What can tired worms tell us about sleep?

New research published in BMC Biology uses C. elegans - a commonly used model organism and the simplest animal model known to sleep - to explore the effects of sleep deprivation. Here, author of the study, David Biron tells us how different organs are affected by sleep deprivation and the protective responses it triggers.

Sleep may be universal in the animal kingdom, yet the underlying reasons for this universality remain controversial. Hypotheses of the functions of sleep include the notion that its utility may differ across species.

The synaptic homeostasis hypothesis proposes that continuous learning during wakefulness saturates neuronal connections. Therefore, downscaling connections during sleep allows the brain to learn new information on the next day.

Other suggestions focus on ‘wear and tear’: wakeful activity in neurons unavoidably accrues protein fragments, unfolded proteins, or biochemically reactive byproducts. On a larger scale, waste clearance from the brain can increase during mammalian sleep. In addition, sleep disruption is linked to abnormal glucose metabolism, diabetes, and appetite regulation. These findings suggest that sleep is key to normal metabolic and hormonal processes outside of the brain.

Worm sleep deprivation

To clarify essential functions of sleep, one can study the effects of deprivation. The cognitive, physiological, and behavioral changes resulting from disrupting human sleep can be subtle and difficult to detect. Likewise, animal models do not typically exhibit substantial brain damage following partial sleep deprivation. Contributing to this are protective responses triggered upon deprivation or shortly thereafter that can prevent or repair accruing damage.

Our study addressed the lasting impact of partial sleep deprivation in the roundworm C. elegans, the simplest animal model known to sleep. The absence of motion served as a proxy for sleep – an admittedly imperfect measure of the interplay between duration and quality. For instance, worms may sleep ‘deeper’ than usual following a disruption. Barring more advanced characterizations, experimenters are blind to such complexities. However, even imperfect measurements can be instructive.

Sleep deprivation triggers a protective response that handles misfolded proteins in the mitochondria. Blocking this response reduced feeding rates in tired worms

The first step to examining potential responses was to establish a method for disrupting sleep without noticeable gross side effects. Of the possible consequences of sleep loss, worms are particularly suitable for studying damage on the cellular level. Cellular damage and repair can occur at different rates and vary in molecular detail. It follows that impacts of deprivation on different organs, developmental maturity, and energetic demands may vary. We therefore adopted a comparative approach to uncover commonalities and differences in the costs of sleep loss to different organs.

The first example we encountered concerned mitochondria – cellular organelles that replenish energy stores and regulate metabolism. Mitochondria are particularly busy in energy hungry cells such as in the worm’s feeding organ, which can pump in liquid food 240 times a minute. Sleep deprivation triggers a protective response that handles misfolded proteins in the mitochondria. Blocking this response reduced feeding rates in tired worms.

Sleep deprivation in worms also triggers a protective response in the endoplasmic reticulum (ER) – an organelle tasked with folding and transporting proteins. Curiously, we found that blocking the ER response in tired worms did not affect feeding but was consequential for sperm cells and egg-laying muscles. Sub-par sperm cells kill themselves through a regulated process called apoptosis, and sleep deprivation causes more of them to do so. Similar phenomena in flies and mice suggest that deprivation induced sperm apoptosis is deeply conserved.

The link between lack of sleep and diabetes, and also the broad changes in gene expression in livers, lungs, and hearts of tired mice argue that the molecular consequences of tiredness are not limited to brains. Our study further demonstrates that sleep contributes to normal function in different organs.  Accumulation of ‘wear and tear’ and its balance with relief and repair can be affected by physiological activity, developmental maturity, or additional factors. The complementing responses that maintain normal feeding, egg-laying muscle activity, and sperm count in tired worms may be explained by such differences.

Taken together, our work indicates that sleep deprivation upsets the biochemical balance in an organism whose common ancestor with mammals dates back almost a billion years. How the balance of damage and repair might scale in different cells with different metabolic loads has not been systematically studied, let alone connected to sleep. The specific protection of feeding by a mitochondrial response suggests that highly active organs may invoke distinct responses in this context. Further comparative studies will likely reveal such underexplored functions of sleep and may lead to the formulation of universal principles.

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