The current study used two inbred mouse strains, C57BL/6 J and A/J, to investigate the genetics of behavioral responses to fentanyl. Mice were tested for conditioned place preference and fentanyl-induced locomotor activity. C57BL/6J mice formed a conditioned place preference to fentanyl injections and fentanyl increased their activity. Neither effect was noted in A/J mice. We conducted RNA-sequencing on the nucleus accumbens of mice used for fentanyl-induced locomotor activity. Surprisingly, we noted few differentially expressed genes using treatment as the main factor. However many genes differed between strains.
Authors:
Samuel J Harp, Mariangela Martini, Will Rosenow, Larry D Mesner, Hugh Johnson, Charles R Farber, Emilie F Rissman
Differential gene expression in nucleus accumbens somatostatin interneurons_cocaine_mice_pvalue
Description:
To characterize transcriptional alterations that cocaine induces in these cells, we perform cell type-specific RNA-sequencing on FACS-isolated nuclei of somatostatin interneurons and identified 1100 DETs enriched for processes related to neural plasticity. To profile the entire (non poly-A selected) transcriptome of NAc somatostatin interneurons, we generated a transgenic reporter line (SST-TLG498 mice) to label the nuclei of these cells with a modified form of EGFP that is retained in the nuclear membrane (EGFP-F)22, enabling their isolation from NAc dissections using FACS. We succeeded in FACS-isolating nuclei suitable for RNA-sequencing from individual SST-TLG498 mice. We proceeded with differential expression analysis of the RNA-sequencing data to identify differentially expressed transcripts (DETs) in NAc somatostatin interneurons in response to repeated cocaine exposure: 778 transcripts were upregulated by cocaine and 322 were downregulated.
Authors:
Efrain A Ribeiro, Marine Salery, Joseph R Scarpa, Erin S Calipari, Peter J Hamilton, Stacy M Ku, Hope Kronman, Immanuel Purushothaman, Barbara Juarez, Mitra Heshmati, Marie Doyle, Casey Lardner, Dominicka Burek, Ana Strat, Stephen Pirpinias, Ezekiell Mouzon, Ming-Hu Han, Rachael L Neve, Rosemary C Bagot, Andrew Kasarskis, Ja Wook Koo, Eric J Nestler
Ethanol Preference from BXD lines span 58586243-108586243. This interval was obtained by using an arbitrary interval width of 25 Mbp around the peak marker (Build 37, MGI, http://informatics.jax.org). Marker Loci associated with 10% Ethanol Preferences Drinking at p<0.05 (Two Tailed) in the BXD RI set and the Correlation Coefficient, p and Estimated LOD. D15Mit33 (83586243 NCBI 37) p=0.05, LOD=0.08 overall LOD BXD & Select Line 2.4.
QTL mapping results for B6D2F2 mice in regions provisionally identified in BXD RI mice for free-choice ethanol consumption. Peak D15Mit33 58586243-108586243. This interval was obtained by using an arbitrary interval width of 25 Mbp around the peak marker (Build 37, MGI, http://informatics.jax.org)
Genes associated with Mus musculus that interact with the MeSH term 'Tetrachlorodibenzodioxin' (D013749). Incorporates data from 2 publications curated by the Comparative Toxicogenomics Database (CTD). ODE Gene scores represent number of supporting publications per gene.
Genes associated with Mus musculus that interact with the MeSH term 'Tetracaine' (D013748). Incorporates data from 12365 publications curated by the Comparative Toxicogenomics Database (CTD). ODE Gene scores represent number of supporting publications per gene.
Genes associated with Mus musculus that interact with the MeSH term 'Acetaminophen' (D000082). Incorporates data from 2 publications curated by the Comparative Toxicogenomics Database (CTD). ODE Gene scores represent number of supporting publications per gene.
Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that act as ligand-activated transcription factors. Although prescribed for dyslipidemia and type-II diabetes, PPAR agonists also possess anti-addictive characteristics. PPAR agonists decrease ethanol consumption and reduce withdrawal severity and susceptibility to stress-induced relapse in rodents. However, the cellular and molecular mechanisms facilitating these properties have yet to be investigated. We tested three PPAR agonists in a continuous access two-bottle choice (2BC) drinking paradigm and found that tesaglitazar (PPARα/γ; 1.5 mg/kg) and fenofibrate (PPARα; 150 mg/kg) decreased ethanol consumption in male C57BL/6J mice while bezafibrate (PPARα/γ/β; 75 mg/kg) did not. We hypothesized that changes in brain gene expression following fenofibrate and tesaglitazar treatment lead to reduced ethanol drinking. We studied unbiased genomic profiles in areas of the brain known to be important for ethanol dependence, the prefrontal cortex (PFC) and amygdala, and also profiled gene expression in liver. Genomic profiles from the non-effective bezafibrate treatment were used to filter out genes not associated with ethanol consumption. Because PPAR agonists are anti-inflammatory, they would be expected to target microglia and astrocytes. Surprisingly, PPAR agonists produced a strong neuronal signature in mouse brain, and fenofibrate and tesaglitazar (but not bezafibrate) targeted a subset of GABAergic interneurons in the amygdala. Weighted gene co-expression network analysis (WGCNA) revealed co-expression of treatment-significant genes. Functional annotation of these gene networks suggested that PPAR agonists might act via neuropeptide and dopaminergic signaling pathways in the amygdala. Our results reveal gene targets through which PPAR agonists can affect alcohol consumption behavior.
