Source: Unsplash+
Sleep or not sleep, it seems to be a choice we can make, but in reality, it is not.
Source Article | "Global Science" Magazine
Article | clefable
Reviewed by | Huang YuJia
A healthy person will not remain awake all the time, nor can they sleep forever. Our lives are forced to be constrained between these two states. No matter how close we manage to approach one end, it seems that we get closer to death.
Aside from oscillating between wakefulness and sleep, most life forms also have an activity that must be carried out: aerobic respiration and energy metabolism. If you ask about the connection between aerobic respiration and sleep, some people might say they are fundamental activities for sustaining life. But if you ask Gero Miesenböck, the director of the Center for Neural Circuits and Behavior (CNCB) at the University of Oxford in the UK, he would tell you that aerobic metabolism is the fundamental reason for needing sleep.
Photo of Gero Miesenböck, source: University of Oxford
Miesenböck has an outstanding research background. As early as 23 years ago, his research team made a breakthrough in optogenetics: they introduced a set of opsin genes into rat neurons, and found that shining light on these modified neurons caused them to fire electrical impulses. Years later, he and his colleagues implanted photosensitive ion channels into the deep brain of fruit flies, and used light to precisely stimulate two specific neurons to control the flight of fruit flies. These studies demonstrated the potential of optogenetics to completely transform neuroscience research.
Now, with the widespread application of optogenetics in neuroscience, it has almost revealed all functions of the brain: sensory and motor, motivation and learning, communication and decision-making. Since 2012, Miesenböck, as one of the pioneers of optogenetics, has become a regular guest at various science awards. "Optogenetics" has also become a hot candidate for the Nobel Prize, and may add another glorious achievement to his resume in the future. On the other hand, Miesenböck has been delving into sleep research with his long-term experimental partner—fruit flies.
The Sleep Countdown
Humans have many sleep habits, such as feeling sleepy at certain times, and making up for lost sleep on weekends. Currently, a widely accepted concept is that sleep is controlled by two physiological processes: the circadian clock (also known as the circadian rhythm) and the sleep homeostasis system.
Source: Unsplash+
The main biological clock in the human body is the suprachiasmatic nucleus in the hypothalamus, which receives light signals from the retina, aligning our circadian rhythms with the surrounding environment. At the same time, it further coordinates the biological clocks in organs and tissues of the body, allowing us to adjust sleep, daily metabolism, and immune responses according to the circadian rhythm.
The sleep homeostasis system mainly controls the intensity and duration of sleep. For example, if you are severely sleep-deprived during the week, the sleep homeostasis system will create a sleep rebound on weekends, allowing you to sleep longer and get enough rest. In fruit flies, the key brain region in this system is the dorsal fan-shaped body (dorsal fan-shaped body, dFB). Some scientists believe that the ventrolateral preoptic area (VLPO) in the human brain has similar functions.
Another consensus among researchers is that mammals like humans and mice and fruit flies have highly conserved mechanisms for controlling and regulating sleep. Although on the surface, the sleep environments of humans and fruit flies seem vastly different: both need about 8 hours of sleep per day, humans require a safe and quiet environment to sleep, while fruit flies simply remain still in one place.
Source: Unsplash
Scientists noticed that when the dFB starts to become active, the fruit fly's sleep begins. This brain region sends sleep signals to other parts of the fruit fly's brain, inducing it to fall asleep. Six years ago, in a paper published in Nature, Miesenböck and his colleagues found that the dFB acts as a steadfast guardian of sleep. During the day, when the brain is awake, most neurons are very active, consuming energy, transmitting nerve signals, and responding precisely to external stimuli. However, during this period, the neurons in the dFB are suppressed and very inactive - this reverse operation is like a night shift worker, but once it's time to sleep, the dFB "starts work", initiating sleep.
Precise Transmission
The entire process of the dFB causing sleep resembles a precise transmission chain. During the day, fruit flies consume large amounts of food, providing sufficient energy substances for neurons. The mitochondria in the neurons metabolize these energy substances, mainly through the four complexes of the oxidative respiratory chain (see the figure below), transferring hydrogen and electrons to synthesize a large amount of directly usable ATP. The dFB neurons do the same.
