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
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
Average rotarod training latency Chr# 12 rs13481614 (102385663) with right flanking marker rs33846822 (30605487) and left marker rs29187760 (115166913). This was mapped in 300 + (b6x129)F2 mice.
Neocortex Gene Expression Correlates for COCA_TIME_COND_CHG measured in BXD RI Males obtained using GeneNetwork Neocortex ILM6v1.1 (Feb08) RankInv. The COCA_TIME_COND_CHG measures Cocaine CPP - difference in time spent relative to baseline drug exposure under the domain Cocaine. The correlates were thresholded at a p-value of less than 0.001.
Authors:
Philip VM, Duvvuru S, Gomero B, Ansah TA, Blaha CD, Cook MN, Hamre KM, Lariviere WR, Matthews DB, Mittleman G, Goldowitz D, Chesler EJ
Striatum Gene Expression Correlates for NEPCOUNT30 measured in BXD RI Males obtained using GeneNetwork Striatum M430V2 (Apr05) RMA. The NEPCOUNT30 measures Novel environment locomotion (activity beam breaks) 15-30 min in the periphery under the domain Morphine. The correlates were thresholded at a p-value of less than 0.001.
Authors:
Philip VM, Duvvuru S, Gomero B, Ansah TA, Blaha CD, Cook MN, Hamre KM, Lariviere WR, Matthews DB, Mittleman G, Goldowitz D, Chesler EJ
Striatum Gene Expression Correlates for NEPCOUNT30 measured in BXD RI Males obtained using GeneNetwork Striatum M430V2 (Apr05) RMA. The NEPCOUNT30 measures Novel environment locomotion (activity beam breaks) 15-30 min in the periphery under the domain Morphine. The correlates were thresholded at a p-value of less than 0.001.
Striatum Gene Expression Correlates for NEPCOUNT30 measured in BXD RI Males obtained using GeneNetwork Striatum M430V2 (Apr05) RMA. The NEPCOUNT30 measures Novel environment locomotion (activity beam breaks) 15-30 min in the periphery under the domain Cocaine. The correlates were thresholded at a p-value of less than 0.001.
Striatum Gene Expression Correlates for NEPDIST30 measured in BXD RI Males obtained using GeneNetwork Striatum M430V2 (Apr05) RMA. The NEPDIST30 measures Novel environment distance (cm) travelled min 15-30 under the domain Morphine. The correlates were thresholded at a p-value of less than 0.001.
Authors:
Philip VM, Duvvuru S, Gomero B, Ansah TA, Blaha CD, Cook MN, Hamre KM, Lariviere WR, Matthews DB, Mittleman G, Goldowitz D, Chesler EJ
Striatum Gene Expression Correlates for NEPDIST30 measured in BXD RI Males obtained using GeneNetwork Striatum M430V2 (Apr05) RMA. The NEPDIST30 measures Novel environment distance (cm) travelled min 15-30 under the domain Morphine. The correlates were thresholded at a p-value of less than 0.001.
Striatum Gene Expression Correlates for NEPDIST30 measured in BXD RI Males obtained using GeneNetwork Striatum M430V2 (Apr05) RMA. The NEPDIST30 measures Novel environment distance (cm) travelled min 15-30 under the domain Cocaine. The correlates were thresholded at a p-value of less than 0.001.
Striatum Gene Expression Correlates for NEPVCOUNT30 measured in BXD RI Females obtained using GeneNetwork Striatum M430V2 (Apr05) RMA. The NEPVCOUNT30 measures Novel environment rears 15-30 min in the periphery under the domain Cocaine. The correlates were thresholded at a p-value of less than 0.001.
Authors:
Philip VM, Duvvuru S, Gomero B, Ansah TA, Blaha CD, Cook MN, Hamre KM, Lariviere WR, Matthews DB, Mittleman G, Goldowitz D, Chesler EJ
Striatum Gene Expression Correlates for ST_MAX_85 measured in BXD RI Males obtained using GeneNetwork Striatum M430V2 (Apr05) RMA. The ST_MAX_85 measures Maximum startle response to 85 db under the domain Basal Behavior. The correlates were thresholded at a p-value of less than 0.001.
Authors:
Philip VM, Duvvuru S, Gomero B, Ansah TA, Blaha CD, Cook MN, Hamre KM, Lariviere WR, Matthews DB, Mittleman G, Goldowitz D, Chesler EJ
Striatum Gene Expression Correlates for ZM_ACTIVITY measured in BXD RI Females & Males obtained using GeneNetwork Striatum M430V2 (Apr05) RMA. The ZM_ACTIVITY measures Zero Maze - Total Activity count; number of beam breaks under the domain Basal Behavior. The correlates were thresholded at a p-value of less than 0.001.
Authors:
Philip VM, Duvvuru S, Gomero B, Ansah TA, Blaha CD, Cook MN, Hamre KM, Lariviere WR, Matthews DB, Mittleman G, Goldowitz D, Chesler EJ
Striatum Gene Expression Correlates for NEINCOUNT15 measured in BXD RI Males obtained using GeneNetwork Striatum M430V2 (Apr05) RMA. The NEINCOUNT15 measures Novel environment locomotion (activity beam breaks) 0-15 min in the center under the domain Cocaine. The correlates were thresholded at a p-value of less than 0.001.
Authors:
Philip VM, Duvvuru S, Gomero B, Ansah TA, Blaha CD, Cook MN, Hamre KM, Lariviere WR, Matthews DB, Mittleman G, Goldowitz D, Chesler EJ
Striatum Gene Expression Correlates for NEINDIST15 measured in BXD RI Males obtained using GeneNetwork Striatum M430V2 (Apr05) RMA. The NEINDIST15 measures Novel environment locomotion (cm) 0-15 min in the center under the domain Cocaine. The correlates were thresholded at a p-value of less than 0.001.
Authors:
Philip VM, Duvvuru S, Gomero B, Ansah TA, Blaha CD, Cook MN, Hamre KM, Lariviere WR, Matthews DB, Mittleman G, Goldowitz D, Chesler EJ
Hippocampus Gene Expression Correlates for VERCNT165 measured in BXD RI Males obtained using GeneNetwork Hippocampus Consortium M430v2 (Jun06) RMA. The VERCNT165 measures Morphine vertical activity counts minutes 150-165 under the domain Morphine. The correlates were thresholded at a p-value of less than 0.001.
Authors:
Philip VM, Duvvuru S, Gomero B, Ansah TA, Blaha CD, Cook MN, Hamre KM, Lariviere WR, Matthews DB, Mittleman G, Goldowitz D, Chesler EJ
Genes downregulated in livers of Eif2ak3(Perk)-mutant mice 30 minutes after perfusion witht tBuHQ. tBuHQ is used to generate ER-stress. Sequences reported in the manuscript were used to search the Mouse Genome Informatics (MGI) resource using the batch query form on June 22, 2018. Sequences that did not match were investigated manually. In some cases, sequence identifiers were identified by cross-referencing the array data in the Gene Expression Omnibus. Sequences that were associated with putative assignments to gene identifiers via a 'probe' relationship in MGI were included. Values represent z-scores. Higher scores were used for genes represented more than once.
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