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. 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 to brain injury 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). 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 are using this model to identify novel signaling factors that can promote adult neurogenesis and improve brain repair and cognitive functioning. 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.

Project Start
Project End
Budget Start
Budget End
Support Year
17
Fiscal Year
2013
Total Cost
$1,223,467
Indirect Cost
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State
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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 :
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
Orihuela, Ruben; McPherson, Christopher A; Harry, Gaylia Jean (2016) Microglial M1/M2 polarization and metabolic states. Br J Pharmacol 173:649-65
Goulding, David R; White, Sally S; McBride, Sandra J et al. (2016) Gestational exposure to perfluorooctanoic acid (PFOA): Alterations in motor related behaviors. Neurotoxicology 58:110-119
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-1α and LPA modulate microglia potassium channels through rho gtpases to regulate cell morphology. Glia 61:1620-8
Brunssen, Susan H; Moy, Sheryl S; Toews, Arrel D et al. (2013) Interleukin-6 (IL-6) receptor/IL-6 fusion protein (Hyper IL-6) effects on the neonatal mouse brain: possible role for IL-6 trans-signaling in brain development and functional neurobehavioral outcomes. Brain Behav Immun 27:42-53
Harry, G Jean (2013) Microglia during development and aging. Pharmacol Ther 139:313-26
Rao, Jagadeesh Sridhara; Kim, Hyung-Wook; Harry, Gaylia Jean et al. (2013) Increased neuroinflammatory and arachidonic acid cascade markers, and reduced synaptic proteins, in the postmortem frontal cortex from schizophrenia patients. Schizophr Res 147:24-31
Rider, C V; Janardhan, K S; Rao, D et al. (2012) Evaluation of N-butylbenzenesulfonamide (NBBS) neurotoxicity in Sprague-Dawley male rats following 27-day oral exposure. Neurotoxicology 33:1528-35

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