Restoring the Molecular Clockwork within the Suprachiasmatic Hypothalamus of an Otherwise Clockless Mouse Enables Circadian Phasing and Stabilization of Sleep-Wake Cycles and Reverses Memory Deficits

Aug 27, 2021The Journal of neuroscience : the official journal of the Society for Neuroscience

Restoring the Internal Clock in the Brain’s Timekeeping Center of Mice Without a Clock Enables Regular Sleep Patterns and Improves Memory

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Abstract

Circadian molecular competence in the suprachiasmatic nucleus (SCN) restored coherent sleep-wake cycles in clockless mice.

The SCN is identified as the principal circadian clock regulating sleep-wake patterns.
Mice without functional circadian clocks exhibited arrhythmic behavior, while those with restored SCN function displayed normal circadian rhythms.
Restoration of circadian function in the SCN led to organized sleep states and improved dynamics of non-rapid eye movement sleep (NREMS) and rapid eye movement sleep (REMS).
Fragmented wakefulness observed in clockless mice was reversed when circadian competence was restored in the SCN.
Sleep-dependent memory deficits were corrected in mice with SCN restoration, indicating the SCN's role in memory consolidation.

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The timing and quality of sleep-wake cycles are regulated by interacting circadian and homeostatic mechanisms. Although the suprachiasmatic nucleus (SCN) is the principal clock, circadian clocks are active across the brain and the respective sleep-regulatory roles of SCN and local clocks are unclear. To determine the specific contribution(s) of the SCN, we used virally mediated genetic complementation, expressing Cryptochrome1 (Cry1) to establish circadian molecular competence in the suprachiasmatic hypothalamus of globally clockless, arrhythmic male-null mice. Under free-running conditions, the rest/activity behavior of-null controls expressing EGFP (SCN) was arrhythmic, whereas Cry1-complemented mice (SCN) had coherent circadian behavior, comparable to that of Cry1,2-competent wild types (WTs). In SCNmice, sleep-wakefulness, assessed by electroencephalography (EEG)/electromyography (EMG), lacked circadian organization. In SCNmice, however, it matched WTs, with consolidated vigilance states [wake, rapid eye movement sleep (REMS) and non-REMS (NREMS)] and rhythms in NREMS δ power and expression of REMS within total sleep (TS). Wakefulness in SCNmice was more fragmented than in WTs, with more wake-NREMS-wake transitions. This disruption was reversed in SCNmice. Following sleep deprivation (SD), all mice showed a homeostatic increase in NREMS δ power, although the SCNmice had reduced NREMS during the inactive (light) phase of recovery. In contrast, the dynamics of homeostatic responses in the SCNmice were comparable to WTs. Finally, SCNmice exhibited poor sleep-dependent memory but this was corrected in SCNmice. In clockless mice, circadian molecular competence focused solely on the SCN rescued the architecture and consolidation of sleep-wake and sleep-dependent memory, highlighting its dominant role in timing sleep.The circadian timing system regulates sleep-wake cycles. The hypothalamic suprachiasmatic nucleus (SCN) is the principal circadian clock, but the presence of multiple local brain and peripheral clocks mean the respective roles of SCN and other clocks in regulating sleep are unclear. We therefore used virally mediated genetic complementation to restore molecular circadian functions in the suprachiasmatic hypothalamus, focusing on the SCN, in otherwise genetically clockless, arrhythmic mice. This initiated circadian activity-rest cycles, and circadian sleep-wake cycles, circadian patterning to the intensity of non-rapid eye movement sleep (NREMS) and circadian control of REMS as a proportion of total sleep (TS). Consolidation of sleep-wake established normal dynamics of sleep homeostasis and enhanced sleep-dependent memory. Thus, the suprachiasmatic hypothalamus, alone, can direct circadian regulation of sleep-wake. Cry1/Cry2Cry1/Cry2Con Cry1Con Cry1Con Cry1Con Cry1Con Cry1SIGNIFICANCE STATEMENT

Key numbers

46.5 ± 6.5%

Percentage of Transfected Cells

Proportion of EGFP-positive cells in the SCN of treated mice.

9.8 ± 3.5 min

NREMS Recovery Time

NREMS duration during sleep deprivation in wild-type mice.

11.58

Discrimination Index

Memory performance measure in the novel object recognition test.

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Restoring the Molecular Clockwork within the Suprachiasmatic Hypothalamus of an Otherwise Clockless Mouse Enables Circadian Phasing and Stabilization of Sleep-Wake Cycles and Reverses Memory Deficits

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