The Glymphatic System
AbdulSamad Olagunju / May 06, 2021
7 min read
Welcome to another awesome blog post! This post will be an informal stream of my thoughts as I read a research article.
Quote of the Post:
"If Louis Pasteur were to come out of his grave because he heard that the cure for cancer still had not been found, NIH would tell him, “Of course we'll give you assistance. Now write up exactly what you will be doing during the three years of your grant.” Pasteur would say, “Thank you very much,” and would go back to his grave. Why? Because research means going into the unknown. If you know what you are going to do in science, then you are stupid! This is like telling Michelangelo or Renoir that he must tell you in advance how many reds and how many blues he will buy, and exactly how he will put those colors together." – Albert Szent-Gyorgi
If you want to read the paper before the article: Direct Link to the Paper
I’ll start this off with something of a preface. I am not a neuroscientist. I have never been in a lab, and I may never well work in a lab. Sometimes, some of the stuff I read feels like what you see in an instructional manual for a machine you will never use. Nevertheless, someday I will have to make money off this shit, so I might as well understand how to read research articles. So we begin. In a lot of neuroscience work on the internet I read, you hear about synaptic connections, and neurotransmitters and their associated receptors, but it seems like I never see anything that tries to take on the complete architecture of the blood vessels and the fluid that moves in the brain. This is the first time I've heard about the glymphatic system, so I'm excited.
First, I want to understand what glymphatic actually means I'm guessing it has something to do with the lymphatic system, but I'm going to use this review article to get started: The Glymphatic System – A Beginner's Guide
From this article, I learn that the glymphatic system is a way to clear waste (probably toxic metabolites) from the brain (I feel like glymphatic = glial + lymphatic). The fluid moves in perivascular channels. These perivascular channels are located between endothelial cells in the brain and astroglial cells. Perivascular spaces allow cerebrospinal Fluid to move easily into the brain. Additionally, the glymphatic system is mostly active in the night-time. When you wake up fresh and healthy after a good night of sleep, I'm assuming the glymphatic system has a lot to do with that.
Here is a good picture of the perivascular space:
Now, time to get back to the article. The first important thing I notice about this article is the mention of AQP4 (Aquaporin 4 water channels). Whenever I hear about some sort of protein channel, I love to google how it looks like, so...Wikipedia pic coming up. It looks like licorice, I have no idea what its doing electrically or how it sticks to the membrane, and how scientists even know it exists. But here it is:
The second thing I notice is the mention of directional transport. Directional transport? What the hell? How in the world does fluid move one directionally in the glymphatic system? Is there a mechanism for giving the fluid nutrients that have diffused out of it as it moves up to the brain once it reaches the brain, some enzyme that cleans up the fluid once our brain extracts what it deems useful? Maybe the glymphatic system is only responsible for cerebrospinal fluid influx in the brain, and another mechanism is responsible for cerebrospinal fluid efflux? Let’s find out together. Read on.
Also, according to the reviewers, we don’t really understand the fluid patterns that occur in the brain of a living human being. We do know that cerebrospinal fluid has a major influx of fluid after a stroke or cardiac arrest...so we really don’t even have a clear picture of the brain of living person after taking they die. This causes the brains of dead people to be swollen, and bigger than what they should be. Tough...but we will carry on. These reviewers wouldn't have written this paper unless this research had some level of accuracy?
Alright, I've got some questions. Why does glymphatic cerebrospinal fluid flow run in the same direction as blood flow? Wouldn’t countercurrent exchange make more sense here (they flow in opposite directions so that when one vessel gives up nutrients to the extracellular fluid another vessel is dealing with the higher solute concentration)? Then again, I may not be visualizing the fluid transport in the brain, and I'm assuming now that glymphatic flow is probably not the only fluid flow occurring in the brain.
I still don’t know what makes astrocytes classified as astrocytes, but apparently they have these important AQP4 channels that move most of this CSF fluid.
Scientists have apparently messed up by not modeling the perivascular space properly, focusing on how to model it from histological sections (dead brains which we know differ significantly from the brains of the living), which have considerably smaller perivascular spaces than people who are—well living. Seems like an important problem, especially when a living animal has a perivascular space ten times larger than its dead counterpart. Its also not that circular, its got more of an ellipses-like shape, which is another problem with their modeling. Scientists who have used the wrong assumptions in your model, don’t freak out, as its still okay to use your data for comparisons between animals. When most mammals die, their blood vessels undergo more or less the same changes.
Onto, the next thing, the AQP4 water channel I previously mentioned. They say AQP4 deals with the transport of water, but they also make it seem like it moves CSF. Which is it? Also, WHAT is a neuropil.
Neuropil: The neuropil has lots of synapses, glial cells, and dendrites, and not a lot of cell bodies. It is a region with a high density of synapses and unmyelinated axons, so there is no myelin to increase conductivity but that is probably balanced by the higher number of synapses per unit area. Fluid movements in the brain indicate that there is convective flow of solutes around the neuropil, however it is not known whether it occurs in the neuropil. Convective flow is the flow of fluid through a porous membrane (think a tube that leaks fluid through the side). Convective flow and diffusion each play a role in the flow of fluids in the glymphatic system. However, organisms perform so many different behavioural processes, who knows whether diffusion takes charge when you breathe vs convective flow taking charge when you piss?
Does the research taking place actually makes sense? The reviewers ask this question a lot. Injecting tracers in animals seems like it tells you where fluid is travelling, but the reviewers argue whether this leads to an artificial increase in fluid, tainting the results from these experiments. However, the reviewers argue that this is probably not the case.
Finally, this paper would not be a neuroscience paper without some sort of discussion about amyloid beta and tau. I’ve heard so much about these two molecules and I’m only in my first real year of neuroscience. Nobody talks about the neuroscience of fevers or other things we do on a daily basis, they’re too complicated. But talk about Alzheimer’s, and everybody gets very excited. The cleanup of these molecules seems dependent on the glymphatic system. Those glial cells clear these chemicals that are dangerous if they build up, and they do it when we sleep. Miss a night of sleep, and get one step closer to dementia. Just kidding—but seriously, stop reading this and get some sleep.
One major question I have. What system moves more neurotransmitters on a daily basis? The glymphatic system, cranial nerves, blood vessels in the brain, or regular old axons in the brain?
The glymphatic system is one of the primary clearance mechanisms of the brain, and I assume that there are many other cells that regulate this system that hopefully we will learn about soon.
On to the next, thanks for reading.
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