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Selection for drinking in the dark alters brain gene coexpression networks.

ABSTRACT: Heterogeneous stock (HS/NPT) mice have been used to create lines selectively bred in replicate for elevated drinking in the dark (DID). Both selected lines routinely reach a blood ethanol (EtOH) concentration (BEC) of 1.00 mg/ml or greater at the end of the 4-hour period of access in Day 2. The mechanisms through which genetic differences influence DID are currently unclear. Therefore, the current study examines the transcriptome, the first stage at which genetic variability affects neurobiology. Rather than focusing solely on differential expression (DE), we also examine changes in the ways that gene transcripts collectively interact with each other, as revealed by changes in coexpression patterns.Naïve mice (N = 48/group) were genotyped using the Mouse Universal Genotyping Array, which provided 3,683 informative markers. Quantitative trait locus (QTL) analysis used a marker-by-marker strategy with the threshold for a significant logarithm of odds (LOD) set at 10.6. Gene expression in the ventral striatum was measured using the Illumina Mouse 8.2 array. Differential gene expression and the weighted gene coexpression network analysis (WGCNA) were implemented largely as described elsewhere.Significant QTLs for elevated BECs after DID were detected on chromosomes 4, 14, and 16; the latter 2 were associated with gene-poor regions. None of the QTLs overlapped with known QTLs for EtOH preference drinking. Ninety-four transcripts were detected as being differentially expressed in both selected lines versus HS controls; there was no overlap with known preference genes. The WGCNA revealed 2 modules as showing significant effects of both selections on intramodular connectivity. A number of genes known to be associated with EtOH phenotypes (e.g., Gabrg1, Glra2, Grik1, Npy2r, and Nts) showed significant changes in connectivity.We found marked and consistent effects of selection on coexpression patterns; DE changes were more modest and less concordant. The QTLs and differentially expressed genes detected here are distinct from the preference phenotype. This is consistent with behavioral data and suggests that the DID and preference phenotypes are markedly different genetically.

SUBMITTER: Iancu OD

PROVIDER: S-EPMC3759151 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Selection for drinking in the dark alters brain gene coexpression networks.

Iancu Ovidiu D OD Oberbeck Denesa D Darakjian Priscila P Metten Pamela P McWeeney Shannon S Crabbe John C JC Hitzemann Robert R

Alcoholism, clinical and experimental research 20130329 8

<h4>Background</h4>Heterogeneous stock (HS/NPT) mice have been used to create lines selectively bred in replicate for elevated drinking in the dark (DID). Both selected lines routinely reach a blood ethanol (EtOH) concentration (BEC) of 1.00 mg/ml or greater at the end of the 4-hour period of access in Day 2. The mechanisms through which genetic differences influence DID are currently unclear. Therefore, the current study examines the transcriptome, the first stage at which genetic variability a ...[more]

PMID: 23550792

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Project description:Binge drinking is common in human adolescents. The adolescent brain is undergoing structural maturation and has a unique sensitivity to alcohol neurotoxicity. Therefore, adolescent binge ethanol may have long-term effects on the adult brain that alter brain structure and behaviors that are relevant to alcohol-use disorders.To determine whether adolescent ethanol (AE) binge drinking alters the adult brain, male C57BL/6 mice were treated with either water or ethanol during adolescence (5 g/kg/d, i.g., postnatal days P28 to P37) and assessed during adulthood (P60 to P88). An array of neurotransmitter-specific genes, behavioral tests (i.e., reversal learning, prepulse inhibition, and open field), and postmortem brain structure using magnetic resonance imaging (MRI) and immunohistochemistry, were employed to assess persistent alterations in adult brain.At P38, 24 hours after AE binge, many neurotransmitter genes, particularly cholinergic and dopaminergic, were reduced by ethanol treatment. Interestingly, dopamine receptor type 4 mRNA was reduced and confirmed using immunohistochemistry. Normal control maturation (P38 to P88) resulted in decreased neurotransmitter mRNA, e.g., an average decrease of 56%. Following AE treatment, adults showed greater gene expression reductions than controls, averaging 73%. Adult spatial learning assessed in the Morris water maze was not changed by AE treatment, but reversal learning experiments revealed deficits. Assessment of adult brain region volumes using MRI indicated that the olfactory bulb and basal forebrain were smaller in adults following AE. Immunohistochemical analyses found reduced basal forebrain area and fewer basal forebrain cholinergic neurons.Adolescent binge ethanol treatment reduces adult neurotransmitter gene expression, particularly cholinergic genes, reduces basal forebrain and olfactory bulb volumes, and causes a reduction in the density of basal forebrain acetylcholine neurons. Loss of cholinergic neurons and forebrain structure could underlie adult reversal learning deficits following adolescent binge drinking.

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Selection for drinking in the dark alters brain gene coexpression networks.

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Selection for drinking in the dark alters brain gene coexpression networks.

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