Authors:
Laura B Ferguson, Dana Most, Yuri A Blednov, R Adron Harris
Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that act as ligand-activated transcription factors. Although prescribed for dyslipidemia and type-II diabetes, PPAR agonists also possess anti-addictive characteristics. PPAR agonists decrease ethanol consumption and reduce withdrawal severity and susceptibility to stress-induced relapse in rodents. However, the cellular and molecular mechanisms facilitating these properties have yet to be investigated. We tested three PPAR agonists in a continuous access two-bottle choice (2BC) drinking paradigm and found that tesaglitazar (PPARα/γ; 1.5 mg/kg) and fenofibrate (PPARα; 150 mg/kg) decreased ethanol consumption in male C57BL/6J mice while bezafibrate (PPARα/γ/β; 75 mg/kg) did not. We hypothesized that changes in brain gene expression following fenofibrate and tesaglitazar treatment lead to reduced ethanol drinking. We studied unbiased genomic profiles in areas of the brain known to be important for ethanol dependence, the prefrontal cortex (PFC) and amygdala, and also profiled gene expression in liver. Genomic profiles from the non-effective bezafibrate treatment were used to filter out genes not associated with ethanol consumption. Because PPAR agonists are anti-inflammatory, they would be expected to target microglia and astrocytes. Surprisingly, PPAR agonists produced a strong neuronal signature in mouse brain, and fenofibrate and tesaglitazar (but not bezafibrate) targeted a subset of GABAergic interneurons in the amygdala. Weighted gene co-expression network analysis (WGCNA) revealed co-expression of treatment-significant genes. Functional annotation of these gene networks suggested that PPAR agonists might act via neuropeptide and dopaminergic signaling pathways in the amygdala. Our results reveal gene targets through which PPAR agonists can affect alcohol consumption behavior.
Authors:
Laura B Ferguson, Dana Most, Yuri A Blednov, R Adron Harris
Genes associated with Mus musculus that interact with the MeSH term 'pirinixic acid' (C006253). Incorporates data from 1 publications curated by the Comparative Toxicogenomics Database (CTD). ODE Gene scores represent number of supporting publications per gene.
Genes associated with Mus musculus that interact with the MeSH term 'sinefungin' (C006235). Incorporates data from 6366 publications curated by the Comparative Toxicogenomics Database (CTD). ODE Gene scores represent number of supporting publications per gene.
Genes associated with Mus musculus that interact with the MeSH term '4,4'-diaminodiphenylmethane' (C009505). Incorporates data from 5 publications curated by the Comparative Toxicogenomics Database (CTD). ODE Gene scores represent number of supporting publications per gene.
Genes associated with Mus musculus that interact with the MeSH term 'Nanotubes, Carbon' (D037742). Incorporates data from 26 publications curated by the Comparative Toxicogenomics Database (CTD). ODE Gene scores represent number of supporting publications per gene.
Genes associated with Mus musculus that interact with the MeSH term 'Ethinyl Estradiol' (D004997). Incorporates data from 6 publications curated by the Comparative Toxicogenomics Database (CTD). ODE Gene scores represent number of supporting publications per gene.
Genes associated with Mus musculus that interact with the MeSH term 'Methionine' (D008715). Incorporates data from 1 publications curated by the Comparative Toxicogenomics Database (CTD). ODE Gene scores represent number of supporting publications per gene.
Genes associated with Mus musculus that interact with the MeSH term 'Folic Acid' (D005492). Incorporates data from 54 publications curated by the Comparative Toxicogenomics Database (CTD). ODE Gene scores represent number of supporting publications per gene.
Genes associated with Mus musculus that interact with the MeSH term 'Choline' (D002794). Incorporates data from 2 publications curated by the Comparative Toxicogenomics Database (CTD). ODE Gene scores represent number of supporting publications per gene.
Genes associated with Mus musculus that interact with the MeSH term 'titanium dioxide' (C009495). Incorporates data from 2 publications curated by the Comparative Toxicogenomics Database (CTD). ODE Gene scores represent number of supporting publications per gene.
In 3-month-old C57BL/6J mice, 2229 genes (1980 up-regulated vs. 449 down-regulated) were differentially expressed 1 hour after fear conditioning when compared with the age-matched control group in the hippocampus. False Discovery rate (FDR) < 5%, fold change log2 ≥ 1.
Authors:
Peleg S, Sananbenesi F, Zovoilis A, Burkhardt S, Bahari-Javan S, Agis-Balboa RC, Cota P, Wittnam JL, Gogol-Doering A, Opitz L, Salinas-Riester G, Dettenhofer M, Kang H, Farinelli L, Chen W, Fischer A
In 3-month-old C57BL/6 mice, 1539 differentially expressed genes (1362 up-regulated vs. 177 down-regulated) were specific for associative learning (learning-regulated genes)in the hippocampus using fear conditioning. False Discovery rate (FDR) < 5%, fold change log2 ≥ 1
Authors:
Peleg S, Sananbenesi F, Zovoilis A, Burkhardt S, Bahari-Javan S, Agis-Balboa RC, Cota P, Wittnam JL, Gogol-Doering A, Opitz L, Salinas-Riester G, Dettenhofer M, Kang H, Farinelli L, Chen W, Fischer A
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