NREM sleep gain in the first 6 h of the dark period after SD is associated with <i>Acot11</i>.

<p>(A) Time course of hourly values of time spent in NREM sleep in baseline, SD (red area), and recovery for the 2 BXD lines showing the largest (BXD70; green) and lowest (BXD83; blue) NREM sleep gain during ZT12–18 (left). NREM sleep gain during 4 consecutive 6 h intervals during recovery compared to corresponding baseline intervals shows that in the recovery dark period (gray area), BXD83 mice did not accumulate extra NREM sleep, while BXD70 mice gained 88 min (middle). Strain distribution of ZT12–18 NREM sleep gain (right). B6-allele carriers compensated less for NREM sleep lost during SD than D2-allele carriers. For color-coding, see <a href="" target="_blank">Fig 4</a>. (B) Hiveplots for NREM sleep gain in 4 six-hour recovery intervals after the end of SD at ZT6. Compared to the other 3 intervals, NREM sleep gain was strongly associated with a number of metabolites during the second 6 h interval, i.e., ZT12–18. (C) NREM sleep gain during ZT12–18 mapped to a significant QTL on chromosome 4, explaining 45% of the total phenotypic variance (top left). PC-ae-C38:2 mapped suggestively to the same region (top right). Prioritization of liver transcripts for both phenotypes yielded <i>Acot11</i> as top-ranked, significant gene (bottom). (D) Hiveplot for the ZT12–18 NREM sleep gain, highlighting <i>Acot11</i>. <i>Acot11</i> was positively correlated with several phosphatidylcholines and to <i>Ovgp1</i> expression in the cortex. (E) Allelic effect of the chromosome 4–associated region on <i>Acot11</i> expression and PC-ae-C38:2 levels in the BXDs. <i>Acot11</i> expression in liver after SD was under a strong <i>e</i>QTL effect (<i>p</i> = 1.6e−13) with <i>B6-</i>allele carriers showing a higher <i>Acot11</i> expression than <i>D2</i>-allele carriers. <i>B6-</i>allele carriers also showed higher PC-ae-C38:2 levels after SD. (F) Both <i>Acot11</i> and PC-ae-C38:2 levels changed after SD. <i>Acot11</i> in liver and PC-ae-C38:2 in blood were significantly down-regulated. In the cortex, <i>Acot11</i> was, however, significantly up-regulated, and the chromosome 4–associated region did not modulate cortical <i>Acot11</i> expression. (G) Mice carrying 1 or 2 KO alleles for <i>Acot11</i> displayed less extra NREM sleep during recovery. In contrast to the BXD panel, this difference was present in the second (ZT18–24, right) and not during the first (ZT12–18, left panel) 6 h of the recovery dark period. <i>Acot11</i>, <i>acyl-CoA thioesterase 11</i>; CPM, counts per million; Ctr, control; <i>e</i>QTL, expression quantitative trait locus; KO, knockout; NREM, non-REM; PC-ae, phosphatidylcholine acyl-alkyl; QTL, quantitative trait locus; SD, sleep deprivation; ZT, zeitgeber time</p>