How support cells in the brain support sleep.

or technically,

Endocytosis at the Drosophila blood-brain barrier as a function for sleep.

[See Original Abstract on Pubmed]

Authors of the study: Gregory Artiushin, Shirley L Zhang, Hervé Tricoire, Amita Sehgal

Almost every day of our lives we close our eyes, count a few sheep, and drift off to sleep. If we don’t get enough sleep, our brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. doesn’t work as well and its normal functions, such as attention and decision-making, are affected. But why does this happen? Why is sleep so important? Although not everything about sleep is known, what scientists do know is that sleep is necessary to maintain the health of the cells in our body, especially the cells in our brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. NeuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles perform essential processes during sleep that they can’t do as efficiently while awake, such as consolidating memories and clearing waste. For this reason, sleep deprivation has serious consequences including build-up of toxic proteins1. Therefore, neuroscientists have been curious about the mechanisms of sleep for quite some time. Gregory Artiushin, a UPenn neuroscience graduate student in the lab of Amita Sehgal, was interested in understanding this sleep process a little deeper, specifically thinking about how different cells in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. may contribute to sleep function.

Although neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles are important in mediating sleep, the non-neuronal support cells of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. (known as glial cells) have also been linked to sleep regulation. Glial cells are a class of cells that surround all neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles and are critical for their survival; they perform important ‘maintenance’ tasks for neuronsA nerve cell that uses electrical and chemical signals to send information to other cells including other neurons and muscles including providing them with nutrients and oxygen, insulating their electrical connections, and clearing dead cells and waste from their surroundings. Glial cells may help with waste clearance in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. during sleep, and can also release molecules that promote sleep2. In order to carry out their functions properly, glial cells have to move cargo into and out of the cell. This is mainly done through endocytosis, where things outside of the cell are captured into sacs and brought into the cell, much like packaging something important for transport. Although this process of endocytosis is important for glial cell performance overall, scientists still aren’t sure if endocytosis in glial cells is important for sleep. Additionally, it is not known which of the many types of glial cells are important in regulating sleep (there are over four main classes of glia).

Greg decided to use fruit flies to study the importance of endocytosis in sleep. Yes, flies sleep too! Not only are their sleeping patterns similar to that of humans, with a long period of sleep at night, but their genesA unit of DNA that encodes a protein and tells a cell how to function can also be easily manipulated in order to help scientists establish which genesA unit of DNA that encodes a protein and tells a cell how to function are important in regulating sleep. About 75% of known human disease genesA unit of DNA that encodes a protein and tells a cell how to function have a recognizable match in the genetic code of fruit flies3. These qualities make them a popular ‘model’ amongst scientists for studying sleep and its underlying mechanisms. To understand how endocytosis changed with increased sleep need, Greg deprived flies of sleep and then looked at how endocytosis was affected in their glial cells. He found that endocytosis was increased after sleep deprivation, and that this correlated with how sleep-deprived the flies were. Since this suggested that endocytosis was somehow linked to sleep, Greg wanted to explore this link further by blocking endocytosis entirely and seeing what happened to sleep. To do this, he generated a mutated form of a geneA unit of DNA that encodes a protein and tells a cell how to function that is critical for endocytosis in flies, allowing him to effectively block endocytosis in these animals. By mutating this geneA unit of DNA that encodes a protein and tells a cell how to function only in glial cells, Greg was able to block endocytosis exclusively in glial cells of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. Interestingly, he saw that this increased how long the flies slept, suggesting that endocytosis in glia somehow controls the process of sleep.

Since there are many types of glial cells, Greg wanted to next understand which type of glial cells were important in sleep. Using the same genetic mutation strategy, Greg blocked endocytosis in each specific type of glial cell: he expressed the mutation in one type of glial cell at a time while leaving endocytosis in all of the other types of glia intact. This allowed him to determine which type of glial cell(s) was responsible for the effects he saw when he blocked endocytosis in all glial cells. He found that endocytosis in one particular type of glial cell was linked to sleep duration. This type of glial cell makes up the blood-brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. barrier in flies. The blood-brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. barrier, or BBB, is composed of tightly-linked glial cells that separate the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. from the rest of the body. This barrier acts as a roadblock that prevents many substances from getting into the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals., which is crucial for protecting the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. from pathogens or toxins. Greg found that blocking endocytosis only in the BBB glial cells caused changes in the structure of the barrier and increased sleep. However, blocking endocytosis in other types of glia did not affect the BBB or sleep.

Greg’s work suggests that endocytosis in the glial cells of the BBB of the fly is an important regulator of sleep, identifying a specific mechanism that may also be crucial in human sleep. Exactly how endocytosis at the BBB affects sleep duration remains unknown, but it is possible that this process may be important in waste clearance or maintenance of the BBB. If endocytosis is disrupted, these processes may be impaired leading us to sleep longer as a way of compensating. Future studies will aim to address why disrupting endocytosis in these BBB glial cells messes up the sleep cycle. Greg’s findings in this study (and future experiments) are important because they allow researchers to understand exactly how these processes at the BBB could be important for human brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. function, and how they may be altered in sleep deprivation and sleep disorders, such as insomnia. Scientists might finally be on track to figure out why pulling an all-nighter turns us into sleep-deprived zombies!
About the brief writer: Claudia Lopez  Claudia is a fourth year Neuroscience graduate student studying HIV-related neurodegeneration. She uses cell culture system to study how HIV infection leads to neuronal dysfunction.

About the brief writer: Claudia Lopez

Claudia is a fourth year Neuroscience graduate student studying HIV-related neurodegeneration. She uses cell culture system to study how HIV infection leads to neuronal dysfunction.

Citations:

  1. Shokri-Kojori E, Wang G, Wier CE, Demiral SB, Guo M, Kim SW . . . Volkow ND. (2018). β-Amyloid accumulation in the human brain after one night of sleep deprivation. Proceedings of the National Academy of Sciences, 115(17): 4483-4488. You can find the paper here.

  2. Halassa MM, Florian C, Fellin T, Munoz JR, Lee S, Abel T . . . Frank MG. (2009). Astrocytic modulation of sleep homeostasis and cognitive consequences of sleep loss. Neuron, 61(2): 213-219. You can find the paper here.

  3. Pandey UB & Nichols CD. (2001). Human disease models in Drosophila melanogaster and the role of the fly in therapeutic drug discovery. Pharmacological Reviews, 11(6): 1114-1125. You can find the paper here.