DESCRIPTION:

Male C57BL/6J and DBA/2J mice (10 weeks old upon arrival) were purchased from the Jackson Laboratory and assigned to either the air control or CIE group (N = 1 per strain/ treatment). Treatment was coded as 0 for AIR and 1 for CIE, 0 for B6 and 1 for D2. Regions were collapsed into three groups based on the PCA clustering and coded as 0 for hippocampus (CA1 and CA3 regions), 1 for cortex (Prl, ILC, and VCX), and 2 for the remaining subcortical and limbic and mesolimbic tissue (VTA, NAc, NAs, DMS, CeA, and BST). The final data set included 11 brain regions and 87 samples. Mice were allowed to self-administer alcohol (15% v/v vs. water) for 2 h a day (5 days a week) 6 weeks prior to treatment in order to establish baseline consumption. Access to 15% alcohol versus water started 30 min prior to the start of the dark cycle. Following establishment of baseline drinking, two male mice representative of each strain were separated into two groups to be exposed to either weekly cycles of CIE exposure (CIE group) or air control (AIR group) exposure. Mice assigned to the CIE treatment group were exposed to alcohol vapor for 16 h a day followed by 8 h of withdrawal for 4 days. Following the fourth vapor exposure, mice were given a 72-h abstinence period before resuming ethanol intake in the home cage for 5 days. Mice in the AIR control treatment group were similarly treated but exposed only to air in the inhalation chambers. This pattern of CIE or air control exposure followed by 5 days of ethanol self-administration was repeated for four cycles. A fifth cycle of CIE (or air) exposure followed the fourth ethanol intake evaluation period, and brain tissue was collected 72 h after the last cycle ended. To capture expression patterns due to region, strain, and treatment or their interactions, we applied a linear model to the expression data: y ∼ Treatment + Strain + Tissue + Treatment*Strain + Treatment*Region (Supplemental Table 4). At a nominal p value (p < 0.01), most expression differences are due to the effect of region (5464 unique genes) or strain (1111 unique genes). Differences due to effect of region or strain are reflected in this gene set (p < 0.01).

LABEL:

DEG effect of brain region 72hrs post-CIE (C57 and D2) (p < 0.01)_pvalue

SCORE TYPE:

P-Value

DATE ADDED:

2024-09-03

DATE UPDATED:

2024-09-27

SPECIES:

AUTHORS:

Megan K Mulligan, Khyobeni Mozhui, Ashutosh K Pandey, Maren L Smith, Suzhen Gong, Jesse Ingels, Michael F Miles, Marcelo F Lopez, Lu Lu, Robert W Williams

TITLE:

Genetic divergence in the transcriptional engram of chronic alcohol abuse: A laser-capture RNA-seq study of the mouse mesocorticolimbic system.

JOURNAL:

Alcohol (Fayetteville, N.Y.) Feb 2017, Vol 58, pp. 61-72

ABSTRACT:

Genetic factors that influence the transition from initial drinking to dependence remain enigmatic. Recent studies have leveraged chronic intermittent ethanol (CIE) paradigms to measure changes in brain gene expression in a single strain at 0, 8, 72 h, and even 7 days following CIE. We extend these findings using LCM RNA-seq to profile expression in 11 brain regions in two inbred strains - C57BL/6J (B6) and DBA/2J (D2) - 72 h following multiple cycles of ethanol self-administration and CIE. Linear models identified differential expression based on treatment, region, strain, or interactions with treatment. Nearly 40% of genes showed a robust effect (FDR < 0.01) of region, and hippocampus CA1, cortex, bed nucleus stria terminalis, and nucleus accumbens core had the highest number of differentially expressed genes after treatment. Another 8% of differentially expressed genes demonstrated a robust effect of strain. As expected, based on similar studies in B6, treatment had a much smaller impact on expression; only 72 genes (p < 0.01) are modulated by treatment (independent of region or strain). Strikingly, many more genes (415) show a strain-specific and largely opposite response to treatment and are enriched in processes related to RNA metabolism, transcription factor activity, and mitochondrial function. Over 3 times as many changes in gene expression were detected in D2 compared to B6, and weighted gene co-expression network analysis (WGCNA) module comparison identified more modules enriched for treatment effects in D2. Substantial strain differences exist in the temporal pattern of transcriptional neuroadaptation to CIE, and these may drive individual differences in risk of addiction following excessive alcohol consumption. PUBMED: 27894806
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