Acute and chronic alcohol exposure was analyzed in 534 (C57BL/6J x C3H/HeJ)F2 mice. Behavioral testing was done using 5 traits, acute drug effect, forced ethanol drinking, withdrawal studies ethanol preference and stress induced ethanol drinking. The following QTL were found in a genome wide scan: Following the QTL is the Chromosome , cM location, and LOD score, Eih1 (Chr 1, 85 cM, LOD 6.6), Eih2 (Chr 7, 10 cM, LOD 3.6), Ceih1 (Chr 3, 55 cM, LOD 4.1), Ceih2 (Chr 6, 24.7 cM, LOD 4.1), Ceih3 (Chr 13, 39 cM, LOD 4.1), Eia1(Chr 1, 65 cM, LOD 10.3 and 10.4), Eiwa1 (Chr 7, 50 cM, LOD 4.4), Eiwa2(Chr 11, 43.1 cM, LOD 4.1),Aldd1(Chr 5, 42 cM, LOD 13.2), Aldd2(Chr 12, 18 cM, LOD 5.3),Eiwax1(Chr 1, 79 cM, LOD 6.5), Eiwax2(Chr 5, 59 cM, LOD 15.0), Eiwax3(Chr 12, 21 cM, LOD 3.6), Methp1(Chr 16, 31.4 cM, LOD 4.3), Mec1(Chr 16, 19.4 cM, LOD 5.1), Epbs1(Chr 16, 33 cM, LOD 4.1), Ecbs1(Chr 16, 29.4 cM, LOD 4.8), Mec2(Chr 1, 109 cM, LOD 3.9), Mec3(Chr 2, 109 cM, LOD 4.3), Mec4(Chr 5, 29 cM, LOD 3.9), Mec5(Chr 10, 2 cM, LOD 5.0), Mec6(Chr 15, 49 cM, LOD 5.2, 95% CI 6.7–56.7).
Authors:
Drews E, Rcz I, Lacava AD, Barth A, Bilkei-Gorz A, Wienker TF, Zimmer A
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)
Drug Naïve DO mice were tested for open field, light dark, hole board, novelty place preference before collecting the striatum. RNA-Seq data was analyzed with WGCNA using a soft thresholding power of 3 selected using the WGCNA scale-free topology R2 threshold of 0.9, signed network with a minimum module size of 30, correlation type is bicor, used numeric labels.
Microglia depletion and alcohol gene expression logFC
Description:
Alcohol abuse induces changes in microglia morphology and immune function, but whether microglia initiate or simply amplify the harmful effects of alcohol exposure is still a matter of debate. Here, we determine microglia function in acute and voluntary drinking behaviors using a colony-stimulating factor 1 receptor inhibitor (PLX5622). We show that microglia depletion does not alter the sedative or hypnotic effects of acute intoxication. Microglia depletion also does not change the escalation or maintenance of chronic voluntary alcohol consumption. Transcriptomic analysis revealed that although many immune genes have been implicated in alcohol abuse, down regulation of microglia genes does not necessitate changes in alcohol intake. Instead, microglia depletion and chronic alcohol result in compensatory upregulation of alcohol-responsive, reactive astrocyte genes, indicating astrocytes may play a role in regulation of these alcohol behaviors. Taken together, our behavioral and transcriptional data indicate that microglia are not theprimary effector cell responsible for regulation of acute and voluntary alcohol behaviors. Because microglia depletion did not regulate acute or voluntary alcohol behaviors, we hypothesized that these doses were insufficient to activate microglia and recruit them to an effector phenotype. Therefore, we used a model of repeated immune activation using polyinosinic:polycytidylic acid
We investigated the role of microglia in a mouse model of alcohol dependence using a colony stimulating factor 1 receptor inhibitor (PLX5622) to deplete microglia and a chronic intermittent ethanol vapor two-bottle choice drinking procedure. Additionally, we examined anxiety-like behavior during withdrawal. We then analyzed synaptic neuroadaptations in the central nucleus of the amygdala (CeA) and gene expression changes in the medial prefrontal cortex (mPFC) and CeA from the same animals used for behavioral studies.
Alcohol Microglia depletion in the medial prefrontal cortex q-value
Description:
dependence using a colony stimulating factor 1 receptor inhibitor (PLX5622) to deplete microglia and a chronic intermittent ethanol vapor two-bottle choice drinking procedure. Additionally, we examined anxiety-like behavior during withdrawal. We then analyzed synaptic neuroadaptations in the central nucleus of the amygdala (CeA) and gene expression changes in the medial prefrontal cortex (mPFC) and CeA from the same animals used for behavioral studies.
Alcohol dependence in the medial prefrontal cortex q-value
Description:
We investigated the role of microglia in a mouse model of alcohol dependence using a colony stimulating factor 1 receptor inhibitor (PLX5622) to deplete microglia and a chronic intermittent ethanol vapor two-bottle choice drinking procedure. Additionally, we examined anxiety-like behavior during withdrawal. We then analyzed synaptic neuroadaptations in the central nucleus of the amygdala (CeA) and gene expression changes in the medial prefrontal cortex (mPFC) and CeA from the same animals used for behavioral studies.
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
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