Living

The brain is encased in the skull and sits atop the spinal column. Its operating mechanism is extremely precise. The nutrients entering the brain are strictly screened and must pass through the blood - brain barrier. There is also a complex protective membrane structure outside the brain. There are more than one unsolved mysteries hidden in this "privileged" space: Since it is so difficult for external substances to enter the brain, how are the wastes expelled?

The brain has one of the highest metabolic levels among all organs in the body. High metabolism inevitably leads to the production of by - products, which need to be cleared in a timely manner. In other parts of the body, there are lymphatic systems running alongside blood vessels. Molecules that have completed their missions enter these fluid - filled tubes and are eventually sent to the lymph nodes for processing. However, the blood vessels in the brain do not have similar outlets. Hundreds of kilometers of blood vessel networks shuttle through this dense and highly efficient tissue, seemingly without a配套 waste - disposal system.

However, there are open, fluid - filled spaces around the blood vessels in the brain. In recent decades, the cerebrospinal fluid (CSF) in these spaces has attracted wide attention from the scientific community. Steven Proulx, who studies the CSF system at the University of Bern, said, "Maybe the CSF in the brain is like a highway, enabling the flow or exchange of various substances."

Recently, a paper published in the journal Cell reported new findings about the fluid dynamics around the brain and in its hidden cavities. A team led by Maiken Nedergaard, a neurologist at the University of Rochester, proposed: Could the slow pumping action of the brain's blood vessels push the fluid to flow between and even through cells, thus forming a kind of waste - disposal system? In a mouse model, researchers injected a fluorescent dye into the CSF and triggered the pumping effect by manipulating the blood vessel walls. Subsequently, they observed a rapid increase in the dye concentration in the brain. They concluded that this movement of blood vessels might be sufficient to push the CSF and even carry waste over long distances in the brain.

This team further put forward their own explanation. Since this pumping is different from the pulse generated by the heartbeat and is often observed during sleep, they speculated that this might explain why sleep makes people feel refreshed. However, not all scientists agree with this hypothesis. Many researchers believe that the truth about whether the fluid flow in the brain has a definite function remains elusive.

The brain's "drainage system"

In the center of the brain, there are several cavities filled with fluid, like pools in the dark, called "ventricles." The CSF slowly seeps out from the walls of the ventricles and then begins to flow. Under pressure, it is released in other parts of the skull, flows towards the neck, and finally enters the spinal column.

Scientists discovered more than a century ago that at the moment of a person's death, the CSF flows back into the brain from the spinal column. This indicates that in a living state, the brain must maintain this flow in some way, but exactly how it flows and where it goes is still a mystery. Any arrow diagrams about the flow direction of the CSF cannot be regarded as completely correct.

Christer Betsholtz, a professor of vascular biology at the Karolinska Institute in Sweden, said, "Everyone agrees that there must be some kind of flow mechanism here. The brain produces about half a liter of CSF in the ventricles every day, and this fluid must be expelled. And people are still arguing about where it is expelled from."

Another question still under debate is: Does the CSF "carry" waste during the expulsion process? If so, how is it achieved? Existing evidence shows that at least small molecules can diffuse in the spaces between cells and eventually enter the CSF and be carried out of the brain. In fact, some researchers believe that the entire system mainly operates through passive diffusion.

However, in 2012, the research results of Nedergaard's team proposed a more "active" mechanism. At that time, Jeffrey Iliff, a neurologist and a post - doctoral fellow in her laboratory, along with her and other colleagues, injected a tracer into the CSF and observed it quickly reaching other areas of the brain. They proposed that the spaces around the blood vessels are connected to the smaller spaces deep in the brain (i.e., between cells). And the CSF may enter these spaces through astrocytes. There, the fluid may "drop off some molecules and pick up others" and then return to the spaces around the blood vessels, ultimately expelling waste from the brain. There may be an unclear driving force behind all this flow.

This idea is refreshing. Nedergaard later further proposed that this phenomenon may also be related to another mysterious question - why sleep makes people feel refreshed. In a 2013 paper, her team pointed out that in mice in a sleeping or anesthetized state, the CSF flow is more active than when they are awake - which may mean that the CSF is "flushing" the waste in the brain during sleep. This process has even been described by the media as "brainwashing" and may partly explain why humans must sleep and why people feel brand - new after a good night's sleep.

"I firmly believe that the restorative effect of sleep is not mainly for memory consolidation," Nedergaard said. "Maybe there is a part of it, but the real key is the 'cleaning' function of sleep."

Since then, a large number of papers supporting this "brain waste - disposal" theory - the so - called "glymphatic hypothesis" - have emerged. This theory is impressive, but it has also raised some doubts among some researchers focusing on the brain's vascular system.

Alan Verkman, an emeritus professor of fluid flow at the University of California, San Francisco, pointed out that some aspects of this theory are not physically credible - for example, the structure of the so - called channels that allow fluid to enter simply cannot perform this function. Betsholtz also said that there is currently no evidence showing that the fluid is really flowing into the spaces around the blood vessels extending from the brain.

Nevertheless, many researchers are still willing to accept the "glymphatic hypothesis." Donald McDonald from the School of Medicine at the University of California, San Francisco, pointed out that this is because the hypothesis just fills the gaps in our understanding of the brain. He personally does not fully believe this theory, but he also admits that it is very popular because it "just fills the space of the unsolved mysteries."

