The Top 5 Neuroscience Experiments from 2009-2013......on Astrocytes
by Ignatius Vincent Trochlear
June 30, 2014
“Why don't you look at me? Are you pretending I don't exist?”
"No, Charlie," she whispered. "I'm pretending I don't exist."
-Flowers for Algernon
The ability for complex communication, imagination and creativity sets our species apart from the rest of the animal world. An orangutan can think to put a leaf on its head to avoid a downpour, but he certainly isn't going to have the wherewithal to construct an umbrella. Or a house for that matter. Maybe at some point in his life he will have the fleeting idea of an umbrella, but he would have no idea what to do with this idea.
Our communication with each other is also innovative and mutable as we evolve socially. Original ideas frequently sprout from our individual and shared creativity to drive our species. This appears to be uniquely human. Traditionally, neuroscientists might point to our large brains as the reason for this seemingly random creative and imaginative ability - the sheer size of it - but a sperm whale has a 17.5 pound brain, and an elephant has a 10.5 pound brain, and a dolphin has a brain nearly twice our size. Ours is only a puny 2.7 pounds on average. Elephants have been shown to have exquisite memories and exhibit behaviors such as mourning their dead, and dolphins seem to name each other and remember these names for years. But they aren't constructing an umbrella either. Although I'm not sure what a dolphin or sperm whale would do with it. However, we can hang our hats on the fact that we have the largest brain:body ratio. But this is somewhat of a meaningless designation. And what about our opposable thumb? - the main evolutionary determinant of our ability for tool manipulation. This doesn't explain what is happening in our brain machinery to compel us to use this thumb. Many other primates have hands and thumbs that would also afford them the ability to manipulate tools sufficiently to exhibit real ingenuity. Besides the Bonobo poking a stick in a termite's nest to get a snack, this is not something that they actively pursue. Nor do they pursue the idea of constructing a device to help them manipulate things a little better. Or constructing a smart phone. What makes us different is our relative clarity of imaginative thought and the subsequent power to act on it (and use those thumbs). So what is different about our brain?
When looking at the brain from one species to the next in order to find clues to these reasons, the one real difference between us and other species is a brain cell called the astrocyte. Most people have probably never heard of a brain cell called the astrocyte. Although some non-neuroscientists may recognize the term 'Glia,' this is actually an overarching classification of anything 'not neuron.' Astrocytes are the glial cell that seem to make us unique, and are larger, much more complex and numerous in our brains compared to other animals. For these reasons, we'll devote our top 5 to the glory of the astrocyte, but before we get there, a little background info:
There are different sub-classifications of astrocytes in the brain, but perhaps the most interesting is the proteoplasmic astrocyte in the cortex of our brains, the area known to be responsible for higher thought. These cells are 2.6 times more complex than astrocytes in mice, with 10 times as many processes extending out to make 2 million connections with neurons compared to the paltry 10s of thousands of connection in the mice, and also a 20% increase in complexity over chimpanzees. Not only are they larger and much more complex, but they have cell specific domains, or territories that they control in the cortex. A neuron in a human, a dolphin, a chimpanzee or a panda bear seem to be similar in terms of size and complexity but astrocytes in humans are different. On top of that, there is a cell type called the interlaminar astroctye that also resides in the cortex, and seems to only exist in human brains.
The neuron has been the real star though, and a lot of people have pinned their hopes and dreams on its superiority, so it's tempting to feel for the poor astrocyte, and champion him as the unsung hero in neuroscience research. Or the poor overlooked cell, the underdog, with so much promise that has been swept under the rug in favor of the powerful neuron - that 20th century icon that takes its rightful place alongside the likes of Marilyn Monroe and Ronald Reagan. We have an engrained notion that our thoughts, memories, creativity and imagination all reside in neurons. It's something we all learn. There's almost a religious fanaticism to neurocentrism. Even researchers that specialize in astrocytes are terrified to upset the apple cart and be branded as heretics.
But maybe that's a bit of an overreaction. Because in the last 10 years, looking at the climate in neuroscience research, that might no longer be the case. Astrocytes are now well-known to prune and tweeze synapses, lording over neural connections, deciding how (and how fast) information should flow from one neuron firing to the next. They are known to respond to this firing, and to cause the firing of neurons themselves. They are the only cells that proliferate in the cortex, and they can differentiate into more astrocytes, and are the stem cell to produce more neurons themselves in certain brain areas, a process called neurogenesis. Astrocyte numbers appear to be low in schizophrenia, and astrocyte dysfunction has been described in injury and degenerative disease. Another interesting curiosity has to do with the 49 regions of the human genome conserved in vertebrates but very different in humans. One (HAR21) is involved in neurogenesis and mutations in this gene have been associated with psychiatric disorders, and could have implications in human astrocyte biology.
