Neuroscientists have just discovered a previously unknown connection between the brain and its surrounding environment

Neuroscientists have just discovered a previously unknown connection between the brain and its surrounding environment

How does the brain rid itself of waste, and how does this process affect our health? In a landmark study led by researchers at Washington University in St. Louis and the National Institute of Neurological Disorders and Stroke, scientists have discovered a direct pathway through which the brain’s waste disposal system communicates with the protective layers surrounding it, challenging long-standing beliefs about the brain’s isolation from the body’s immune system.

This discovery sheds light on the mechanisms that allow waste and immune signals to travel between the brain and its outer protective covering, potentially opening new horizons for understanding and treating neurological diseases. The results were published in the journal nature.

The motivation for this study stems from a fundamental question in neuroscience: How does the brain, an organ known for its delicate and complex functions, maintain its health by removing waste and interacting with the body’s immune system? Traditionally, the brain was thought to operate in a kind of splendid isolation, protected by barriers that keep out the immune system and potentially harmful substances.

However, this isolation may also mean that the brain has limited options for removing waste, a crucial function for disease prevention. In this study, the researchers set out to explore the possibility of a direct communication pathway between the brain and the protective layers surrounding it, which could revolutionize our understanding of brain health and disease.

Daniel S. said: “Waste fluids move from the brain into the body in a way that is very similar to the way sewage comes out of our homes,” said Dr. Reich, a senior researcher at NINDS. “In this study, we asked the question of what happens when the ‘drain pipes’ leave the ‘home’ – in this case, the brain – and connect to the city sewer system inside the body.”

To investigate these questions, the study used a comprehensive approach that combines advanced imaging techniques and genetic analysis in both humans and mice. In humans, the team used high-resolution magnetic resonance imaging (MRI) to monitor the movement of a magnetic dye, gadobutrol, which was injected into participants to visualize the pathways through which waste might exit the brain.

In parallel, the researchers conducted experiments on mice, injecting them with light-emitting molecules to track the movement of fluids across the brain’s protective barriers. The study also used single-core RNA sequencing to analyze gene expression of cells within these barriers and electron microscopy to visualize cell structures in detail.

The researcher identified specific areas, called arachnoid cuff exit (ACE) points, where a “cuff” of cells surrounds blood vessels as they pass through the brain’s protective arachnoid barrier into the dura mater. The dura mater is the outermost and toughest layer of the three layers of membranes called meninges that surround and protect the brain and spinal cord. This membrane consists of dense fibrous connective tissue.

These ACE points act as gateways, allowing the transfer of waste fluids, immune cells and other molecules between the brain and the dura, contrary to the previous belief that such communication was nearly impossible due to the brain’s protective barriers.

This discovery reveals that the brain is not as isolated as previously thought, and has a direct way to eliminate waste and interact with the immune system.

“If your sink is clogged, you can remove the water from the sink or fix the faucet, but ultimately you need to fix the drain,” explained Jonathan Kipnis, a professor at Washington University in St. Louis. “In the brain, blockages at ACE points may prevent waste from getting out. If we can find a way to clear these blockages, we may be able to protect the brain.

Fluids containing light-emitting molecules were seen to slide through the arachnoid barrier where blood vessels passed. (nends)

The study in mice showed that these pathways are involved in the immune system’s response to disorders, such as when immune cells attack the brain’s protective myelin in conditions that mimic multiple sclerosis. Blocking the interaction of immune cells with ACEs reduced the severity of the condition, highlighting the importance of these pathways in brain health and disease.

“The immune system uses molecules to deliver that transit from the brain to the dura mater,” Kipnis said. “This transit needs to be strictly regulated, otherwise harmful effects on brain function can occur.”

The researchers also noted that the efficiency of these ACE points and their role in removing waste and monitoring immunity may decrease with age. This was suggested by the observation that older study participants showed increased extravasation of magnetic dye into the surrounding fluid and perivascular spaces, suggesting a possible breakdown in the efficiency of these ACE points over time.

This aspect of the study points to a possible link between the aging process and an increased risk of neurological diseases, suggesting that the deterioration of these ACE points could contribute to the accumulation of waste products and altered immune responses in the aging brain.

“This may indicate a slow breakdown in ACEs over the course of aging, and this may have an effect where the brain and immune system can now react in ways they’re not supposed to,” Reich said.

The discovery of ACEs revolutionizes our understanding of brain physiology, suggesting a direct pathway of waste clearance and immune system interaction that was previously unknown. But the study is not without limitations. The exact mechanism by which these ACEs work and their relative importance compared to other waste removal pathways and immune system reaction pathways in the brain remains unclear. Furthermore, while the study provides compelling evidence in mice and through MRI in humans, more research is needed to fully understand the implications of these findings for human health and disease.

Future research directions include exploring how the efficiency of the ACE score changes with age, as the study observed increased magnetic dye leakage in older participants, suggesting that the effectiveness of this waste disposal system may decrease over time. This could have profound implications for understanding age-related neurological diseases, where impaired waste clearance could play a crucial role.

http://dx.doi.org/10.1037/0033-295X.112.2.212, Google Scholar Leon CD Smith, Di Xu, Serhat V. Okar, Taitea Dykstra, Justin Rustenhoven, Zachary Papadopoulos, Kesshni Bhasin, Min Woo Kim, Antoine Drieux, Tornik Mamuladze, Susan Blackburn, Zhengxing Guo, Maria I. Gaitan, Govind Nair, Steven E. Stork, Siling Du, Michael A. White, Peter Bygoinov, Igor Smirnov, Krikor Dikranian, Daniel S. Reich, and Jonathan Kipnis.

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