Environmentally Induced Alterations In Neuron And Glia Development and Aging

National Institute Of Environmental Health Sciences

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Abstract

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 synuclein, 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 and contribute to a vast array of neurological and neurodegenerative disorders. 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 and provided a pipeline to cross-bridge between studies conducted is cells and outcomes observed in the intact nervous system. In our work with chemical exposure we have identified distinct types of responses from which we can generate microglia and neuroinflammatory profiles. We have identified unique profiles induced by chemical exposures that can compromise the ability of these critical immune cells to perform their normal function and thus, protect the brain from injury. Using a model of neural progenitor cells, we are examining the interactions between microglia and newly generated neurons to facilitate brain development and repair following injury. For these studies we continue to use various methods to examine alterations following exposure to environmental agents including in vivo imaging of neuroinflammation, immunohistochemistry, con-focal imaging, flow cytometry, mass-cytometry, mitochondrial bioenergetics, live-cell imaging of inflammasome activation, molecular techniques to examine mRNA level such as qRT-PCR, microarray, RNAseq, neuroprogenitor cell cultures, adult derived neural stem/progenitor cells, as well as assessment of neurobehavioral functioning.