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Genetics of the human circadian clock and sleep homeostat.

ABSTRACT: Timing and duration of sleep are controlled by the circadian system, which keeps an ~24-h internal rhythm that entrains to environmental stimuli, and the sleep homeostat, which rises as a function of time awake. There is a normal distribution across the population in how the circadian system aligns with typical day and night resulting in varying circadian preferences called chronotypes. A portion of the variation in the population is controlled by genetics as shown by the single-gene mutations that confer extreme early or late chronotypes. Similarly, there is a normal distribution across the population in sleep duration. Genetic variations have been identified that lead to a short sleep phenotype in which individuals sleep only 4-6.5?h nightly. Negative health consequences have been identified when individuals do not sleep at their ideal circadian timing or are sleep deprived relative to intrinsic sleep need. Whether familial natural short sleepers are at risk of the health consequences associated with a short sleep duration based on population data is not known. More work needs to be done to better assess for an individual's chronotype and degree of sleep deprivation to answer these questions.

SUBMITTER: Ashbrook LH

PROVIDER: S-EPMC6879540 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Genetics of the human circadian clock and sleep homeostat.

Ashbrook Liza H LH Krystal Andrew D AD Fu Ying-Hui YH Ptáček Louis J LJ

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20190810 1

Timing and duration of sleep are controlled by the circadian system, which keeps an ~24-h internal rhythm that entrains to environmental stimuli, and the sleep homeostat, which rises as a function of time awake. There is a normal distribution across the population in how the circadian system aligns with typical day and night resulting in varying circadian preferences called chronotypes. A portion of the variation in the population is controlled by genetics as shown by the single-gene mutations t ...[more]

PMID: 31400754

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Project description:The human circadian timing system is most sensitive to the phase-shifting effects of light during the biological nighttime, a time at which humans are most typically asleep. The overlap of sleep with peak sensitivity to the phase-shifting effects of light minimizes the effectiveness of using light as a countermeasure to circadian misalignment in humans. Most current light exposure treatments for such misalignment are mostly ineffective due to poor compliance and secondary changes that cause sleep deprivation. Using a 16-day, parallel group design, we examined whether a novel sequence of light flashes delivered during sleep could evoke phase changes in the circadian system without disrupting sleep. Healthy volunteers participated in a 2-week circadian stabilization protocol followed by a 2-night laboratory stay. During the laboratory session, they were exposed during sleep to either darkness (n = 7) or a sequence of 2-msec light flashes given every 30 sec (n = 6) from hours 2 to 3 after habitual bedtime. Changes in circadian timing (phase) and micro- and macroarchitecture of sleep were assessed. Subjects exposed to the flash sequence during sleep exhibited a delay in the timing of their circadian salivary melatonin rhythm compared with the control dark condition (p < 0.05). Confirmation that the flashes penetrated the eyelids is presented by the occurrence of an evoked response in the EEG. Despite the robust effect on circadian timing, there were no large changes in either the amount or spectral content of sleep (p values > 0.30) during the flash stimulus. Exposing sleeping individuals to 0.24 sec of light spread over an hour shifted the timing of the circadian clock and did so without major alterations to sleep itself. While a greater number of matched subjects and more research will be necessary to ascertain whether these light flashes affect sleep, our data suggest that this type of passive phototherapy might be developed as a useful treatment for circadian misalignment in humans.

Project description:The need to sleep is sensed and discharged in a poorly understood process that is homeostatically controlled over time. In flies, different contributions to this process have been attributed to peripheral ppk and central brain neurons, with the former serving as hypothetical inputs to the sleep homeostat and the latter reportedly serving as the homeostat itself. Here we re-evaluate these distinctions in light of new findings using female flies. First, activating neurons targeted by published ppk and brain drivers elicits similar phenotypes - namely sleep deprivation followed by rebound sleep. Second, inhibiting activity or synaptic output with one type of driver suppresses sleep homeostasis induced using the other type of driver. Third, drivers previously used to implicate central neurons in sleep homeostasis unexpectedly also label ppk neurons. Fourth, activating only this subset of co-labeled neurons is sufficient to elicit sleep homeostasis. Thus, many published contributions of central neurons to sleep homeostasis can be explained by previously unrecognized expression of brain drivers in peripheral ppk neurons, most likely those in the legs that promote walking. Lastly, we show that activation of certain non-ppk neurons can also induce sleep homeostasis. Notably, axons of these as well as ppk neurons terminate in the same ventral brain region, suggesting that a previously undefined neural circuit element of a sleep homeostat may lie nearby.SIGNIFICANCE STATEMENT:The biological need(s) that sleep fulfills are unknown, but they are reflected by an animal's ability to compensate for prior sleep loss in a process called sleep homeostasis. Researchers have searched for the neural circuitry that comprises the sleep homeostat so that the information it conveys can shed light on the nature of sleep need. Here we demonstrate that neurons originating outside of the brain are responsible for phenotypes previously attributed to the proposed central brain sleep homeostat in flies. Our results support a revised neural circuit model for sensing and discharging sleep need in which peripheral inputs connect to a sleep homeostat through previously unrecognized neural circuit elements in the ventral brain.

Dataset Information

Genetics of the human circadian clock and sleep homeostat.

Publications

Genetics of the human circadian clock and sleep homeostat.

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