Neuroimmune signaling in alcohol abuse

Chronic alcohol use produces vast changes in gene expression and function across peripheral organs and the brain. These ethanol-induced adaptations eventually lead to alcohol dependence and alcohol use disorder (AUD), depending on both genetic and environmental factors. Recent evidence suggests that the interplay between brain, behavior and immune response plays a crucial role in the transition from alcohol misuse to dependence and the development of AUD. Previous work has connected neuroimmune signaling to regulation of alcohol behaviors. This dissertation seeks to address two major gaps in knowledge in our field: (1) which innate immune signaling pathway mediates alcohol behaviors; (2) when microglia, the primary immune cell in the brain, are casual regulators of alcohol behaviors. I apply immunological, pharmacological, and network-based approaches to gain mechanistic insight into how neuroimmune signaling regulates alcohol abuse. In this dissertation I provide evidence that neuroimmune signaling regulates alcohol abuse. First, I developed a viral innate immune model of excessive drinking. I demonstrated that toll-like receptor 3 (TLR3) mediates alcohol consumption in a sex- and genotype-specific manner, dependent upon the duration of innate immune activation. Using RNA-sequencing and bioinformatics, I further defined the transcriptomic and cell type-specific perturbations that regulate neuroimmune-induced escalations in alcohol intake—microglial immune response and the extracellular matrix. Further characterization of peripheral immune cell recruitment demonstrated that plasmacytoid dendritic cells may be an important cell type in this model. I also found that although microglia are implicated in alcohol abuse and dependence, microglia depletion does not change many alcohol behaviors. Instead, transcriptomic analysis implicated astrocytes in regulation of acute and voluntary drinking. Whereas, microglia regulated context-specific behaviors. The final component of this dissertation examined how we can leverage gene expression information to predict novel therapeutic compounds to treat alcohol abuse. I applied transcriptome-based computational approaches to predict compounds that regulate excessive drinking. Top predictions were validated in vivo, reinforcing a role for type I interferon signaling, the extracellular matrix and anti-inflammatory drugs in alcohol abuse. The results of this dissertation further our understanding of how neuroimmune signaling regulates alcohol abuse and proposes several new therapeutic targets to treat excessive drinking.Neuroscienc