Abstract
Long lasting abusive consumption, dependence, and withdrawal are characteristic features of alcohol use disorders (AUD). Mechanistically, persistent changes in gene expression are hypothesized to contribute to brain adaptations leading to ethanol toxicity and AUD. We employed repeated chronic intermittent ethanol (CIE) exposure by vapor chamber as a mouse model to simulate the cycles of ethanol exposure and withdrawal commonly seen with AUD. This model has been shown to induce progressive ethanol consumption in rodents. Brain CIE-responsive expression networks were identified by microarray analysis across five regions of the mesolimbic dopamine system and extended amygdala with tissue harvested from 0-hours to 7-days following CIE. Weighted Gene Correlated Network Analysis (WGCNA) was used to identify gene networks over-represented for CIE-induced temporal expression changes across brain regions. Differential gene expression analysis showed that long-lasting gene regulation occurred 7-days after the final cycle of ethanol exposure only in prefrontal cortex (PFC) and hippocampus. Across all brain regions, however, ethanol-responsive expression changes occurred mainly within the first 8-hours after removal from ethanol. Bioinformatics analysis showed that neuroinflammatory responses were seen across multiple brain regions at early time-points, whereas co-expression modules related to neuroplasticity, chromatin remodeling, and neurodevelopment were seen at later time-points and in specific brain regions (PFC or HPC). In PFC a module containing Bdnf was identified as highly CIE responsive in a biphasic manner, with peak changes at 0 hours and 5 days following CIE, suggesting a possible role in mechanisms underlying long-term molecular and behavioral response to CIE. Bioinformatics analysis of this network and several other modules identified Let-7 family microRNAs as potential regulators of gene expression changes induced by CIE. Our results suggest a complex temporal and regional pattern of widespread gene network responses involving neuroinflammatory and neuroplasticity related genes as contributing to physiological and behavioral responses to chronic ethanol.
Highlights
Alcohol abuse and dependence have significant health and social consequences
All animal studies were approved by the Institutional Animal Care and Use Committee at the Medical University of South Carolina (MUSC) and conducted in accordance with the guidelines outlined in the NIH Guide for the Care and Use of Laboratory Animals [21]
The majority of gene regulation in all brain regions was observed during the first 8h after the final cycle of chronic intermittent ethanol
Summary
Alcohol abuse and dependence have significant health and social consequences. Alcohol Use Disorder (AUD) is characterized by chronic excessive alcohol consumption, often alternating with periods of abstinence. Genomic approaches involving microarrays or RNA-seq, together with scale-free network analyses, have recently shown that gene networks of highly correlated expression patterns are associated with acute or chronic ethanol exposure in brain tissue derived from animal models and human autopsies [5,6,7] Such networks often have conserved biological functions or regulatory mechanisms [8, 9] providing novel mechanistic information about the neural actions of ethanol and other drugs of abuse [10]. Network topology analysis allows the identification of highly connected “hub genes” that have been shown to provide key regulatory functions over expression networks [6, 8] Applying such approaches to animal models of alcohol dependence could provide new understanding of mechanisms underlying associated neuroplasticity, and identify new therapeutic targets for intervention in AUDs
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