Abstract
Chronic alcohol abuse alters the molecular structure and function of brain cells. Recent work suggests adaptations made by glial cells, such as astrocytes and microglia, regulate physiological and behavioral changes associated with addiction. Defining how alcohol dependence alters the transcriptome of different cell types is critical for developing the mechanistic hypotheses necessary for a nuanced understanding of cellular signaling in the alcohol-dependent brain. We performed RNA-sequencing on total homogenate and glial cell populations isolated from mouse prefrontal cortex (PFC) following chronic intermittent ethanol vapor exposure (CIE). Compared with total homogenate, we observed unique and robust gene expression changes in astrocytes and microglia in response to CIE. Gene co-expression network analysis revealed biological pathways and hub genes associated with CIE in astrocytes and microglia that may regulate alcohol-dependent phenotypes. Astrocyte identity and synaptic calcium signaling genes were enriched in alcohol-associated astrocyte networks, while TGF-β signaling and inflammatory response genes were disrupted by CIE treatment in microglia gene networks. Genes related to innate immune signaling, specifically interferon pathways, were consistently up-regulated across CIE-exposed astrocytes, microglia, and total homogenate PFC tissue. This study illuminates the cell-specific effects of chronic alcohol exposure and provides novel molecular targets for studying alcohol dependence.
Highlights
Glial cells, such as astrocytes and microglia, are important for proper brain development and function[1]
Enrichment analysis demonstrated that overlapping changes in astrocytes, microglia, and total homogenate were consistently involved in type I interferon signaling (Fig. 2D)
The transcriptomes of astrocytes and microglia in the mouse prefrontal cortex (PFC) were strongly perturbed by a chronic alcohol exposure paradigm that induces alcohol dependence
Summary
Glial cells, such as astrocytes and microglia, are important for proper brain development and function[1]. Transcriptome studies of human alcoholic and chronic alcohol-exposed rodent brains identified gene expression changes that were related to glial function[14,15,16,17]. Recent studies showed that chronic, voluntary alcohol consumption produces distinct changes in gene expression in astrocytes and microglia that are mostly not detected in total homogenate[33,34] Delineating these cellular effects is a crucial step towards understanding the complex molecular brain adaptations associated with AUDs. Here, we establish the astrocyte- and microglia- specific transcriptome alterations in mouse prefrontal cortex (PFC) following chronic intermittent ethanol vapor exposure (CIE). We used weighted gene co-expression network analysis (WGCNA) to identify unique co-expressing networks of genes altered in CIE-treated in astrocytes and microglia From these networks, we discovered novel cell type-specific genes that may be involved in the pathophysiology of alcohol dependence
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