Influence of Circadian System on Sleep and Sleep Disorders

Complex interactions of the homeostatic and circadian processes that regulate sleep duration and intensity respectively, ensure that sleep occurs at optimal times. However, the exact physiological mechanisms by which these processes regulate the sleep-wake cycle is currently unknown. Recent studies have shown the circadian clock cells structure sleep, primarily through the inhibition of sleep-promoting cells and other forms of sleep inhibition. The exact interactions between these sleep-promoting cells in sleep-regulatory/homeostatic brain regions and circadian clock cells however, are still unknown. To better understand the interactions of these homeostatic and circadian processes and their influences on sleep, Dr. Daniel J. Cavanaugh’s research studied the circadian rhythm in Drosophila, a model in which the circadian system is well-characterized.

One such study in his research made use of the effectors dTRPA1 (neuronal activator) and Shibirets1 (neuronal inhibitor) to selectively and timely activate circadian clock cells like 201y-GAL4+ and UAS-dTrpA1 to determine the effects of their activation on sleep. Comparisons of gene activation and inactivation made between normal control flies and cyc01-mutant flies that lacked their circadian clock, showed that activation of 201y-GAL4+ cells promoted sleep with increased intensity and duration under high temperatures in comparison to control flies (reduced sleep at high temperature). Flies containing homologous copies of both 201y-GAL4+ and UAS-dTrpA1 exhibited longer more intense sleep states. Additionally, upon return to room temperature, the flies expressing excess amounts of 201y-GAL4+ than could be activated by normal concentration of dTRPA1 slept less than control flies due to negative sleep rebound (accumulation of excess sleep results in inability to induce sleep at later times, times that would’ve otherwise been optimal to sleep). Furthermore, bidirectional control of sleep via these cells was shown when inhibition of 201y-GAL4+ by Shibirets1 decreased the amount of time flies spent sleeping. From these data, it was concluded that activation of 201y-GAL4+ cells promote sleep and inhibition of them inhibit sleep or promote arousal.

It was also found that dTRPA1-mediated activation of 201y-GAL4+ neurons increased (promoted sleep) during the peaks of day (afternoon) and night (midnight). However, between transitions of night and day, activation of 201y-GAL4+ neurons did not have as much of a sleep-promoting effect. In fly cyc01 mutants that lacked a functional circadian rhythm, activation of 201y-GAL4+ neurons were not time-of-day dependent, and mutants experienced constant sleep increases during the day due to lack of inhibitive regulation of sleep administered by circadian clock. Hence, this important finding in Dr. Cavanaugh’s research has clarified the inhibitive mechanism by which the circadian system acts, in showing that it regulates/gates the sleep-promoting effect of 201y-GAL4+ neuron activation. Lastly, the effect of 201y-GAL4+ neuron activity on the brain region involved in fly sleep homeostasis, the dorsal fan-shaped body (dFSB) arises from the fact the 201y-GAL4+ neurons synapse on dFSB neurons in the mushroom body calyx and the superior medial protocerebrum. The latter brain region, is rich in dFSB neurons, suggesting that the dFSB is downstream of the 201y-GAL4+ neurons in circadian clock circuit controlling sleep.

Comparing these results to humans, it is known that dysregulations in or disturbances to the circadian system are observed in both transient and chronic sleep disorders like jet lag and insomnia respectively. Hyperactivity of the circadian rhythm can lead to excessive inhibition of sleep-promoting neurons like 201y-GAL4+ cells in flies. For example, studies have shown that individuals with attention-deficit/hyperactivity disorder often suffer from chronic sleep-onset insomnia (SOI) due to a delayed circadian rhythm. ADHD adults, when compared to controls in a research setting, tended to have lower sleep efficiency and longer sleep-onset latency. ADHD adults with SOI also had delayed beginnings and endings of their sleep periods, delayed melatonin (sleep-regulating hormone) onset as well. Whether or not this is explicitly due to the hyperactivity of an individual/hyperactivity of circadian rhythm is still to be determined. Studies like the one Dr. Cavanaugh has carried in his attempt to clarify the mechanisms by which the interaction of the circadian and homeotic regulate sleep can therefore, aid in the creation of novel treatments of those suffering circadian sleep disorders.

Sources:
Cavanaugh, Daniel J., Abigail S. Vigderman, Terry Dean, David S. Garbe, and Amita Sehgal.
"The Drosophila Circadian Clock Gates Sleep through Time-of-Day Dependent Modulation of Sleep-Promoting Neurons." Sleep 39.2 (2016): 345-56.

Veen, Maaike M. Van, J.j. Sandra Kooij, A. Marije Boonstra, Marijke C.m. Gordijn, and Eus
J.w. Van Someren. "Delayed Circadian Rhythm in Adults with Attention-Deficit/Hyperactivity Disorder and Chronic Sleep-Onset Insomnia." Biological Psychiatry 67.11 (2010): 1091-096.


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