Adolescent Alcohol, Corticosterone Exposure, and NLRP3 Inflammasome Expression

About This Grant

PROJECT SUMMARY/ABSTRACT Early life stress is a prominent risk factor for initiation of alcohol use and increased lifetime alcohol consumption. Both adolescent stress and alcohol use increase the risk for developing depression during adulthood, and both exposures negatively influence the neuroimmune system, resulting in a sensitized or exaggerated response to a neuroimmune challenge. However, in rodent models, the interactive effects of alcohol and stress co-exposure are not widely studied. Because there is a bidirectional relationship among adolescent stress and alcohol use, it is critical for these exposures to be studied independently as well as simultaneously to capture synergistic or opposing effects. Therefore, one overall goal of the current proposal is to utilize an exposure paradigm that captures both the independent effects of adolescent intermittent ethanol (AIE) and chronic corticosterone (CORT) consumption in the drinking water, a commonly used model to mimic the downstream effects of one primary component of chronic stress by a tractable means. One component of the neuroimmune system that sits at the nexus between chronic stress and ethanol exposure is the inflammasome, nucleotide-binding oligomerization domain-like (NOD-like) receptor protein 3 (NLRP3). The NLRP3 inflammasome is highly expressed in the resident immune cell of the brain, microglia, and NLRP3 inflammasome expression is increased following both stress and ethanol exposures, causing a sensitized cytokine response upon challenge. Increased cytokine expression has been implicated in dopaminergic dysfunction, such as decreased dopamine availability and downregulated dopamine receptor expression, which may explain AIE- or stress-induced dysfunction of reward and motivation pathways as well. Therefore, the overall goal of the proposed studies is to determine the independent and interactive effects of AIE and CORT on 1) neuroimmune function, measured by NRLP3 expression and microglial activation state, and 2) changes to the reward and motivational systems including behavioral measures such as sucrose preference for anhedonia and effort-based decision making (EBDM) for motivation, as well as dopaminergic dysfunction such as expression of ΔFosB, D1, D2, and DAT. Specifically, whether the NLRP3 inflammasome plays a mechanistic role as a neuroimmune target for future treatment. Overall, this proposal will provide essential scientific and professional development, so enabling me to reach my goal of becoming an independent researcher.