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This article comes from the official account of Wechat: ID:fanpu2019, author: Kestrel

I wake up to sleep while others sleep to wake up.

In the giant brown algae forest off the coast of Southern California, there is a creature that looks like a miniature pumpkin called a Tethya californiana. No one used to pay attention to it until 2017, when William Joiner, a neurobiologist at the University of California, San Diego (UCSD), decided to study whether they sleep.

Figure 1. Tethya californiana | By Ed Bierman-Flickr: Puffball Sponge, Tethya aurantia, CC BY 2.0, https://commons.wikimedia.org/ w / index.php?curid=18999005 at first glance, you may think this question is stupid. I don't even have a brain. What kind of sleep do you sleep? But in recent years, some studies on nematodes, jellyfish and hydra have challenged the traditional view that "sleep is the exclusive privilege of brained animals." David Raizen, a neuroscientist at the University of Pennsylvania, said: "now, the search for animals that do not have nerve cells but can sleep is at the forefront of the sleep field."

Sponge is one of the earliest animal groups on earth, and it is the best candidate to break the traditional view. Catching a dozing sponge may directly subvert the academic definition of sleep and change our understanding of the purpose of sleep.

Scientists generally define sleep as a "temporarily unconscious state", which is dominated by the brain and is good for the brain. Therefore, the study of "sleep" in anencephalic animals is controversial. Many people think that the unresponsive state seen in jellyfish and hydra can only be called "sleep-like state", not "sleep". They don't believe that these animals can sleep, at least not like humans.

Obviously, this involves how to define sleep. Of course, it is impossible for lower animals to show sleep characteristics like ours, but if some of the sleep-related molecular mechanisms from jellyfish to humans are conservative, we can call the unresponsive state of jellyfish "original sleep". "original sleep" means that it is evolutionarily related to "sleep".

Figure 2. Various groups represent the sleep characteristics of animals [1] it has been generally believed that sleep is accompanied by the evolution of vertebrates. But there are other scientists who take a different view, arguing that sleep occurs after the emergence of the most primitive animals.

"as long as he is alive, he will sleep." Paul Shaw, a neuroscientist at the University of Washington, mentioned that the earliest biological form evolved from no response to the external environment, while sleep returned to the "default state" (default state). "We have evolved not the function of sleep, but the function of awakening," Shaw said. "

-- wait! Have you heard this sentence somewhere? Do you remember the conversation between the actor and the old man in the basement when he was looking for a powerful hypnotic in Inception?

"they come to bed every day?"

"No. They came here to wake up. Dreams have become their real world."

Figure 3. The view of the scene related to Inception may seem mysterious, but what is more interesting is its hidden premise: is there really an animal without the so-called "awakening function"? Does the reason why plants are plants and why fungi are fungi have anything to do with the fact that they have not evolved the "awakening function"?

If so, the sleep behavior of humans, rodents and other vertebrates is a highly evolved form of sleep adapted to the needs and lifestyle of the body. In order to study the nature of sleep behavior, it may be difficult to get a glimpse of Tang'ao directly from these higher animals, or to find the basic form of sleep in simpler and more primitive animal groups.

So the researchers found sponges from fruit flies and nematodes, and discoids from sponges (placozoan, an amoeba-like multicellular animal). They found that sleep is not just good for the brain, but also for the muscles, immune system and intestines. These efforts may shift the focus of sleep from the effects of sleep on complex cognitive processes to the effects on basic cellular activity.

In the early days, sleep was defined by its "change in behavior": lying down, closing your eyes, not moving, losing awareness in the outside world-this is sleep. The consequences of not sleeping are also obvious, such as being unable to concentrate in meetings and even taking a nap while driving.

