Stress-response pathways are altered in the hippocampus of chronic alcoholics.
- Authors
- McClintick, Jeanette N; Xuei, Xiaoling; Tischfield, Jay A; Goate, Alison; Foroud, Tatiana; Wetherill, Leah; Ehringer, Marissa A; Edenberg, Howard J
- Year
- 2013
- Journal
- Alcohol (Fayetteville, N.Y.)
- PMID
- 23981442
- DOI
- 10.1016/j.alcohol.2013.07.002
- PMCID
- PMC3836826
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) β€ 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-ΞΊB 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).
Distribution of fold changes for the 743 transcripts significant at FDR β€ 0.20
LLM interpretation
This is a histogram showing the distribution of fold changes for 743 transcripts significant at FDR β€ 0.20. The x-axis represents fold change bins, and the y-axis represents the number of significant transcripts. The distribution is right-skewed, with the highest frequency of transcripts occurring in the 1.1β1.2 fold change bin.
Ingenuity Pathway Analysis network with NF-ΞΊB as central hubRed: genes with increased expression; green: genes with decreased expression; gray: gene in dataset but was not significantly changed; white: not in the data set used for analysis.
LLM interpretation
This is an Ingenuity Pathway Analysis (IPA) network diagram centered on the NF-ΞΊB hub. The network displays interconnected genes and proteins, with red nodes indicating increased expression, green nodes indicating decreased expression, and gray nodes indicating no significant change. Directed edges represent interactions between the central NF-ΞΊB hub and various peripheral genes, such as NR1D1, SERPINA3, and SCLY.
Key pathways affected by ethanolEthanol intake increases cortisol and activates NF-ΞΊB via Toll-like receptor 4 (TLR4). NF-ΞΊB activation increases innate immune activity. Hippocampal neurogenesis is inhibited via NFΞΊB. NR4A2 represses NF-ΞΊB transactivation of other genes. When stress cannot be resolved by the eIF2 pathway, transcription of TXNIP is increased which also increases NF-ΞΊB transactivation. Red and Green vertical arrows indicate pathways, genes, or signaling molecules that have increased/decreased expression or activity in the hippocampus of alcoholics.
LLM interpretation
This is a pathway diagram illustrating the molecular effects of ethanol in the hippocampus. Ethanol is shown to increase cortisol and activate TLR4 and the TXNIP pathway (via unresolved stress/eIF2), all of which converge to activate NF-ΞΊB. NF-ΞΊB activation is depicted as promoting innate immunity (increasing IL1Ξ² and IL6) while inhibiting neurogenesis and myelination.
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