Transcriptome Analysis of Alcohol Drinking in Non-Dependent and Dependent Mice Following Repeated Cycles of Forced Swim Stress Exposure

Farris, Sean P.; Tiwari, Gayatri R.; Ponomareva, Olga N.; López, Marcelo F.; Mayfield, R. Dayne; Becker, Howard C.

doi:10.3390/brainsci10050275

Cited by 14 publications

(11 citation statements)

References 40 publications

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“…Acute alcohol exposure induces Hspa1a in human monocytes and is required for inhibition of TLR4/MyD88 (but not TLR4/TRIF) signaling in macrophages [ 63 ]. Hspa1a and Hspa1b transcripts are also dysregulated after ethanol exposure in rodent in total brain homogenates [ 64 – 66 ], astrocytes [ 67 , 68 ], and microglia [ 68 ]. Depending on the time point at which gene expression was assayed and perhaps other differences between the protocols employed, these studies have shown increases or decreases in their transcript abundance.…”

Section: Discussionmentioning

confidence: 99%

Blood and brain gene expression signatures of chronic intermittent ethanol consumption in mice

et al. 2022

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Alcohol Use Disorder (AUD) is a chronic, relapsing syndrome diagnosed by a heterogeneous set of behavioral signs and symptoms. There are no laboratory tests that provide direct objective evidence for diagnosis. Microarray and RNA-Seq technologies enable genome-wide transcriptome profiling at low costs and provide an opportunity to identify biomarkers to facilitate diagnosis, prognosis, and treatment of patients. However, access to brain tissue in living patients is not possible. Blood contains cellular and extracellular RNAs that provide disease-relevant information for some brain diseases. We hypothesized that blood gene expression profiles can be used to diagnose AUD. We profiled brain (prefrontal cortex, amygdala, and hypothalamus) and blood gene expression levels in C57BL/6J mice using RNA-seq one week after chronic intermittent ethanol (CIE) exposure, a mouse model of alcohol dependence. We found a high degree of preservation (rho range: [0.50, 0.67]) between blood and brain transcript levels. There was small overlap between blood and brain DEGs, and considerable overlap of gene networks perturbed after CIE related to cell-cell signaling (e.g., GABA and glutamate receptor signaling), immune responses (e.g., antigen presentation), and protein processing / mitochondrial functioning (e.g., ubiquitination, oxidative phosphorylation). Blood gene expression data were used to train classifiers (logistic regression, random forest, and partial least squares discriminant analysis), which were highly accurate at predicting alcohol dependence status (maximum AUC: 90.1%). These results suggest that gene expression profiles from peripheral blood samples contain a biological signature of alcohol dependence that can discriminate between CIE and Air subjects.

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Section: Discussionmentioning

confidence: 99%

Blood and brain gene expression signatures of chronic intermittent ethanol consumption in mice

et al. 2022

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“…Previous work with the same animals identified transcriptional changes associated with CIE+FSS in the mouse cortex[22]. Cortical transcriptional signatures from the same alcohol-dependent, stressed animals provide an opportunity to identify overlapping gene expression changes between PFC and NTS.…”

Section: Resultsmentioning

confidence: 98%

Transcriptome analysis of alcohol dependence and stress interactions in the nucleus of the solitary tract

Grantham

Tiwari

Ponomereva

et al. 2022

Preprint

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Stress exposure contributes to the development of drug and alcohol use disorders. In animal models, stress exacerbates escalations in alcohol consumption in alcohol-dependent animals. The nucleus of the solitary tract (NTS) is a critical brainstem region for integrating and relaying peripheral signals to regulate stress responses. To define the molecular adaptions within this brain region that may contribute to stress-induced alcohol drinking, we exposed animals to chronic intermittent bouts of ethanol vapor (CIE), forced swim stress (FSS), or both (CIE + FSS) and then transcriptionally profiled the NTS at three different timepoints after the last vapor exposure (0-hr, 72-hr, and 186-hr). We identified interferon (IFN) signaling as a critical gene network correlated with alcohol consumption levels. Using a likelihood ratio test, we identified genes that were differentially expressed across time and between groups. Clustering analysis of these genes to identify unique expression patterns identified a subset of genes that fail to normalize in the CIE + FSS group, but not the others. These genes were enriched for cell-to-cell interaction and cellular movement pointing to long-term structural and functional changes in this brain region caused by the unique interaction of alcohol dependence and stress. Specific genes of interest identified in this group include Aqp4, Il16, Reln, Grm4, Gabrd, and Gabra6. We also compared gene expression changes in the NTS to the PFC and found a significant overlap of genes between the two brain regions. Overlapping NTS/PFC genes in the CIE + FSS group were enriched for type I IFN signaling. Finally, we tested the hypothesis that activation of type I IFN signaling increases alcohol consumption based on the three lines of evidence identifying type I IFN signaling as critical for escalations in alcohol intake. Mice treated with recombinant IFNβ showed significantly elevated levels of alcohol intake in a two-bottle choice procedure compared to saline-treated controls. Overall, these results define the transcriptomic changes across time in the NTS that may be critical to the development of stress-induced increases in alcohol consumption and alcohol dependence.

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“…The present data demonstrate that apremilast effectively reduces ethanol intake in stressed and non-stressed alcohol dependent and non-dependent mice. Notably, others have found that male C57BL/6J mice subjected to forced swim stress and CIE had persistent increases in immune-related, alcohol responsive genes, including Pde4b expression 57 . Moreover, previous work showed that nonspecifically targeting phosphodiesterases (via peripheral administration of ibudilast) reduced dependence-induced alcohol intake in C57BL/6J mice 49 .…”

Section: Discussionmentioning

confidence: 99%

The FDA-approved drug apremilast suppresses alcohol intake: clinical and pre-clinical validation

Grigsby

et al. 2021

Preprint

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Treatment options for Alcohol Use Disorders (AUD) have minimally advanced since 2004, while the annual deaths and economic toll have become alarmingly high. Bringing potential therapeutics beyond the bench and into the clinic for AUD requires rigorous pharmacological screening across molecular, behavioral, pre-clinical, and clinical studies in neuroscience. The repurposing of FDA approved compounds is an effective and expedited means of screening pharmacotherapies for AUD. Here, we demonstrate that apremilast, a phosphodiesterase type 4 inhibitor that is FDA approved for psoriasis and psoriatic arthritis, reduces binge-like alcohol intake and behavioral measures of motivation in unique, preclinical genetic risk models for drinking to intoxication and reduces excessive alcohol drinking in models of stress facilitated drinking and alcohol dependence. In a double blind, placebo-controlled human laboratory study in non-treatment seeking individuals with AUD, apremilast significantly reduced the number of drinks per day. Lastly, using site-directed drug infusions and electrophysiology we determined that apremilast may act by increasing neural activity in the nucleus accumbens, an important alcohol-related brain region, to reduce alcohol intake in mice. These results demonstrate that apremilast reduces excessive alcohol drinking across a spectrum of AUD severity and support its importance as a potential therapeutic for AUD.

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Transcriptome Analysis of Alcohol Drinking in Non-Dependent and Dependent Mice Following Repeated Cycles of Forced Swim Stress Exposure

Cited by 14 publications

References 40 publications

Blood and brain gene expression signatures of chronic intermittent ethanol consumption in mice

Blood and brain gene expression signatures of chronic intermittent ethanol consumption in mice

Transcriptome analysis of alcohol dependence and stress interactions in the nucleus of the solitary tract

The FDA-approved drug apremilast suppresses alcohol intake: clinical and pre-clinical validation

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