Deoxycorticosterone (DOC) is an endogenous neurosteroid found in brain and serum, precursor of the GABAergic neuroactive steroid (3alpha,5alpha)-3,21-dihydroxypregnan-20-one (tetrahydrodeoxycorticosterone, THDOC) and the glucocorticoid corticosterone. These steroids are elevated following stress or ethanol administration, contribute to ethanol sensitivity and their elevation is blunted in ethanol dependence. To systematically define the genetic basis, regulation and behavioral significance of DOC levels in plasma and cerebral cortex we examined such levels across 47 male C57BL/6J (B6) x DBA/2J (D2) (BXD) recombinant inbred mouse strains. Mice were injected with saline or 0.075 mg/kg dexamethasone sodium salt at 8:00 am and were sacrificed 6 hours later. DOC levels were measured by radioimmunoassay. Quantitative trait loci (QTL) and bioinformatics analyses of DOC levels in relation to behavior and gene regulation were conducted. Basal cerebral cortical DOC levels ranged between 1.4 and 12.2 ng/g, resulting in 8.7-fold genetic variation [F(43,246) = 4.33, p<0.0001]. Heritability for this trait was estimated 0.37 using intraclass correlation (http://www.genenetwork.org/glossary.html#H) or 0.68 using the Hegmann and Possidente's method. Basal plasma DOC levels across the BXD strains ranged between 2.8 and 12.1 ng/ml, resulting in a 4.3-fold genetic variation [F(48,282) = 3.69, p<0.0001]. Heritability was estimated 0.32 using the intraclass correlation or 0.65 using the Hegmann and Possidente's method. QTLs for basal DOC levels were identified on chromosomes 4 (cerebral cortex) and 14 (plasma). Dexamethasone-induced changes in DOC levels showed a 4.4-fold variation in cerebral cortex and a 4.1-fold variation in plasma, but no QTLs were identified. DOC levels and its responses to dexamethasone were linked to several behavioral measures of ethanol sensitivity previously determined across the BXD strains by multiple laboratories. Both basal and dexamethasone-suppressed DOC levels are positively correlated with ethanol sensitivity suggesting that the neurosteroid DOC may be a putative biomarker of alcohol phenotypes. Basal DOC levels were also found to regulate networks of genes associated with neuronal function, innate immune pathways and steroid metabolism, likely linked to behavioral phenotypes.
Genetic analysis of the neurosteroid deoxycorticosterone and its relation to alcohol phenotypes: identification of QTLs and downstream gene regulation
Porcu P;
2011
Abstract
Deoxycorticosterone (DOC) is an endogenous neurosteroid found in brain and serum, precursor of the GABAergic neuroactive steroid (3alpha,5alpha)-3,21-dihydroxypregnan-20-one (tetrahydrodeoxycorticosterone, THDOC) and the glucocorticoid corticosterone. These steroids are elevated following stress or ethanol administration, contribute to ethanol sensitivity and their elevation is blunted in ethanol dependence. To systematically define the genetic basis, regulation and behavioral significance of DOC levels in plasma and cerebral cortex we examined such levels across 47 male C57BL/6J (B6) x DBA/2J (D2) (BXD) recombinant inbred mouse strains. Mice were injected with saline or 0.075 mg/kg dexamethasone sodium salt at 8:00 am and were sacrificed 6 hours later. DOC levels were measured by radioimmunoassay. Quantitative trait loci (QTL) and bioinformatics analyses of DOC levels in relation to behavior and gene regulation were conducted. Basal cerebral cortical DOC levels ranged between 1.4 and 12.2 ng/g, resulting in 8.7-fold genetic variation [F(43,246) = 4.33, p<0.0001]. Heritability for this trait was estimated 0.37 using intraclass correlation (http://www.genenetwork.org/glossary.html#H) or 0.68 using the Hegmann and Possidente's method. Basal plasma DOC levels across the BXD strains ranged between 2.8 and 12.1 ng/ml, resulting in a 4.3-fold genetic variation [F(48,282) = 3.69, p<0.0001]. Heritability was estimated 0.32 using the intraclass correlation or 0.65 using the Hegmann and Possidente's method. QTLs for basal DOC levels were identified on chromosomes 4 (cerebral cortex) and 14 (plasma). Dexamethasone-induced changes in DOC levels showed a 4.4-fold variation in cerebral cortex and a 4.1-fold variation in plasma, but no QTLs were identified. DOC levels and its responses to dexamethasone were linked to several behavioral measures of ethanol sensitivity previously determined across the BXD strains by multiple laboratories. Both basal and dexamethasone-suppressed DOC levels are positively correlated with ethanol sensitivity suggesting that the neurosteroid DOC may be a putative biomarker of alcohol phenotypes. Basal DOC levels were also found to regulate networks of genes associated with neuronal function, innate immune pathways and steroid metabolism, likely linked to behavioral phenotypes.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