In the 1950s and 1960s, researchers gradually accepted polysomnography (polysomnography), a technique that measures brain activity, eye movement and muscle tone at the same time, creating the gold standard for defining sleep. Neuroscientists place electrodes on the surface of the scalp to record EEG activity and divide the human sleep process into two stages: rapid eye movement sleep (rapid eye movement,REM) and non-rapid eye movement sleep (non-REM). The former is the stage of general dream generation, while the latter is characterized by synchronized slow wave EEG.

Figure 4. Human polysomnography [3] previous behavioral and physiological experiments have shown that the sleep characteristics of animals are diverse. Cows and other large herbivores sleep standing up; dolphins can swim while sleeping, and some birds can fly while sleeping, allowing half of the brain to nap while the other half continues to work. Bats sleep about 20 hours a day, while wild elephants sleep only 2 hours.

At the same time, in most animals studied with electrophysiological techniques, sleep consists of at least two stages, although the detailed characteristics of each animal may be different. The color of the octopus changes during sleep, and it seems that the octopus sleeps in stages.

At the turn of the century, evidence of sleep from animals other than mammals surfaced, prompting scientists to dig for species at the base of the evolutionary tree. Naturally, they first have to determine how to define sleep in these simpler species. Jellyfish look the same when they sleep as they do when they are awake, but you can't put electrodes on them. Researchers must find out when and where these species rest, figure out what behaviors they stop when they sleep, sometimes poke to make sure they don't respond, and see how sleep deprivation affects them.

In 2017, Michael Abrams, a graduate student at the California Institute of Technology, and two classmates conducted an experiment with Cassiopea. Cassiopeia jellyfish like to stay at the bottom of the sea, their tentacles beating upward to allow symbiotic photosynthetic microbes to shine more sunlight. They found that the frequency of tentacles beating at night fell from 60 per minute to 39 per minute.

To further verify whether the jellyfish were really "asleep", they built a fake "bottom of the sea" and removed the cushion under the jellyfish in the experiment to see how the jellyfish would react when they found that the bottom of the jellyfish was lowered. As a result, the jellyfish look "drowsy" at night and swim to the new sea floor more slowly than during the day. They also created water to harass jellyfish, and as a result, the jellyfish were not very active the next day, as if they had insomnia. Finally, the jellyfish were given melatonin, a hormone that regulates the biological clock, and the frequency of tentacles fell to nocturnal levels, just as people take melatonin to help them sleep. Note that the jellyfish does not have a real brain, it only has a circle of nerve cell plexus, distributed at the edge of the bell-shaped part.

Figure 5. Neuronal distribution of jellyfish (left, stained dark) and schematic diagram of nervous system (right) [4]. Later, the researchers caught the brainless but napping animal, Hydra vulgaris, which, like the jellyfish, belongs to the phylum Cnidaria. Taichi Itoh, a biological clock expert at Kyushu University in Japan, and others placed Hydra in the laboratory during a 12-hour alternating light and dark cycle to photograph their tentacles. They found that the tentacles twisted more slowly when the light was dim.

The above jellyfish and hydra studies follow past standards, using "decreased responsiveness" as a sign of sleep. In addition, some scientists have begun to pay attention to the molecular level, looking for genes that play a role in signaling pathways that promote sleep. In 2020, for example, the Itoh team reported changes in the activity of more than 200 genes in sleep-deprived hydra, some of which also play a role in Drosophila sleep [6].

"our definition of sleep is increasingly shifting from a behavioral and physiological perspective to a cellular and molecular perspective," said Philippe Mourrain, a neurobiologist at Stanford University. "the wider the definition of sleep, the closer we are to a comprehensive understanding of its function."

For animals with brains, sleep is naturally good for the brain, such as consolidating memory, allowing cerebrospinal fluid to wash away toxic metabolic waste, and may even help maintain synaptic plasticity of the brain [7]. But these reasons don't make sense for animals without brains. "since sleep characteristics are so conservative, it may also have a more basic role, that is, to maintain basic physiological processes." Commented Amita Sehgal, a neuroscientist at the University of Pennsylvania.

