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. A large body of literature supports this hypothesis with the involvement of microglia in various neurodevelopmental disorders such as autism, in response to injury such as traumatic brain injury or ischemia, or in the progression of neurodegenerative diseases such as Alzheimer's Disease and Parkinson's Disease. We have examined the process by which the microglia can be altered as a function of development, aging, and in disease states such as rodent models of human immunodeficiency virus under combined antiviral therapy, 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 (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 cells - both cell lines and primary cells obtained from the brain and are translating these methods to human microglia. In our work with chemical exposure we have identified distinct types of responses from which we can generate a profile. For example, using arsenic as a chemical that can alter the human immune system, we have generated a profile of an exposure that causes a 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. Our work has further characterized the involvement of mitochondria in the brain inflammatory response demonstrating an additional mechanism by which microglia can be functionally compromised in disease states or with environmental exposures. Additional work within the framework of neuroinflammation has been undertaken using the HIV-1 transgenic rat. This model was examined to understand the link between microglia response, neuroinflammation, and the deficit in the dopaminergic system. While neuroinflammation has been associated with HIV, in the rat model we demonstrated that any inflammatory response was likely linked to changes in the dopaminergic system rather than an initiating factor. 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 if this interaction and repair ability changes as a function of age or if an injury in the adolescent will compromise repair ability in the aged. 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, 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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McPherson, Christopher A; Zhang, Guozhu; Gilliam, Richard et al. (2018) An Evaluation of Neurotoxicity Following Fluoride Exposure from Gestational Through Adult Ages in Long-Evans Hooded Rats. Neurotox Res 34:781-798
Goulding, David R; Nikolova, Viktoriya D; Mishra, Lopa et al. (2018) Inter-?-inhibitor deficiency in the mouse is associated with alterations in anxiety-like behavior, exploration and social approach. Genes Brain Behav :e12505
Goulding, David R; White, Sally S; McBride, Sandra J et al. (2017) Gestational exposure to perfluorooctanoic acid (PFOA): Alterations in motor related behaviors. Neurotoxicology 58:110-119
Avdoshina, Valeria; Caragher, Seamus P; Wenzel, Erin D et al. (2017) The viral protein gp120 decreases the acetylation of neuronal tubulin: potential mechanism of neurotoxicity. J Neurochem 141:606-613
Orihuela, Ruben; McPherson, Christopher A; Harry, Gaylia Jean (2016) Microglial M1/M2 polarization and metabolic states. Br J Pharmacol 173:649-65
Szabo, Steven T; Harry, G Jean; Hayden, Kathleen M et al. (2016) Comparison of Metal Levels between Postmortem Brain and Ventricular Fluid in Alzheimer's Disease and Nondemented Elderly Controls. Toxicol Sci 150:292-300
Kraft, Andrew D; McPherson, Christopher A; Harry, G Jean (2016) Association Between Microglia, Inflammatory Factors, and Complement with Loss of Hippocampal Mossy Fiber Synapses Induced by Trimethyltin. Neurotox Res 30:53-66
McPherson, C A; Merrick, B A; Harry, G J (2014) In vivo molecular markers for pro-inflammatory cytokine M1 stage and resident microglia in trimethyltin-induced hippocampal injury. Neurotox Res 25:45-56
Awada, Rana; Saulnier-Blache, Jean Sébastien; Grès, Sandra et al. (2014) Autotaxin downregulates LPS-induced microglia activation and pro-inflammatory cytokines production. J Cell Biochem 115:2123-32
Muessel, Michelle J; Harry, G Jean; Armstrong, David L et al. (2013) SDF-1? and LPA modulate microglia potassium channels through rho gtpases to regulate cell morphology. Glia 61:1620-8

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