Stress–response pathways are altered in the hippocampus of chronic alcoholics

Abstract

The chronic high-level alcohol consumption seen in alcoholism leads to dramatic effects on the hippocampus, including decreased white matter, loss of oligodendrocytes and other glial cells, and inhibition of neurogenesis. Examining gene expression in post mortem hippocampal tissue from 20 alcoholics and 19 controls allowed us to detect differentially expressed genes that may play a role in the risk for alcoholism or whose expression is modified by chronic consumption of alcohol. We identified 639 named genes whose expression significantly differed between alcoholics and controls at a False Discovery Rate (FDR) ≤ 0.20; 52% of these genes differed by at least 1.2-fold. Differentially expressed genes included the glucocorticoid receptor and the related gene FK506 binding protein 5 (FKBP5), UDP glycosyltransferase 8 (UGT8), urea transporter (SLC14A1), zinc transporter (SLC39A10), Interleukin 1 receptor type 1 (IL1R1), thioredoxin interacting protein (TXNIP), and many metallothioneins. Pathways related to inflammation, hypoxia, and stress showed activation, and pathways that play roles in neurogenesis and myelination showed decreases. The cortisol pathway dysregulation and increased inflammation identified here are seen in other stress-related conditions such as depression and post-traumatic stress disorder and most likely play a role in addiction. Many of the detrimental effects on the hippocampus appear to be mediated through NF-κB signaling. Twenty-four of the differentially regulated genes were previously identified by genome-wide association studies of alcohol use disorders; this raises the potential interest of genes not normally associated with alcoholism, such as suppression of tumorigenicity 18 (ST18), BCL2-associated athanogene 3 (BAG3), and von Willebrand factor (VWF).

Chronic alcohol exposure differentially affects activation of female locus coeruleus neurons and the subcellular distribution of corticotropin releasing factor receptors

“…The LC is profoundly impacted by stress and its dysregulation can increase the risks of both ethanol dependence and the potential for relapse (Morilak et al 2005). Intra-gastric delivery of ethanol to non-handled, freely moving rats increases LC neuronal activity, as measured by accumulation of c-Fos, a marker of recent neuronal activation, supporting the notion that acute ethanol induces activation of LC neurons (Kolodziejska-Akiyama et al 2005; McClintick et al 2013; Lee et al 2011). Additionally, administration of ethanol intracerebroventricularly normally stimulates adrenocorticotropin (ACTH) release from the PVN; however, when the LC was lesioned, release was potentiated (Selvage 2012), indicating a direct role for the LC in ethanol induced HPA axis activation.…”

Understanding the addiction cycle: A complex biology with distinct contributions of genotype vs. sex at each stage

“…Notably, bioinformatic analysis to identify cell-type-specific gene expression indicates involvement of astrocytes in females during intoxication. Evidence of glial activation and some aspects of neuroinflammation have been observed in postmortem brain tissue from alcoholics (Zou and Crews, 2012, Crews et al, 2013, McClintick et al, 2013). Chronic alcohol exposure can result in immune dysfunction and immunosuppression, at least in some tissues (Kaphalia and Calhoun, 2013, Khocht et al, 2013, Mehta et al, 2013, Parlet et al, 2014), and alcoholics frequently develop severe respiratory infections which result in increased hospital stays and a higher likelihood of intensive care unit admission (Saitz et al, 1997).…”

FKBP5 Moderates Alcohol Withdrawal Severity: Human Genetic Association and Functional Validation in Knockout Mice

“…Furthermore, genotype-specific FKBP5 DNA methylation may mediate these genechildhood trauma interactions (Klengel et al, 2013). More importantly, a recent study has reported differential expression of the FKBP5 gene in postmortem brains of alcoholics (McClintick et al, 2013), suggesting a role for this gene in the pathophysiology of AD. Here, we examined whether genetic variation at the FKBP5 locus moderates the severity of alcohol withdrawal in alcohol-dependent patients who had consumed their last drink within 48 h of admission to an inpatient unit.…”