Abstract and Project Summary A growing number of studies show strong evidence that one mechanism predisposing older adults to an increased risk of chronic pain conditions is an age-related decline in conditioned pain modulation (CPM), a psychophysical index of endogenous pain inhibition. However, the central mechanisms underlying age differences in CPM and the causal links between dysfunctional CPM and chronic pain conditions are largely unknown. This project explores the brain networks that underlie age differences in descending noxious inhibitory control (DNIC), a measure that is similar to CPM in preclinical settings, and the mechanistic links between dysfunctional DNIC and osteoarthritis (OA)-related pain, a chronic pain condition that disproportionately affects the aged population. Our prior work has demonstrated that the efficiency of DNIC is reduced in young female rats, and DNIC efficiency is also impaired in old rats of both sexes. Additionally, we demonstrated that OA-related primary mechanical hyperalgesia was longer-lasting and more pronounced in older rats, with aged female rats experiencing the most severe aging effects. We then provided compelling evidence that the altered DNIC in young female rats and old rats is strongly associated with a weaker resting functional connectivity (FC) between the rostral anterior cingulate cortex (rACC) and the periaqueductal gray (PAG). Our studies collectively suggest that strong rACC to PAG FC is a cornerstone of efficient DNIC, and age-related alteration in rACC to PAG FC leads to dysfunctional DNIC and chronic OA pain. Here we propose that enhancement of the rACC to PAG circuit in aged rats will lead to improved DNIC and that strengthening DNIC in aged rats will effectively attenuate chronic OA pain responses. We will investigate our proposal with three specific aims (SAs). (SA1) We hypothesize that selective activation of rACC neurons projecting to PAG will significantly enhance DNIC efficiency in aged rats. We will use a behavioral paradigm for DNIC paired with chemogenetics to experimentally manipulate the strength of the rACC to PAG circuit in aged male and female rats. (SA2) We will investigate the potential causal relationship between DNIC and OA responses in aged rats. We hypothesize that scaling up DNIC efficiency by enhancing the rACC to PAG circuit significantly improves OA outcomes in aged rats. We will conduct a concurrent fMRI study to confirm that experimental manipulation of DNIC circuitry restores OA-induced changes in the brain networks of aged male and female rats. (SA3) Exercise is known to enhance CPM in humans. Our preliminary data show that regular exercise can also significantly improve DNIC in aged rats. We hypothesize that exercise increases the strength of the rACC to PAG circuit, thereby enhancing DNIC, reducing OA-related pain, and restoring altered brain networks in aged male and female rats. These studies will significantly improve our knowledge regarding the impac...