Some clues from anencephalic animals suggest that sleep is designed for energy budget and metabolism. The Raizen team found that Caenorhabditis elegans napped only when metabolic needs were high; its larvae were in a sleep-like "wilting" state during the hour or two of molting. When high temperature or ultraviolet radiation causes the stress response of nematodes, they also wilt. The team also found that a protein called salt-induced kinase 3 (salt-inducible kinase-3) was directly associated with sleep and metabolism. This protein can regulate mammalian sleep, while in nematodes, it can mobilize fat reserves and increase the level of energy metabolism of nematodes [8]. In Hydra, Itoh's team also found a gene that both affects metabolism and regulates sleep.

Sleep deprivation studies have also shown that sleep affects metabolism. Sehgal found a sleep-deprived mutant Drosophila melanogaster, which has abnormal nitrogen metabolism, resulting in abnormal protein turnover (synthesis and degradation) and abnormal treatment of nitrogenous waste, resulting in the accumulation of polyamines in the body, resulting in DNA and RNA damage. In other words, when we are deprived of sleep, it is not just the brain that is affected.

In 2020, for example, Dragana Rogulja, a biologist at Harvard Medical School, published a study in the journal Cell, saying that sleep deprivation seems to affect the intestines of fruit flies and mice-causing the accumulation of reactive oxygen species (reactive oxygen species,ROS), damaging cellular DNA and other intracellular substances, and causing cell death. Rogulja speculates that the gut, one of the earliest evolved organs in multicellular animals, may be the most original beneficiary of sleep, which develops so many new functions as animals evolve more and more complex.

In this way, to understand the nature of sleep, it is necessary to study more primitive species that do not even have intestines. Raizen decided to study placozoan, a group of transparent, round, flat creatures the size of sesame seeds, with only two layers of cells and cilia on both sides. Flat disk animals have no nerve cells, and the cells communicate with each other through chemical signals to coordinate the movement of cilia. It can be said that, except for some parasites, the flatfish is the simplest animal on earth.

Figure 4. Flat disk animals, as the name implies, resemble flat plates, are generally about one millimeter in diameter and only 25 microns thick, and move like magnified amoebas. They have no tissue and organ levels, and there is no obvious symmetry in the body. there are only six types of cells with a total of thousands of cells forming a three-layer structure. [9-10] flat disk animals crawl everywhere on the rocks of the tide line and stop to eat when they come across microalgae. Bernd Schierwater, an evolutionary biologist at Hannover Veterinary University, believes that the slow-down behavior of oblate animals represents the first step in the evolution of sleep rhythms, allowing them to build up energy for the next feeding cycle. Flat disk animals lack high-power neurons, which may be enough for them.

Before the discovery that hydra and jellyfish could sleep, neuroscientist Carolyn Smith also thought the idea that platytes could sleep was stupid. But now, she even suspects that the behavior of these flat disk animals turning in circles is also a form of sleep. Flat disk animals will cringe when exposed to ultraviolet light, which can be used to find out whether they are "asleep" or not.

However, simple animals may not be easy to feed. Smith provided some samples of flat plate animals for Raizen, but they were so picky that they all died. Joiner encountered a similar problem when studying puffer sponges. He worked with Greg Rouse, a biologist at the Scripps Institute of Oceanography, to take good care of the sponges, drawing some water for them at the seaside on his way to work every day, because puffer sponges need to eat microbes in the sea. They fixed the sponge tank to the thermostat to control the light and temperature. Finally, they added a magnetic mixer to the tank to keep the sponge in a healthier state.

Joiner and Rouse set up a digital camera above the tank to record the slight contraction of the body as the sponge filtered. The results show that the sponge in the tank shrinks about every three hours. The finding means that researchers have finally found a reliable behavioral trait that can be used to monitor changes in sponge sleep.