Astrocytes communicate very differently from neurons - through spread of calcium ions from one cell to the next that is released from their internal stores when they are stimulated by adjacent astrocytes or neurons. This is the same calcium spread that causes transmitter release from astrocytes. This entirely different level of communication in astrocytes is modulating high speed neuronal communication. How could this not be involved in thought? For the neuroscientist, it is now imperative to imagine the possibilities of how they contribute to our cognition. Cortical astrocytes could hold the information of persons, places and things - with the neural circuitry linking them together in situations that we call 'memories.' Is the astrocyte muscle the creative force driving the neuronal network? And behind all this is the glaring evidence that astrocytes are much more complex and numerous in the cortex of humans than in other mammals, and that this number and complexity increases as you go up the evolutionary ladder, with the most abundant cell in the human cortex being the astrocyte. So how are they underdogs? For instance, watching this World Cup, Costa Rica was considered an underdog, but they won arguably the toughest group and made it to the round of 16. Then they won again to make the quarters. Yet, it seems they are perceived of as an aberration. But how can that be if they can compete with anyone at this high level? Virtually none of their players are on major clubs in Europe, or even in the MLS for that matter. Will the clubs recognize their talent now or continue with the notion this is an aberration? Who do they need to beat to get credibility? Will the Netherlands suffice? Do they need to win the whole thing?
Fortunately (or unfortunately, depending on how you look at it), science is different than the World Cup, and with the accumulating evidence, the astrocyte has now earned its place as at least an equal partner to the neuron. It's important for the good and noble scientist to be tempered and skeptical, and base concepts on solid experimental evidence, and not to jump and leap at every new and wild idea like a maniacal pollyanna. It's wise to remember that the origins of neurocentrism are not as clear cut or with as much experimental evidence as something like Darwin's Origin of Species. It arose out of one researcher's tireless work that linked neurons in the brain with those that extended in and out from the body. His work effectively disproved the idea that human thought was an extension of some divine process, and unquestionably demonstrated the origin of our cognition was from actual cells in our body, not from the heavens, edifying the cell theory. This was likely difficult for some people to accept. But the evidence was clear, and our ~86 billion neurons were embraced as the end of the story, the cellular units of cognition. However, Santiago Ramón y Cajal - who performed this painstaking work over 100 years ago and was the major champion of 'The Neuron Doctrine' at the time - wasn't sure of the function of the innumerable astrocytes in the brain, and lamented the lack of technology to study them. He said about the astrocyte, "The prejudice that...glia...are for merely filling or support is the main obstacle that the researcher needs to remove to get a rational concept about the activity of glia."
Excitingly, that technology now exists. As researchers have begun to study these cells in the last 25 years, it is incredible what has been revealed. To review the overwhelming experimental evidence, and still claim that astrocytes are not involved in thought processes, is ironically clinging to dogma that simply does not have a solid basis in any evidence, and this leads to serious obstruction to needed change. Just as flippant semantics that describe astrocytes as 'support' for neurons is clearly antiquated (and was antiquated 100 years ago) and should be avoided. They are obviously both involved in cognition and connected, and this is the only thing truly known right now about our mind on the cellular level from the experimental evidence of the last 100 years.
As research into astrocytes progresses we'll learn a lot more about our elusive thought processes. Philosophically, there's a notion that it may be impossible to understand the mind, because it is the mind that is attempting to understand itself - a catch-22 that devolves into a paradox. But this is just a trap - negative obstruction to the quest for discovery. There is no difference in this attitude to someone who says we shouldn't try to understand the origin of species because of gaps in the fossil record.
So we are free to speculate on these two cell types. For instance, let's say the brain is a business modeled after the Mad Men archetype. It could be that the astrocyte is Don Draper responsible for creative, and the neuron is an accounts man responsible for implementing the creative idea. Cell cooperation between astrocytes and neurons in the brain is a lot like human social interaction and communication, and you need the creativity of the astrocyte to advance and prosper but the power of the neuron, with its high speed communication and connections to the body, to achieve it. Extending the analogy further, this is a dichotomy not unlike an artist and a tycoon in society. Ideally, they should have mutual respect and support for each other to inspire and advance. Fortunately in our brains, the tycoon obliges the artist. The idea of the astrocyte as the creative cell is also the physical representation of something we already know - we are all inherent possessors of imagination if we exercise it. Then we arrive at an important question - what do we choose to think about?
