Magnetic Resonance Imaging of Outbred Rats with Variable Vulnerability to Compulsive Alcohol Use

About This Grant

PROJECT SUMMARY/ABSTRACT Advancements in neuroscience, including magnetic resonance imaging (MRI), have significantly improved our understanding of alcohol use disorder (AUD) and brain function, yet due to the heterogeneity in the disorder and complexity of the brain, controlled comprehensive approaches in diverse populations are a necessity to characterize individual variability. Here, longitudinal multi-parametric MRI will be employed to assess brain features associated with AUD in a large cohort (N=100, 50% female) of genetically diverse (heterogeneous stock) rats sourced from the NIAAA-funded Rat Alcohol Biobank (1R01AA030048, 5R01AA029688), which provides rats with fully characterized genome and addiction-like behaviors, going through a state-of-the-art pipeline with escalation of alcohol intake following intermittent exposure to alcohol vapor. Leveraging features from structural, diffusion, and functional MRI, our investigation seeks to capture the individual differences in the brain, at baseline before alcohol exposure (Aim 1: pre-existing), and following the alcohol paradigm during acute withdrawal (24 h) and protracted abstinence (5 weeks) (Aim 2: alcohol-induced), within the same rats that show vulnerability or resilience to developing alcohol addiction-like behaviors. We hypothesize that there will be an interaction between the results from both aims. The brain of a subset of animals will be harvested after longitudinal MRI for complementary single-cell whole-brain imaging (SCWBI), using light sheet microscopy following brain clearing and immunohistochemistry co-labeling of neurons (NeuN), activation (Fos), and stress signaling (CRF), to provide insights into the cellular underpinnings of the observed MRI brain features associated with AUD (Aim 3). We hypothesize that neuronal loss and activation of the stress circuit will correlate with the alcohol addiction-like behaviors, some MRI brain features, and underlying genomic differences. Through this collaborative endeavor with the Rat Alcohol Biobank, we anticipate the generation of a large, diverse, and high-quality dataset that will be made publicly available and will contribute significantly to our understanding of the diverse impact of alcohol on the brain and individual differences in vulnerability to AUD. This Katz proposal provides a unique opportunity to disentangle pre-existing differences from those that are a consequence of exposure to alcohol using a, for the PI new, clinically relevant approach, which will complement her current preclinical work with SCWBI and simplify the translation of the findings for human applications. Ultimately, this research seeks to pave the way for improved prevention and personalized treatment strategies, thereby reducing illness and disability associated with AUD.