Sleeping with Two Clocks

“Tik, Tok...”

My anxiety increases with every elapsing second. I have stared at the screen for hours and my fingers are now resting lifelessly on the keyboard. It is 12:29 am -- I have no idea how to finish this draft which is due  hours later... “Ah, another night without sleep...”

At this moment, only Professor Cirelli and Professor Tononi could give me condolence by asking, wryly, “What if sleep is not required but rather a kind of extreme indolence that animals indulge in when they have no more pressing needs, such as eating or reproducing?” However, they quickly shatter my illusion that I do not need to sleep. In their article, "Is Sleep Essential?" they argue that sleeping is universal among animals, and sleep deprivation brings about cognitive impairments and physiological disorders.  

Although these are depressing words to me, their work answers essential questions about sleeping -- how does it happen? How does it help us? And how does the sleep-deprivation lead to impairments? Through studies on cell-signaling, scientists are now able to elucidate the mechanisms behind the biological system of sleeping.

By successfully isolating the period gene and PER, the protein encoded by period, Jeffrey Hall and Michael Rosbash discovered the molecular mechanism that regulates our biological clock (circadian rhythm). This groundbreaking work won them the 2017 Nobel Prize in Physiology or Medicine. Another Nobel laureate, Michael Young, discovered the TIM protein, which combines with PER to form an inhibitory feedback loop. Combining their work, we now understand the circadian cycle as the accumulation of the PER protein at night and the degradation of it during the daytime. The key role of PER protein as a biosignal highlights the function of cell signaling in our physiological functions.

The work of Hall, Rosbash, and Young opened up a new horizon for circadian biology. A recent study conducted by Mikhail et al further connects the circadian cycle to sleeping, showing how the extracellular signal-regulated kinase (ERK) pathway influences sleeping and waking. By analyzing the interactions between the ERK pathway and neurotransmitters like norepinephrine (NE), histamine, and dopamine, Mikhail shows the ERK pathway plays a major role in controlling sleep-related behaviors. For example, they find that by inhibiting the phosphorylation of the ERK pathway, mice models experience a significant decrease of non-rapid eye movement sleep (NREM). NREM constitutes about 80% of human sleeping duration and plays a major role in the “qualitative side” of sleep, namely to reduce the physiological functions and prevent easy arousal. On the other hand, the activation of the ERK pathway inhibits the transcription of Dbp, a protein important to the circadian cycle and prolongs the sleeping. The work of Mikhail et al connects the circadian cycle to sleeping and displays the cell-signaling as a bridge between the “biological clock” and our physiological functions.

Cell-signaling not only helps us understand the mechanism of sleeping, but it also explains why sleeping is important to us. Though abnormal sleeping patterns have long been related to mental disorder and neurodegenerative diseases, it is only through the recent studies on cell-signaling that the underlying reason is understood. One of the most important neural functions closely related to sleeping is memory. In the review of Havekes et al, the authors highlight that Hippocampal function is particularly sensitive to sleep loss, which explains how the sleep deprivation impairs long-term memory. The research of Christopher G. Vecsey et al proves this point of view by providing insights into cell-signalling. The team focus on analyzing the effects of sleep-deprivation on hippocampal long-term potentiation (LTP), a form of neural plasticity which is believed to be important for memory consolidation. The researchers notice that the activity of phosphodiesterase 4 (PDE4) in the hippocampus of their mouse models significantly increases after sleep-deprivation. The activation of enzyme PDE4 will degrade cAMP, a signalling pathway important for inducing LTP and forming memory.

Cell signaling not only plays a pivotal role in regulating our biological clock, which is independent of the actual day and night, but it also controls our sleeping according to this circadian cycle. As many researchers noticed, we are now in a modern society where people generally suffer from sleep deprivation. Nationwide surveys in Canada and the United States found that more than 20% of the general adult population suffers from insomnia. Fortunately, as Vecsey et al point out, a deeper understanding of the molecular mechanism of sleep will enable us to manipulate biomolecules like PDE4 inhibitor to control cAMP pathway -- and in doing so, we will be able to rescue synaptic plasticity and memory deficits due to sleep deprivation. Though this requires further research, the potential medical applications are very exciting. Due to its importance to understand the human physiology and its potential to solve serious social issues, circadian biology, powered by further understanding of cell-signaling, will be an essential field of research to the modern world.

It’s 4 AM, and I have finished the article. I return to my dorm, where my roommate has waited for me for a long time - “Shawn, look at the clock!” In my post-article fog, I wonder, which one is he referring to, the one on the wall, or the one in my body? Nevertheless, I respond: “I’m sorry, Raymond. I’ll turn off the light. Good night.”

Sources:

Cirelli C, Tononi G (2008) Is sleep essential? PLoS Biol 6(8): e216. doi:10.1371/journal. pbio.0060216

Press release. NobelPrize.org. Nobel Media AB 2018. Sat. 3 Nov 2018. <https://www.nobelprize.org/prizes/medicine/2017/press-release/>

C. Mikhail, A. Vaucher, S. Jimenez, M. Tafti, ERK signaling pathway regulates sleep duration through activity-induced gene expression during wakefulness. Sci. Signal. 10, eaai9219 (2017)

Rechtschaffen, Allan. "Current Perspectives on the Function of Sleep." Perspectives in Biology and Medicine, vol. 41 no. 3, 1998, pp. 359-390. Project MUSE, doi:10.1353/pbm.1998.0051

Wulff, K., Gatti, S., Wettstein, J. G., & Foster, R. G. (2010, 07). Sleep and circadian rhythm disruption in psychiatric and neurodegenerative disease. Nature Reviews Neuroscience, 11(8), 589-599. doi:10.1038/nrn2868

Havekes, R., Vecsey, C. G., & Abel, T. (2012). The impact of sleep deprivation on neuronal and glial signaling pathways important for memory and synaptic plasticity. Cellular signalling, 24(6), 1251-60.

Vecsey, C. G., Baillie, G. S., Jaganath, D., Havekes, R., Daniels, A., Wimmer, M., Huang, T., Brown, K. M., Li, X. Y., Descalzi, G., Kim, S. S., Chen, T., Shang, Y. Z., Zhuo, M., Houslay, M. D., … Abel, T. (2009). Sleep deprivation impairs cAMP signalling in the hippocampus. Nature, 461(7267), 1122-5.

Stranges, S., Tigbe, W., Gómez-Olivé, F. X., Thorogood, M., & Kandala, N. B. (2012). Sleep problems: an emerging global epidemic? Findings from the INDEPTH WHO-SAGE study among more than 40,000 older adults from 8 countries across Africa and Asia. Sleep, 35(8), 1173-81. doi:10.5665/sleep.2012