Even more excitingly, it's entirely plausible that the duality and difference of signaling of astrocytes and neurons in the cortex could be the biological satisfaction of the perceived Cartesian duality of mind/body, or the more modern idea of the ghost in the machine, that has been the domain of philosophers. Or even more bluntly, the modes of communication between the two cell types could be the physiological basis for the conscious and the subconscious. There is so much untapped promise for us to understand.
4. Astrocytes and Development. Ben Barres' research at Stanford on astrocytes has been integral to the understanding of how the astrocyte in involved in synapse formation. Recently he has tried to learn how connections are formed in the brain during development. Originally identifying thrombospondins released from astrocytes as the impetus for new synapse creation, Barres has also learned that astrocytes are responsible for excitatory synapse formation in neurons during brain development through the release of glypicans 4 and 6. Nicola Allen's original article from Barres' lab with colleagues at Stanford published in Nature is here - but his excellent review articles are worth a read - especially this one from 2012 with Laura Clarke that discusses all the information available regarding astrocytes and cortical development.
3. The Glymphatic System. Maiken Nedergaard and colleagues at the the University of Rochester Medical Center, Huazhong University in China and the University of Oslo in Norway attempted to understand the unique juxtaposition of astrocytes with blood vessels. Working in Nedergaard's lab, Jeffrey Iliff discovered them to be involved in a circulating system essential to the health of the brain, that they coined the glymphatic system. The brain has no lymphatic system to remove waste products. It was known the cerebrospinal fluid (CSF) was a sink in the brain for waste products but it was unsure how they were removed. Using fluorescent tracers, they found that astrocytes are actively involved in the flow of fluid in the brain tissue through aquaporin-4 water channels, and that this is responsible for removing unwanted waste products out of the brain and into the blood. The researchers pinpointed amyloid-β, that culprit that accumulates as plaques in Alzheimer's disease as being one of the products removed through this process. The removal of waste from the brain is an astrocyte driven phenomenon and reminds us why studying these cells in terms of disease research is so important. For a video and simplified explanation click here.
2. Astrocytes are the Reason you Take a Breath. In another influential experiment of the last 5 years, Alexander Gourine and researchers from the University College London along with Sergey Kasparov and colleagues at the University of Bristol and Stanford University published an article in Science that explained why the phrenic nerve fires from the brain stem to stimulate the diaphragm to cause you to take a breath. They learned that when breathing was repressed in rats, and the pH level in the blood decreased due to the increase in CO2, it was sensed by astrocytes monitoring the blood vessels. A calcium wave in those astroctyes then spread and transmitter released from them stimulated the phrenic nerve to fire, and subsequently a breath was taken. The breathing process was originally thought to be driven entirely by neurons on a feedback loop. Here's an explanation as covered by Nature News.
1. Human Astrocyte Implants into the Cortex of Mice. Nedergaard again. In a fantastic experiment published last year that recalls Flowers for Algernon, Nedergaard, Xiaoning Han and colleagues at the University of Rochester Medical Center along with collaborators at the UCLA engrafted human glial progenitor cells into the brains of mice, which then differentiated into human astrocytes, and discovered that the mice were much better at maze tasks and other learning and memory assessments than ones that did not receive implants. The astrocytes were also shown to make connections with neurons, communicate 3 times faster than mouse astrocytes, and stimulate neuronal firing on the cellular level. Although some neuroscientists may still claim astroctyes are still there to support neurons, and that these experiments reveal that the learning and memory increases are because support may simply be more robust with human astrocytes - it begs to question, what do we call support for learning? Isn't that thought? Here's an article about the exquisite experiment aptly called "Human Cells Make Mice Smarter" in Scientific American Mind.
Honorable Mention. Jeff Lichtman's Astrobow. While discussing his 'brainbow' and crucial brain mapping experiments at the Neuroscience conference, Harvard Neurobiologist Jeff Lichtman mentioned that they had also achieved the 'astrobow' originally in mice when attempting to do it in neurons, and that it happened by mistake. Three fluorescent colors randomly labeled all the astrocytes in the mouse brain, and a slice of brain viewed under a fluorescent microscope reveals the astrocytes looked like "paint ball splotches," as Lichtman put it. It is astounding, has never been published and shows astrocytes and their individual domains. The most covered area is the cortex, and it's fun to imagine what they may be thinking.