Environmentally Induced Alterations In Neuron And Glia Development and Aging

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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.