants, and a library of chemicals associated by gene profiling for neurodevelopment disruption) to modify the normal functional ability of microglia. To develop a systematic approach to assess microglia dysfunction we have established methods to assess the various functions of microglia including the production of inflammatory factors, functional changes in microglia action, and energy dynamics. We have established these methods using rodent and human microglia. In our work with chemical exposure we have identified distinct types of responses from which we can generate profiles. For example, we reported distinct profiles of responses regarding inflammation and mitochondrial signaling for flame retardants. The ability of environmental organometallic that are toxic to the mitochondria, to dysregulate the inflammatory response and possibly contribute to chronic inflammation. Using arsenic as a chemical that can alter the human immune system, we identified dysfunction of microglia in that the pro-inflammatory and the anti-inflammatory properties are diminished coupled with an alteration in functional actions such as the clearance of bacterial fragments. We have been able to translate these findings in cells to effects that occur in the animal. In addition, we have demonstrated that exposure to arsenic can produce long-lasting effects possibly via an epigenetic mechanism. To evaluate the contribution of microglia on the brain repair response we developed a model system to examine the progenitor cell population from the subgranular zone of the hippocampus of mice. 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. We are currently examining this interaction and how repair ability changes as a function of age. For these studies we continue to use a number of methods to examine alterations following exposure to environmental agents including in vivo imaging of neuroinflammation, immunohistochemistry, con-focal imaging, flow cytometry, mass-cytometry, seahorse mitochondrial bioenergetics, live-cell imaging of inflammasome activation, 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.