Postoperative recovery in humans varies over a large range and the mechanisms involved are poorly understood. Peripheral monocytes and brain microglia adopt activation states that can be detrimental to inflammation resolution pathways involved in postoperative comorbidities like pain and delirium that impact recovery. The range of activation states correlates to the range of postoperative recovery possibilities observed in both clinical and experimental settings. This potentially explains the inability of researchers and clinicians to adequately predetermine a patient’s pain or delirium outcome after surgery, despite extensive basic and translational studies. The overarching focus of my research program is to identify neuroimmune mechanisms that contribute to variations in postoperative recovery, such as, pain, cognition, and depression, accounting for age and sex. Our approach will combine innovative technologies and relevant pre-clinical experimental models to investigate monocyte/microglia involvement in postoperative recovery with a focus on pain and delirium. In the past 5 years, we have begun to elucidate how age and sex influences neuroinflammatory processes involved in pain and cognitive deficits to inflammatory stimuli, a condition like surgery. We and others have determined that changes in pain and cognitive states in age is related to “priming” of the immune system and not “current” conditions. Building from our current work, over the next five years we propose to: 1) Build a clinically relevant postoperative assessment system to evaluate recovery phases in the context of pain and delirium in rodents. Initial experiments to assess weight loss, body temperature, and ambulatory movement in male and female young and advanced age groups will set an important premise. 2) Determine how age and sex influence monocytes (pain) and microglia (delirium) to modulate neuronal processing is an imperative step toward therapeutic development. We will apply the genomics method of “translating ribosome affinity purification”, (TRAP) to peripheral monocytes and brain microglia. A major strength of TRAP is the ability to identify a cell-specific “functional transcriptome”. This approach utilizes transgenic mice and captures actively translating mRNAs located on ribosomes during protein synthesis. This allows for quantification of translated RNAs using sequencing techniques. An important point of innovation and impact for our proposed work is that the identity of functional mRNAs in immune cells in aging, sex, and surgery will be revealed. Of most interest will be regulation of inflammatory cytokines known to promote pain and/or delirium after surgery. The work proposed is highly innovative because it integrates advanced methods to resolve our understanding of postoperative pain and delirium, to eventually move these molecular insights toward new therapeutic strategies, which aligns with the growing emphasis on human molecular neuroscience in my home depar...