Adolescent Alcohol, Corticosterone Exposure, and NLRP3 Inflammasome Expression
openNIAAA - National Institute on Alcohol Abuse and Alcoholism
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.
Up to $35K
health research