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There is a fundamental gap in understanding the mechanisms underlying precipitous cognitive declines experienced by the elderly following a surgery or infection. These peripheral innate immune challenges, can and do activate central inflammatory responses, which in the aged brain can produce potentiated and prolonged neuroinflammatory responses, causing robust cognitive declines. This represents an important problem because advanced age and longer-lasting impairments following these events are among the strongest predisposing factors for the development of dementia later in life. Post-operative analgesic treatment with morphine was recently found to potently exacerbate the declines in the ability to form new long-term memories produced by surgery in aging rodents. The long-term goal is to develop appropriate and effective therapies to prevent and reverse inflammation-induced cognitive impairments in the elderly. There are 2 overall objectives in our current research. The first is to identify key mechanisms that may underlie the persistent behavioral manifestations in this “double hit” model. The focus is to to characterize the neuroinflammatory response to surgery and morphine in young and aged rats; and to determine the roles of HMGB1 and microglia in mediating POCD. The guiding hypothesis for this objective is that surgery releases the danger associated molecular pattern high mobility group box-1 protein (HMGB1) in specific brain regions, and that this protein acts at TLR4s on microglia to prime them. The morphine that follows also acts at TLR4 via direct ligation, and so the microglia remain inflammatory for a very prolonged period. A variety of new methods are used in this project, including the development of microglia specific DREAADs.