Circadian Chimeric Mice Reveal an Interplay Between the Suprachiasmatic Nucleus and Local Brain Clocks in the Control of Sleep and Memory.

Abstract

Sleep is regulated by circadian and homeostatic processes. Whereas the suprachiasmatic nucleus (SCN) is viewed as the principal mediator of circadian control, the contributions of sub-ordinate local circadian clocks distributed across the brain are unknown. To test whether the SCN and local brain clocks interact to regulate sleep, we used intersectional genetics to create temporally chimeric CK1ε Tau mice, in which dopamine 1a receptor (Drd1a)-expressing cells, a powerful pacemaking sub-population of the SCN, had a cell-autonomous circadian period of 24 h whereas the rest of the SCN and the brain had intrinsic periods of 20 h. We compared these mice with non-chimeric 24 h wild-types (WT) and 20 h CK1ε Tau mutants. The periods of the SCN ex vivo and the in vivo circadian behavior of chimeric mice were 24 h, as with WT, whereas other tissues in the chimeras had ex vivo periods of 20 h, as did all tissues from Tau mice. Nevertheless, the chimeric SCN imposed its 24 h period on the circadian patterning of sleep. When compared to 24 h WT and 20 h Tau mice, however, the sleep/wake cycle of chimeric mice under free-running conditions was disrupted, with more fragmented sleep and an increased number of short NREMS and REMS episodes. Even though the chimeras could entrain to 20 h light:dark cycles, the onset of activity and wakefulness was delayed, suggesting that SCN Drd1a-Cre cells regulate the sleep/wake transition. Chimeric mice also displayed a blunted homeostatic response to 6 h sleep deprivation (SD) with an impaired ability to recover lost sleep. Furthermore, sleep-dependent memory was compromised in chimeras, which performed significantly worse than 24 h WT and 20 h Tau mice. These results demonstrate a central role for the circadian clocks of SCN Drd1a cells in circadian sleep regulation, but they also indicate a role for extra-SCN clocks. In circumstances where the SCN and sub-ordinate local clocks are temporally mis-aligned, the SCN can maintain overall circadian control, but sleep consolidation and recovery from SD are compromised. The importance of temporal alignment between SCN and extra-SCN clocks for maintaining vigilance state, restorative sleep and memory may have relevance to circadian misalignment in humans, with environmental (e.g., shift work) causes.