The ebb and flow

Imagine a sealed water bottle. If you want to study the natural state of the water in the bottle, you have to make a hole in the bottle - and this is exactly the dilemma faced by scientists studying the CSF flow. Laura Lewis, a neuroscience professor at the Massachusetts Institute of Technology, said, "When you study a fluid and make a hole in the system, you have actually changed the whole system." Fluid dynamics is very susceptible to external interference. Moreover, some basic life activities of living animals, such as breathing and heartbeat, also directly affect the fluid flow.

Therefore, it is a very complex task to establish a convincing evidence base for new hypotheses in this field. In the paper recently published in the journal Cell by Nedergaard's team, they tried to explore an extremely attractive connection - not only explaining how the CSF is "pumped" between brain cells but also linking this process to the sleep state.

In the experiment, the researchers performed surgery on mice and implanted sensors, wires, and catheters in their brains - it was like opening an observation window in that "water bottle." Their goal was to inject a tracer dye at a certain position in the brain and then observe its oscillation and dynamic flow during the mice's sleep.

The data showed that when the mice entered the non - rapid eye movement (NREM) sleep stage, the concentration of the tracer dye showed a rhythmic fluctuation. According to Natalie Haugland, the first author of the paper, this wave - like rise and fall pattern could be seen from the sensors above the brain surface. "It's like a wave current."

So, what drives this rhythmic flow? The researchers thought of a neurotransmitter called norepinephrine, which can cause blood vessels to contract. Nedergaard pointed out, "Norepinephrine is well - known for controlling blood flow." They believe that during the contraction and relaxation of blood vessels, enough pressure may be exerted on the surrounding CSF to push it through the brain tissue.

More interestingly, the level of norepinephrine itself also fluctuates rhythmically during the NREM sleep stage. This neurotransmitter may be the key linking the two phenomena - the physical flow of the CSF and the "brain cleaning" during sleep.

The team then designed a genetically engineered mouse in which the secretion of norepinephrine could be controlled. The results showed that when the level of this neurotransmitter increased, the total amount of CSF in the brain also increased, indicating that it did change the way the CSF flowed to some extent.

Then, to verify whether the "pumping" of blood vessels can really push the CSF to flow, the researchers modified a mouse model in which the blood vessel walls could be directly manipulated. Instead of letting the blood vessels pump slowly naturally, they artificially increased the frequency - from once every 50 seconds to once every 10 seconds. Haugland said that when they did this, they did enhance the CSF flow in a small stimulated area of the brain. "This is a very local effect... There was no change in other brain areas."

For Nedergaard, Haugland, and their colleagues, these findings established a connection among norepinephrine, the physical movement of blood vessels, and the flow of CSF in the brain. Nedergaard also emphasized that these results were consistent with the earlier discovery of her team that "the clearance of brain waste increases during sleep."

"We've been looking for the reason why the 'glymphatic system' mainly works during sleep," Nedergaard said. "And this paper is actually saying: We've now found the 'engine' - the driving force for how we clean our brains during sleep."

However, for the critics of this theory, there are still too many unsolved problems.

Under pressure

McDonald pointed out that this research is very complex and involves a large number of sophisticated technical means. However, he is worried that Nedergaard is "working backwards" - that is, she is looking for an explanation to support her hypothesis rather than objectively exploring the real operating mode of the system itself. He said, "In this paper, the line between explanation and data is not clear. In the early part, their explanations were taken as factual data." He gave an example, saying that the schematic diagrams showing the fluid dynamics lack sufficient data support in his opinion.

Proulx questioned whether the tracer dye was really moved by some "active" force. He pointed out that this molecule is very small and could completely move through diffusion. He envisioned an experiment: using the technology that Nedergaard's laboratory had used to inject larger molecules into the CSF. If the time point of the rhythmic release of norepinephrine corresponds exactly to the appearance of a macromolecular tracer on the sensors on the brain surface, it would be a very interesting discovery. "This is what I hope to see," he said. For him, such an experiment would establish a clearer causal relationship between norepinephrine and CSF flow than the current research.

The criticism of Nedergaard's research is relatively sharp, partly because her theory is currently the most influential mainstream hypothesis about CSF flow. Of course, this situation may change as other scientists put forward new verifiable ideas. Another complicating factor is that there are also differences in the definition of the term "glymphatic system."

Laura Lewis said, "Some people say that the 'glymphatic system' refers to the brain's waste - clearance system; while others think it is a very specific mechanism model." She added, "We can be sure that the brain does need a waste - clearance mechanism... The key is to explore what it is exactly and how it works."

Haugland, who is currently a post - doctoral researcher at the University of Oxford, is also well aware that the "glymphatic hypothesis" is controversial. "It has indeed received some criticism. I'm not sure if we understand it accurately enough myself," she said. "But no matter who puts forward what kind of hypothesis, as long as everyone is working hard to figure out how it works - it will promote the development of the whole field and bring more knowledge."

"The research results are what they are. They reveal some biological phenomena," she continued. "We've raised a lot of questions, and we may not always be good at asking these questions because we don't really understand the whole picture."

Proulx said, "No one really knows how the brain inside the skull cleans up waste. Some people think they know, but I think we don't."