However, the key point is that the dFB neurons are extremely inactive during the day, consuming little ATP, so these ATPs accumulate and continue to increase. This is similar to the process of queuing up and going down stairs, where the first ATP cannot be consumed in time, causing a blockage. The entire oxidative respiratory chain becomes blocked, remaining stagnant for a long time. At this point, complex 3, which easily leaks electrons in the respiratory chain, will more easily leak electrons. These electrons are received by oxygen, forming superoxide radicals (⋅O₂⁻) - which marks the beginning of the sleep countdown.
The complete oxidative respiratory chain, also known as the electron transport chain, exists in the mitochondria of eukaryotic cells. Image source: Wikipedia
In fact, this congestion-induced oxidative stress is still under the control of the dFB. This stress continues to be transmitted within the dFB neurons until it triggers a new switch - a voltage-gated potassium ion channel located on the cell membrane. Specifically, this oxidative stress acts on an enzyme associated with the ion channel.
This enzyme is always bound to NADPH (reduced coenzyme II, responsible for transferring hydrogen in many reactions), but when NADPH is oxidized to NADP⁺, the enzyme undergoes a change. This change is decisive, causing the potassium ion channel to remain open for a long time, increasing the spontaneous firing frequency of the dFB neurons, allowing them to enter an active state. At this point, the dFB neurons send signals to other brain regions, prompting them to rest, and the fruit fly falls into sleep.
Whole-brain Oxidation
However, what happens if the urge to sleep comes but you cannot sleep on time? In March and July of this year, Miesenböck's team published two papers in Nature, adding more details to their 2019 research and revealing the damage that sleep deprivation (or staying up late) causes to the brain.
In the study published in March of this year, they found that superoxide radicals produced by the mitochondria of dFB neurons oxidize unsaturated fatty acids inside the cells first. They analyzed nearly 3,000 fruit fly brain neurons and found that after 12 hours of sleep deprivation (equivalent to staying up all night), the number of 380 types of glycerophospholipids on the surface of neuronal cell membranes increased or decreased by more than twice.
The top image shows the cell membrane, and the bottom shows glycerophospholipids. The latter is the main component of the cell membrane and is easily oxidized by superoxide radicals. Source: Wikipedia
If normal rest is maintained, the four most abundant glycerophospholipids in the fruit fly's brain have fatty acid chains that are long and highly unsaturated (an average of five double bonds, with a maximum of twelve). However, after experiencing sleep deprivation, the main types of glycerophospholipids decrease, and their fatty acid chains not only become shorter, but the number of double bonds also significantly decreases (an average of two double bonds).
The image intuitively shows the changes in glycerophospholipids in the fruit fly's brain under rest and sleep deprivation conditions. From the left image showing the comparison between rest and sleep deprivation, it can be seen that the number of many glycerophospholipids decreases, with only a few increasing. The two images on the right also show this change. The image source is a paper published in Nature in March of this year.
In other words, staying up late reduces the diversity of glycerophospholipids and shortens the fatty acid chains, which leads to a decrease in the rigidity of the cell membrane and a significant decline in antioxidant capacity. These are results of superoxide radical damage, indicating that the fruit fly's brain has entered a state of whole-brain oxidation.
When awake, a large number of active neurons in the brain rapidly oxidize and supply energy, but there are electron leaks, causing oxidation, but not as noticeable as in the dFB. Therefore, when the dFB promotes sleep due to high oxidative stress, it also allows other areas of the brain to rest and repair, preventing severe oxidation.
This research also reveals the true culprit behind triggering sleep - 4-oxo-2-nonenal (4-ONE). Researchers found that oxidized glycerophospholipids generate lipid hydroperoxides (LOOH). LOOH then undergoes cleavage and rearrangement, ultimately producing various short-chain or long-chain aldehydes and ketones, including 4-ONE. Once 4-ONE reaches the cell membrane, it oxidizes NADPH in the potassium ion channel to NADP⁺, making the dFB become excited.
Mitochondria First Fragment, Then Decrease
Besides causing whole-brain oxidation, staying up late or sleep deprivation has another serious consequence: it causes mitochondria to split and their numbers to drop sharply. Miesenböck's team found that in fruit flies deprived of sleep for 12 hours, the mitochondria in the dFB neurons undergo significant changes. In July of this year, they published this finding in Nature.
