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.
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