Project Summary:
Binge alcohol consumption remains a significant public health crisis in the U.S. In 2021, more than 178,000 reported deaths were attributable to excessive alcohol use, making alcohol one of the leading preventable causes of death in the U.S. At the state level, Wisconsin consistently ranks among the highest in the nation for binge drinking rates. The consequences of this high rate of alcohol misuse are stark, as alcohol-related deaths in Wisconsin have also seen a disturbing upward trend over the past decade. Since 2010, the state experienced a nearly 25% increase in alcohol-related fatalities, with more than 1,500 deaths attributed to alcohol in 2020 alone. These deaths encompass a range of causes, including liver disease, alcohol poisoning, and accidents related to alcohol impairment.
Despite the substantial public health crisis this represents both in Wisconsin and nationwide, very few effective treatment options exist for alcohol use disorder (AUD). In 2022, fewer than 10% of individuals with AUD in the U.S. received treatment of any kind, and of those, only 2.2% received medication-assisted treatment. For individuals who are successful in seeking out treatment, more than 30% relapse in their first year of sobriety. Although relapse rates decline slightly with each additional year of sobriety, ultimately more than 70% of those struggling with alcohol abuse relapse at some point during recovery. These dismal recovery rates highlight the critical need for better therapeutic options to aide those struggling with AUD at the national and local levels.
Addressing this issue requires vast improvements in the understanding of the cellular and molecular processes that govern relapse vulnerability. This project team proposes addressing this issue by using cutting-edge approaches (e.g., single-nucleus RNA sequencing (snRNA-seq); RNAscope) to understand how binge alcohol withdrawal modifies the molecular landscape of a key node involved in withdrawal and relapse behaviors, the central amygdala (CeA). They focus on the CeA because prior work has identified this region as a critical mediator of anxiety and negative affect behaviors that arise during protracted withdrawal in both humans and rodent model systems.
The goal of this project is to address the urgent need for effective, evidence-based interventions to reduce alcohol misuse in Wisconsin and worldwide. The long-term objective is to pinpoint the cellular and molecular mechanisms that govern alcohol withdrawal and relapse vulnerability in an effort to develop personalized treatment strategies to combat AUD. To achieve this goal, the team will identify key, cell-type specific withdrawal gene targets for future mechanistic interrogation using CRISPR-based epigenetic editing strategies. Collectively, these approaches will allow the researchers to determine which specific transcriptional alterations are key drivers of alcohol relapse and enable the development of novel and individualized CRISPR-based intervention strategies in subsequent studies.
Beyond the specific scientific goals of the project, another primary objective of this initiative is to enhance and diversify preclinical substance use disorder (SUD) research within the pharmacology and toxicology department, and at the Medical College of Wisconsin (MCW) in general.
AHW funding will provide essential funding to establish a foundational dataset for future R-level NIAAA grant submissions aimed at dissecting the role of gene targets identified here in regulating functional cellular and behavioral outcomes relevant to AUD. It will also facilitate the broader goal of fostering a collaborative network of MCW investigators dedicated to advancing alcohol research and improving public health outcomes for Wisconsin residents who suffer from AUD.