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Dynamic neuroimmune interactions in the onset and progression of FASD

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PROJECT SUMMARY Fetal alcohol spectrum disorders (FASD) and associated neurologic sequelae occur in almost 5% of children in the U.S. ? the deficits are life-long ? and there is no cure. The goal of the proposed studies is to define the dynamic roles of microglia and astrocytes in ethanol-induced neuroinflammation and neuropathology in FASD. Ethanol-induced neuroinflammation in the developing CNS is believed to contribute to the long-term sequelae associated with FASD. However, critical gaps in knowledge remain concerning the dynamic interactions between microglia, astrocytes and neurons which mediate the transition from normal CNS development to FASD neuropathology. Furthermore, the cellular and molecular mechanisms mediating transition to and progression of the neuropathology have not been elucidated, which prevents targeted treatment. The proposed studies directly address these critical gaps in knowledge. Hypothesis: Alcohol exposure in the developing CNS elicits neuroimmune activation of microglia and astrocytes which disrupts normal dynamic interactions between these glial cells and neurons during onset and progression of FASD, producing neuropathology. Further, elucidating molecular mechanisms (currently unexplored) that regulate ethanol-induced neuroinflammation, neuron loss, and alterations in normal glia-neuron interactions will reveal therapeutic targets for FASD. Aim 1. Determine the dynamic role of microglia and astrocytes in the transition from normal cerebellar development to ethanol-induced neuropathology and progression of FASD. (SubAim A) Evaluate changes in cell-cell interactions between microglia, astrocytes, and neurons visualized at the level of glial processes and neuronal dendrites, spines, and somas. This will be done with high resolution 3D reconstructions. Define and compare the temporal pattern of neuroinflammation and neuron loss following ethanol exposure. Neuroinflammation will be assessed by glial activation and by directed qRT-PCR arrays and multiplex protein arrays of immune molecules. Purkinje neuron loss will be assessed by unbiased stereology. (SubAim B) Probe dynamic changes in the transcriptome using unbiased RNA-Seq and bioinformatic analyses. Analyses will be performed on the whole cerebellum as well as purified glia and neurons. (SubAim C) Examine the role of specific cell types in ethanol-induced neuroimmune signaling and neuropathology. This will be achieved through cell-type specific knockout of Toll-like Receptor (TLR)4 in astrocytes or microglia. Aim 2. Quantify ethanol-induced changes in dynamic microglia-neuron and astrocyte-neuron interactions in vivo in the transition from normal cerebellar development to ethanol-induced neuropathology and progression of FASD. (SubAim A) Establish whether ethanol alters microglia interactions with dendrites and spines. (SubAim B) Determine whether ethanol alters astrocyte signaling in response to neuronal activity and interactions with neurons. Studies in Aim 2 will use in vivo time-lapse two-photon imaging and immuno-electron microscopy.

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