The Brain’s Clockwork
A new study finds that the brain has hundreds of trillions of clocks—synapses!
Posted Oct 10, 2019
How many times a day do you check the time? Estimates are that people between the ages of 18-34 check the clock between 50-74 times a day! Staying in sync is essential for any complex system; whether it's a machine, social organization, or transportation system, chaos would erupt if the intricate processes involved were not precisely coordinated in time. Our bodies are stringently regulated by the time of day, and the brain is perhaps the organ most highly tuned to the time of day, with its rhythmic cycles of sleep and wakefulness.
As we all know from suffering sleep deprivation or jet lag, when our body clocks are out of whack, our mental function crashes. New research appearing this week in the journal Science finds that the brain has an astonishing number of clocks, hundreds of trillions of them—synapses!
Synapses are the primary mechanism of communication in neural networks. These microscopic points of communication between neurons send signals by releasing neurotransmitters, which either excite the down-stream neuron or inhibit it from firing. Learning and memory depend on changes in synaptic communication, and changes in synaptic communication make new neural networks that hold bits of information and drive our thinking, emotion, and behaviors.
Studies led by Steven Brown and colleagues at the Institute of Pharmacology and Toxicology, University of Zürich, Switzerland, investigated whether the machinery of synaptic transmission changes throughout the day/night cycle. What they found were trillions of synaptic clocks.
The researchers isolated synapses from the forebrains of mice, and then extracted the individual proteins that comprise them; some 4,000 distinct proteins were identified. To determine whether the abundance of these different proteins might rise and fall like clockwork, they took samples every four hours around the clock. What they found was that 11.7% of the synaptic proteins increased and decreased rhythmically throughout the day and night in sync with sunrise and sunset. The biggest surges were seen right at dusk and dawn. Most of the proteins that surged in abundance upon waking were ones known to be involved in synaptic transmission that stimulates neurons, and the categories of proteins that increased at the onset of sleep were involved in cellular metabolism. This raises the question of how this rhythmic cycle of synaptic proteins is produced.
The ultimate source of information to make a specific protein is coded in DNA. This information is read out by another molecule, mRNA, which carries the instructions from the nucleus of the cell to the protein synthesis machinery in the cell body, called ribosomes. Here the blueprint for building a specific protein encoded in a specific mRNA molecule directs the synthesis of a specific protein. The logical hypothesis that the scientists investigated was that mRNA molecules of different types might also change in abundance around the clock in sync with dawn and dusk.
The researchers isolated over 3,104 different mRNA molecules from synapses, each one of which contributes to the formation of distinct proteins. Remarkably, 67% of these (2,085 mRNA “transcripts”) were cycling in abundance on a 24-hour cycle. This number of mRNA transcripts undergoing a daily rhythm of changes in abundance is more than found in any other body tissue to date. The mRNAs that increased in abundance in anticipation of waking coded for proteins known to be involved in synaptic transmission, and implicated in learning and memory. Those that increased in anticipation of sleep coded proteins involved in maintaining cellular functions, controlling cell division, and development.
Realizing how severely impaired mental function can become after sleep deprivation, the researchers wondered if the day/night cycles of these mRNA and protein molecules would be affected by keeping the mice awake. What they found was that 4 hours of sleep deprivation (a poor night’s sleep) imposed by waking the animals and gently handling them at specific times in the day/night cycle, had little effect on the rhythmicity of most of these cycling mRNAs. Thus, mRNAs were being regulated by the day/night cycle, but the proteins in the synapses from these sleep-deprived animals no longer cycled. Since it is the proteins that carry out cellular activities and synaptic transmission, disrupting the normal day/night synaptic protein cycling by sleep deprivation would necessarily impair synaptic function.
The fact that the day/night cycling of synaptic proteins was disrupted by sleep deprivation, but mRNA molecules that provide the blueprint for making the proteins kept their daily rhythm, means that sleep disruption was not having its effect by impairing the readout of the genetic code from DNA to mRNA, but rather was somehow affecting the synthesis of proteins from the mRNA transcripts. This type of regulation is called “posttranslational” regulation, because protein synthesis is being affected after the DNA code is translated into mRNA.
The authors favor the view that the day/night cycling of mRNA abundance in synapses is being regulated by processes that degrade mRNAs and transport them to the synapse where proteins are synthesized from them. The synthesis of the proteins is then regulated locally within the synapse in part by the level of activity of the animal during different phases of the sleep/wake cycle. If awaked, this clock-like regulation of protein synthesis in the synapses is disrupted and the lights never go out, so to speak, on the protein synthesis factories in synapses.
This quashing of clock-like cycling of synaptic proteins by awakening happened regardless of when in the day/night cycle sleep was disrupted, indicating that the cycles of synaptic protein abundance are driven by neural activity rather than by an internal clock.
This research has important implications for understanding how our brain revs up and goes idle like clockwork, and how shift workers and others suffering sleep deprivation will struggle with mental performance.
However, sleep itself is a very complex process. Every night our brain goes through a very distinct sequence of cognitive states that are reflected in radical changes in our brainwave activity, brain and body function. During rapid eye movement (REM) sleep, for example when we are dreaming, the brain is in a highly active state, much like the awake state.
As neuroscientist Chiara Cirelli, who together with Giulio Tononi wrote an article accompanying this new study, says: “These signals require hours to change, because hours is the time scale of sleep in rodents as well as in humans. The goal [of this study] is to have a global picture of the overall effects of sleep."
Future work will be required to distinguish possible differences between distinct phases of sleep. It is also important to remember that many other types of cells in the brain, including non-neuronal cells called glia, also undergo rhythmic day/night changes, something Cirelli and Tononi have studied in their own research on sleep deprivation. Clearly the brain’s cellular clockwork is even more intricate than this important study has uncovered.