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Initial genetic dissection of serum neuroactive steroids following chronic intermittent ethanol across BXD mouse strains.

ABSTRACT: Neuroactive steroids modulate alcohol's impact on brain function and behavior. Ethanol exposure alters neuroactive steroid levels in rats, humans, and some mouse strains. We conducted an exploratory analysis of the neuroactive steroids (3?,5?)-3-hydroxypregnan-20-one (3?,5?-THP), (3?,5?)-3,21-dihydroxypregnan-20-one (3?,5?-THDOC), and pregnenolone across 126-158 individuals and 19 fully inbred strains belonging to the BXD family, which were subjected to air exposure, or chronic intermittent ethanol (CIE) exposure. Neuroactive steroids were measured by gas chromatography-mass spectrometry in serum following five cycles of CIE or air exposure (CTL). Pregnenolone levels in CTLs range from 272 to 578 pg/mL (strain variation of 2.1 fold with p = 0.049 for strain main effect), with heritability of 0.20 ± 0.006 (SEM), whereas in CIE cases values range from 304 to 919 pg/mL (3.0-fold variation, p = 0.007), with heritability of 0.23 ± 0.005. 3?,5?-THP levels in CTLs range from 375 to 1055 pg/mL (2.8-fold variation, p = 0.0007), with heritability of 0.28 ± 0.01; in CIE cases they range from 460 to 1022 pg/mL (2.2-fold variation, p = 0.004), with heritability of 0.23 ± 0.005. 3?,5?-THDOC levels in CTLs range from 94 to 448 pg/mL (4.8-fold variation, p = 0.002), with heritability of 0.30 ± 0.01, whereas levels in CIE cases do not differ significantly. However, global averages across all BXD strains do not differ between CTL and CIE for any of the steroids. 3?,5?-THDOC levels were lower in females than males in both groups (CTL -53%, CIE -55%, p < 0.001). Suggestive quantitative trait loci are identified for pregnenolone and 3?,5?-THP levels. Genetic variation in 3?,5?-THP was not correlated with two-bottle choice ethanol consumption in CTL or CIE-exposed animals. However, individual variation in 3?,5?-THP correlated negatively with ethanol consumption in both groups. Moreover, strain variation in neuroactive steroid levels correlated with numerous behavioral phenotypes of anxiety sensitivity accessed in GeneNetwork, consistent with evidence that neuroactive steroids modulate anxiety-like behavior.

SUBMITTER: Porcu P

PROVIDER: S-EPMC5253318 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Initial genetic dissection of serum neuroactive steroids following chronic intermittent ethanol across BXD mouse strains.

Porcu Patrizia P O'Buckley Todd K TK Lopez Marcelo F MF Becker Howard C HC Miles Michael F MF Williams Robert W RW Morrow A Leslie AL

Alcohol (Fayetteville, N.Y.) 20161110

Neuroactive steroids modulate alcohol's impact on brain function and behavior. Ethanol exposure alters neuroactive steroid levels in rats, humans, and some mouse strains. We conducted an exploratory analysis of the neuroactive steroids (3α,5α)-3-hydroxypregnan-20-one (3α,5α-THP), (3α,5α)-3,21-dihydroxypregnan-20-one (3α,5α-THDOC), and pregnenolone across 126-158 individuals and 19 fully inbred strains belonging to the BXD family, which were subjected to air exposure, or chronic intermittent etha ...[more]

PMID: 27884493

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Project description:The transition from acute to chronic ethanol exposure leads to lasting behavioral and physiological changes such as increased consumption, dependence, and withdrawal. Changes in brain gene expression are hypothesized to underlie these adaptive responses to ethanol. Previous studies on acute ethanol identified genetic variation in brain gene expression networks and behavioral responses to ethanol across the BXD panel of recombinant inbred mice. In this work, we have performed the first joint genetic and genomic analysis of transcriptome shifts in response to chronic intermittent ethanol (CIE) by vapor chamber exposure in a BXD cohort. CIE treatment is known to produce significant and sustained changes in ethanol consumption with repeated cycles of ethanol vapor. Using Affymetrix microarray analysis of prefrontal cortex (PFC) and nucleus accumbens (NAC) RNA, we compared CIE expression responses to those seen following acute ethanol treatment, and to voluntary ethanol consumption. Gene expression changes in PFC and NAC after CIE overlapped significantly across brain regions and with previously published expression following acute ethanol. Genes highly modulated by CIE were enriched for specific biological processes including synaptic transmission, neuron ensheathment, intracellular signaling, and neuronal projection development. Expression quantitative trait locus (eQTL) analyses identified genomic loci associated with ethanol-induced transcriptional changes with largely distinct loci identified between brain regions. Correlating CIE-regulated genes to ethanol consumption data identified specific genes highly associated with variation in the increase in drinking seen with repeated cycles of CIE. In particular, multiple myelin-related genes were identified. Furthermore, genetic variance in or near dynamin3 (Dnm3) on Chr1 at ?164 Mb may have a major regulatory role in CIE-responsive gene expression. Dnm3 expression correlates significantly with ethanol consumption, is contained in a highly ranked functional group of CIE-regulated genes in the NAC, and has a cis-eQTL within a genomic region linked with multiple CIE-responsive genes.

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Dataset Information

Initial genetic dissection of serum neuroactive steroids following chronic intermittent ethanol across BXD mouse strains.

Publications

Initial genetic dissection of serum neuroactive steroids following chronic intermittent ethanol across BXD mouse strains.

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