Sandie Degnan and Bernard Degnan, marine biologists at the University of Queensland in St. Lucia, Australia, studied a different kind of sponge: Amphimedon queenslandica, a sponge found on the Great Barrier Reef. This is the first sponge animal to be sequenced throughout the genome. It has several genes, and the expression level of homologues in other species fluctuates over a 24-hour cycle [11]. Today, the Degnan team has observed that the contraction of the sponge may have a circadian rhythm, and that some sponges do not pump water even during the day, as if they were sleeping just after the night shift, which is very close to sleep. They believe that the periodic rest of sponges may be to reorganize and reinvigorate their own cells. after all, they pump about 1000 times their own volume of water in a day.

Next, the researchers plan to use glutamate (an excitatory neurotransmitter in more advanced animals) or other drugs to pump water endlessly for days or even weeks, and then see if their health is affected. If so, it suggests that multicellular animals need such periodic behavior to allow time for tissue repair and regeneration.

If cells all over the body can benefit from sleep, we can reasonably assume that cells all over the body have a say in when to sleep. In this way, studying the underlying mechanism of sleep control may point out a new direction for the treatment of sleep disorders. After all, sleep disorders affect the lives of 60 million people in the United States alone.

Ketema Paul, a neurobiologist at the University of California, Los Angeles (UCLA), studied a protein called Bmal1. Bmal1 is ubiquitous, regulates gene expression and keeps sleep-deprived mice awake. Until now, researchers have believed that this is why the brain produces the Bmal1 protein. However, Paul's team found that Bmal1 in sleep-deprived mice is actually produced by muscles [12]. He speculates that the protein may be part of a signaling pathway that allows the brain to couple muscle fatigue with brain-generated drowsiness.

Other studies in mice have shown that the digestive tract, pancreas and adipose tissue produce signal molecules that affect the start and end of sleep. These signaling molecules are called neurohormones (neurohormone). It is clear that understanding the feedback pathways of these organs to the brain may find new drugs for the treatment of sleep disorders, which no longer act only on the brain, but can target other parts of the brain. Paul believes that in the future, there may be a muscle-targeted Bmal1 drug that can combat the adverse effects of staying up all night.

Fifteen years ago, when Mourrain first began to study the sleep of fish, many people thought that fish did not sleep. Until two years ago, his team developed polysomnography for fish and used the technique to find that fish-similar to humans-also experience quiet and active sleep [13]. "this is a turning point in our field," Mourrain said. "it can convince skeptics that fish are like mammals and good animal models in sleep."

Now, Mourrain's team is developing a new experimental method that can observe how information is transmitted from cell to cell. They chose a thumbnail-sized transparent fish (Danionella translucida) and used fluorescence or other types of markers to track the fish's brain and body to see how different types of cells control sleep over time and benefit from it.

Fig. 7 small transparent fish (Danionella translucida) with a body length of only 1 cm [1]. So, after the fish, can the puffy sponge become the next animal to refute the skeptics? It may not be that fast-they can't stay healthy long enough in a laboratory environment to get reliable experimental data, and the research team has been messing with the device. Then, the COVID-19 epidemic broke out, the experiment had to stop, and now we can not even find enough manpower to restart the experiment.

Can the previously mentioned hydra, which can twist its tentacles, be a candidate? Let's wait and see.

reference

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[3] Liu, D., & Dan, Y. (2019). A Motor Theory of Sleep-Wake Control: Arousal-Action Circuit. Annu Rev Neurosci, 42, 27-46. Https://doi.org/10.1146/annurev-neuro-080317-061813

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Jindrich, Katia, Roper, Kathrein E., Lemon, Sussan, Degnan, Bernard M., Reitzel, Adam M., and Degnan, Sandie M. (2017). Origin of the animal circadian clock: diurnal and light-entrained gene expression in the sponge Amphimedon queenslandica. Frontiers in Marine Science 4 (OCT) 327. Https://doi.org/10.3389/fmars.2017.00327

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