Research Project
10225184
Project Summary The research proposed in this supplement tests the hypothesis that developmental domoic acid (DA) exposure affects microglia, the resident immune cells in the brain, resulting in altered function, impacts on neuron health, and neurobehavioral deficits. Microglia play an important role in inflammation and responding to immune challenge in the brain. Microglial dysfunction in development can be caused by exposure to environmental chemicals and can lead to changes in brain structure, function, and neurobehavior. Early life impacts on microglia can have far-reaching impacts, including increased sensitivity to subsequent stressors causing elevated neuroinflammation and eventual neurodegeneration. Despite the importance of this cell type, very little is known about the role of microglia in mediating the effects of harmful algal toxins, including DA. The proposed research will investigate the impacts of developmental DA on microglial activation and assess the impacts of early life inflammation on neuronal survival and learning. In specific aim 1, we test the hypothesis that developmental DA exposure causes microglial activation in zebrafish brain. We will utilize confocal imaging and transgenic zebrafish expressing cell-specific fluorescent markers to assess changes in microglial morphology indicative of activation. This study will also identify windows of susceptibility. In specific aim 2, we will investigate the impacts of developmental exposure on sensitivity to later life insults. We will test the hypothesis that developmental exposure to DA will cause increased inflammation and neurodegeneration, as well as neurobehavioral changes, in response to exposure in adult fish. This aim will utilize well-characterized behavioral assays of associative learning and histological markers of neuroinflammation and neurodegeneration. In specific aim 3, we will test the hypothesis that developmental DA exposure causes altered gene expression and upregulation of inflammatory factors in microglia. We will characterize the microglia-specific transcriptional profiles associated with DA exposure using fluorescence-activated cell sorting followed by RNA sequencing. The results from the proposed study will provide important information about the role of microglia as a potential target of domoic acid, and the risks of developmental exposure.