In July 2025, an article on the cover of "Global Science" magazine stated that mitochondria form a dynamic network in living cells, organs, and even more broadly in the human body, communicating and helping each other. And as early as 2008, a study published in the "EMBO Journal" found that mitochondria normally reshape through division and fusion, which is a relatively normal process - provided that we sleep normally.
Image source: Cover article of "Global Science" magazine in July 2025, "Systemic Communication: Mitochondria Also Socialize"
However, when sleep is deprived or one stays up late, the splitting of mitochondria in the dFB is more like a desperate measure. They have to split to eliminate dysfunctional parts caused by oxidation - damaged parts are sent to the recycling system. These smaller mitochondria are unable to fuse again because sleep deprivation has depleted the key phosphatidic acid needed for their fusion.
Luckily, these smaller mitochondria seek help from the endoplasmic reticulum, taking lipids from it to repair the mitochondrial membrane, thus maintaining the mitochondria in a relatively healthy condition, although the number has significantly decreased.
This image shows the condition of mitochondria in the dFB of fruit flies under resting, sleep-deprived, and 24 hours of recovery after sleep deprivation. After sleep deprivation, mitochondria are clearly fewer and smaller. Image source: a paper published in Nature in July of this year.
If continued wakefulness is maintained, these smaller mitochondria will have to reorganize themselves. With the arrival of the next batch of energy substances, the oxidative respiratory chain will further block, and another round of reactive oxygen species damage will come.
Repairing Oxidation, Energy Restart
Every day in our bodies, reactive oxygen species are continuously produced due to aerobic metabolism, continuously damaging neurons and putting them in a "battle-damaged" state. Therefore, although we can barely maintain learning and thinking during the day, it is difficult to sustain for a longer period. If we push the damage caused by reactive oxygen species to extremes, it is not hard to imagine why continuous wakefulness leads to death.
Extensive research shows that sleep has many unique functions: restoring energy levels, synthesizing biological molecules for tissue regeneration, and clearing free radicals. During the recovery period brought by sleep, our body's metabolic rate decreases by about 5% to 15%, and the brain's glucose metabolism also decreases. At this time, the brain can clear reactive oxygen species (ROS) and other metabolic waste and replenish energy reserves. On the other hand, sleep also promotes the production of antioxidants, including melatonin and antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase, helping to remove free radicals, which will help improve mitochondrial health.
In the nervous system, mitochondria in neurons and astrocytes are the main sources of reactive oxygen species. A small amount of ROS can fine-tune the release of neurotransmitters and even enhance cognitive functions such as learning and memory. However, since the brain is in a high-oxygen consumption and lipid-rich environment, when ROS levels are too high and the brain cannot resist, it is particularly susceptible to oxidative stress.
In the discussion section of the July Nature paper, Miesenböck and his colleagues traced the origin of sleep all the way back to the emergence of aerobic metabolism: in the Great Oxidation Event 2.4 billion years ago, eukaryotes first maximally obtained energy from organic matter; and from 750 million to 570 million years ago, another Great Oxidation Event laid the foundation for the Cambrian Explosion of life.
With the high-energy oxidative metabolism, a high-energy nervous system emerged, and consequently, the need for sleep arose. However, sleep has also been fully utilized in evolution, such as using sleep to consolidate memories and restore emotional regulation, etc. But the most basic function of sleep remains to repair the damage caused by metabolism, ensuring that we can start a new day with fresh energy and breathe in fresh air.
Sorry, this article has increased the level of oxidation in your brain. Wishing you a good night's sleep.
References:
https://www.frontiersin.org/journals/aging/articles/10.3389/fragi.2025.1605070/full?
https://www.dpag.ox.ac.uk/team/gero-miesenboeck
https://medium.com/oxford-university/shedding-light-on-the-brain-the-dawn-of-optogenetics-caedbf823b95
https://www.nature.com/articles/s41586-025-09261-y#Bib1
https://www.nature.com/articles/s41586-019-1034-5
https://www.nature.com/articles/s41586-025-08734-4
https://www.science.org/doi/10.1126/science.1202249
https://pmc.ncbi.nlm.nih.gov/articles/PMC4614783/?
https://pmc.ncbi.nlm.nih.gov/articles/PMC4614783/?
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Original: https://www.toutiao.com/article/7543438577015734826/
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