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Human glial cells make mice think faster
Now, glial cells appear to be essential to the unique complexity of the human brain. Scientists reached this conclusion after demonstrating that when human cells are transplanted into mice, they can influence communication within the brain, allowing the mice to learn quickly.
The study in the journal Cell Stem Cell, suggests that the evolution of a subset of glia called astrocytes - which are larger and more complex in humans than other species - may have been one of the key events that led to the higher cognitive functions that distinguish us from other species.
"This study indicates that glia are not only essential to neural transmission, but also suggest that the development of human cognition may reflect the evolution of human-specific glial form and function," said University of Rochester Medical Center (URMC) neurologist Steven Goldman, MD, PhD, co-senior author of the study. "We believe that this is the first demonstration that human glia have unique functional advantages. This finding also provides us with a fundamentally new model to investigate a range of diseases in which these cells may play a role."
In recent years scientists have begun to understand and appreciate the role that glia cells - and more specifically astrocytes - play in brain function. Researchers at URMC have been pioneers in unlocking the secrets of astrocytes and demonstrating that they not only serve to support the neurons in the brain, but also communicate with neurons and each other.
"The role of the astrocyte is to provide the perfect environment for neural transmission," said Maiken Nedergaard, MD, DMSc, co-senior author of the study and director, along with Goldman, of the URMC Center for Translational Neuromedicine. "As the same time, we've observed that as these cells have evolved in complexity, size, and diversity - as they have in humans - brain function becomes more and more complex."
Astrocytes are far more abundant, larger, and diverse in the human brain compared to other species. In humans, individual astrocytes project scores of fibers that can simultaneously connect with large numbers of neurons, and in particular their synapses, the points of communication where two adjoining neurons meet. As a result, individual human astrocytes can potentially coordinate the activity of thousands of synapses, far more than in mice. It was this observation that suggested that human astrocytes might play a significant role in integrating and coordinating the more complex signaling activity found in human brains, and hence help regulate our higher cognitive functions. This in turn suggested that, when transplanted into mice, human glia may influence underlying patterns of neural activity.
"In a fundamental sense are we different from lower species," said Goldman. "Our advanced cognitive processing capabilities exist not only because of the size and complexity of our neural networks, but also because of the increase in functional capabilities and coordination afforded by human glia."
"I have always found the concept that the human brain is more capable because we have more complex neural networks to be a little too simple, because if you put the entire neural network and all of its activity together all you just end up with a super computer," said Nedergaard. "But human cognition is far more than just processing data, it is also comprised of the coordination of emotion with memory that informs our higher abilities to abstract and learn."
The research team wanted to determine if human glial cells provide the human brain with unique capabilities, by examining what happened when these cells were allowed to co-exist with normal mice nerve cells.
"The human glia cells essentially took over to the point where virtually all of the glial progenitor cells and a large proportion of the astrocytes in the mice were of human origin, and essentially developed and behaved as they would have in a person's brain," said Goldman.
The team then set out to examine the functional impact that these cells had on the animals' brains, specifically the speed and retention of signals between cells in the brain and its plasticity - the ability of the brain to form new memories and learn new tasks.
They found two important indicators of brain function drastically improved in mice with human glia:
• First — measuring a phenomenon called calcium wave, which is the speed and distance at which a signal spreads within and among adjoining astrocytes in the brain, they noted the speed of wave transmission in transplanted mice was faster than normal mice, and more similar to that of human brain tissue.
• Second — long-term potentiation (LTP), or how long brain neurons are affected by a brief electrical stimulation — considered one of the central mechanisms underlying learning and memory, researchers found that transplanted mice developed more rapid and sustained LTP, suggesting improved learning capability.
On the basis of these findings, the team then evaluated the mice in a series of behavioral tasks designed to test memory and learning ability. They found the transplanted mice were more rapid learners and both acquired new associations and performed a variety of tasks significantly faster than mice without the human glial cells.
"The bottom line is that these mice demonstrated an increase in plasticity and learning within their existing neural networks, essentially changing their functional capabilities. This tells us that human glia have a species-specific role in intellectual capability and cognitive processing. While we've suspected for a while that this might be the case, this is really the first proof of this point."
• Neonatal implantation of human glial progenitors generates glial chimeric brains
• Hominid-specific astrocytic properties are retained in a cell-autonomous fashion
• Human glial chimerization enhances TNF?-dependent long-term potentiation
• Human glial chimeric mice are faster learners across a range of behavioral tests
Summary Human astrocytes are larger and more complex than those of infraprimate mammals, suggesting that their role in neural processing has expanded with evolution. To assess the cell-autonomous and species-selective properties of human glia, we engrafted human glial progenitor cells (GPCs) into neonatal immunodeficient mice. Upon maturation, the recipient brains exhibited large numbers and high proportions of both human glial progenitors and astrocytes. The engrafted human glia were gap-junction-coupled to host astroglia, yet retained the size and pleomorphism of hominid astroglia, and propagated Ca2+ signals 3-fold faster than their hosts. Long-term potentiation (LTP) was sharply enhanced in the human glial chimeric mice, as was their learning, as assessed by Barnes maze navigation, object-location memory, and both contextual and tone fear conditioning. Mice allografted with murine GPCs showed no enhancement of either LTP or learning. These findings indicate that human glia differentially enhance both activity-dependent plasticity and learning in mice.
All authors of the study: Xiaoning Han, Michael Chen, Fushun Wang, Martha Windrem, Su Wang, Steven Shanz, Qiwu Xu, Nancy Ann Oberheim, Lane Bekar, Sarah Betstadt, Alcino J. Silva, Takahiro Takano, Steven A. Goldman, Maiken Nedergaard
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The evolution of a subset of glia called astrocytes, which are larger and more complex in humans
than in other species, may be one of the key events leading to human higher thinking.
Image credit: University of Rochester Medical Center (URMC)