Investigating the role of neuroinflammation in environmental exposure-induced anxiety disorders

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Project Summary This R21 proposal tests the hypothesis that environmental chemicals target microglia, the resident immune cells in the brain and alterations in microglial function contributes to the risk of development of neuropsychiatric and neurodegenerative disorders. Microglia play an important role in responding to inflammation and immune challenge in the brain. They also have been shown to have a number of important roles beyond immune response, including synaptic pruning during development and adult neurogenesis. Microglial activation has been shown to be involved in the progression of different neurodegenerative diseases as well as in several neuropsychiatric conditions. Accumulating evidence suggests that environmental chemical exposure increases the susceptibility to the development of various neurodegenerative and neuropsychiatric disorders. A majority of the studies investigating the impacts of environmental chemical exposure on microglia have been conducted using in vitro cell culture systems and very little is known about in vivo effects, especially during early life. The proposed research is aimed at understanding the role of environmental chemical exposure on microglial dysfunction in vivo in a well-established developmental model system using imaging, molecular and behavioral approaches. It has two specific aims. In specific aim 1, we test the hypothesis that exposure of zebrafish to polychlorinated biphenyls (PCBs) causes microglial activation. These studies will be conducted using a range of environmentally relevant concentrations of PCB126, a dioxin-like PCB that is ubiquitously distributed in the environment. Using transgenic zebrafish expressing cell-specific fluorescent markers and time-lapse confocal imaging, we will measure microglial morphology in response to exposure. In addition, the potential effects of microglial activation on neuronal network as well as neurobehaviors will be quantified. In specific aim 2, we will test the hypothesis that PCB-induced microglia dysfunction is AHR dependent. Using AHR null zebrafish, we will characterize the role of AHR in microglial activation. Wild type and AHR null zebrafish will be exposed to a concentration of PCB126 that affected microglia and characterize the effects both immediately after exposure and later in life. We will characterize the brain specific transcriptional and epigenetic profiles associated with these changes using single cell RNA sequencing and single cell DNA methylation profiling. The results from the proposed studies will provide fundamental knowledge about the role of environmental chemicals on immune cells in the brain.