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Glia Cells in Human Brain Can Improve Cognitive Functions of Mice
#1
Our nervous system is composed of two types of cells - neurons and glial cells (glial cells, neuroglia). A new discovery shows that glial cells are not just "glue" of the nervous system, as previously thought, but that they are much more important in the unique complexity of our brains. Scientists came to this conclusion after seeing that transplantation of glial cells of the human nervous system in the mouse nervous system can affect connections within the mouse brain, thus enabling it to learn a lot faster.

The Importance of Astrocytes

The study, published in the journal "Cell Stem Cell", suggests that the evolution of astrocytes (a type of glial cell) - which are much larger and more complex in humans compared to other species - may be one of the key events that have caused the higher cognitive functions that make us so different from other species.

"This study shows that glial cells are not necessary only for neural data transfer, but suggests that the evolution of human cognition is driven by evolution of glial cells, which are by form and function specific to humans," explains neurologist dr Steven Goldman, MD from University of Rochester Medical Center – URMC and co-author of the research. "We believe this is the first evidence that human glial cells have unique functional benefits. This discovery gives us important new research model for a number of diseases in which these cells may play a significant role. "
Over the past few years, scientists have begun to understand and appreciate the role of glial cells (especially astrocytes) on our brains.

URMC researchers are the pioneers in unlocking the secrets of astrocytes and proving that they not only serve as a support to neurons in the brain, but that they also communicate with neurons and with each other.
"The role of astrocytes is to form a perfect environment for neural transmission," continues Prof. Maiken Nedergaard, coauthor of the research and one of the managers at Center for Translational Neuromedicine at URMC's. "However, we noticed that when this station evolves and becomes more complex, larger and more diverse - as in humans - the brain's functions are becoming increasingly complex."
Astrocytes are far more numerous, bigger and more diverse in the human brain comparing to other species. In humans, one astrocyte ejects the fiber sufficient to simultaneously connect a large number of neurons, and particularly with their synapses, transfer points where two adjacent neurons are touching. Therefore, one astrocyte in humans has the potential to coordinate thousands of synapses, which is much more than mouse astrocyte can.

The Astrocytes as Key Constituent of Human Inteligence

This observation hinted that human astrocytes may play a significant role in integrating and coordinating highly complex signaling activity in the human brain, thereby assisting in the regulation of our higher cognitive functions. Also, this observation is what gave the idea to transplant human glial cells into mice, assuming that our glial cells would affect the underlying patterns of brain activity in mice.

"In essence, we are very different from lower species," says Goldman. "Our advanced cognitive processing abilities are not only due to the size and complexity of neural networks, but also because of increased functional capacity and coordination that the glial cells enable."

"I always thought that the concept that the human brain is more capable because we have a little more complex neural networks is too simple, because if you bring together the entire neural network and all of its functions together - we would get super computer," says Nedergaard. "But human cognition is far more than mere data processing, it is also the coordinating of emotion and memory, which shapes our ability to learn."

The Experimental Design

The researchers decided to find out if the human glial cells are the cause of unique abilities of the human brain, by testing what would happen if human glial cells coexisted with ordinary nerve cells in mice. In order to succeed, the researchers first isolated glial progenitors- cells in the central nervous system, which allow the growth of astrocytes - from brain tissue. Then these cells were transplanted into the brains of newborn mice. As the mice grew, the human glial cells exceeded hosts glial cells, but at the same time they have left the existing neural network of mice intact.

"In essence, the human glial cells spread to the point where almost all glial progenitor and a large amount of astrocytes in mice were of human origin, and have developed and behaved as if they werewould in the human brain," says Goldman.

The team of scientists then decided to investigate the functional impact that these cells have on animal brains, with special attention to the speed and retention of signals between cells in the brain and its plasticity - the brain's ability to form new memories and to adopt new tasks. They found that two important indicators of brain function have improved dramatically in mice with transplanted human glial cells. First, the measurement of the phenomenon called "calcium wave" (as astrocytes connect with the help of calcium) - speed and distance at which the signal is spread within and between adjacent astrocytes in the brain - the researchers noted that the speed of the wave transmission in mice with transplanted human glial cells is faster than in normal mice, similar to the movements that take place in the tissues of the human brain.

Second, the researchers checked long-term potentiation , a process that measures how long the neurons in the brain are affected during a brief electrical stimulation. Long-term potentiation is considered one of the most important points of the molecular mechanisms responsible for learning and memory. In this test the researchers found that the mice with transplanted human glial cells developed faster and more sustained long-term potentiation, which means that learning ability of these mice increased.

Based on these findings, series of behavioral tasks were designed to test memory and learning ability. The results were as follows; mice with transplanted human glial cells learned more quickly, they gained new associations faster, and they performed a number of different tasks significantly faster than mice without the transplanted human glial cells.
"The point is that the mice with transplanted human glial cells exhibited increased plasticity and increased learning capacity within its neural networks, which significantly changed their functional abilities," said Goldman. "This tells us that human glial cells have a specific role in human body in the sense of intellectual capacity and cognitive processing. Though we have for some time suspected that this could be the case, this is really the first evidence of this hypothesis. "

Possible Uses of The Experimental Model

Researchers believe that this animal model, which now has the name of human glial chimera mouse, provides the medical community a new tool for understanding and treating neurological disorders that occur because of abnormalities in the glial cells. This could be especially important for those of neurological and neuropsychiatric disorders that are more likely to occur in humans than in other species. In these diseases, astrocytes’ features specific to the human species would be of particular importance for the process of development of these diseases. Goldman, Nedergaard and colleagues have used these mice to study human neuropsychiatric and neurodegenerative diseases, in which the pathology of glial cells could significantly contribute to the research results.
#2
Glial cells and the immune response

The potential importance of glial cells in human cognition is emphasised in the previous article in this thread. Human glial cells are recognised to play many other important roles however, for example in the regulation of innate immune responses in the central nervous system. Both glial cells and neurons express toll-like receptors (TLRs). However, glial cells are much more abundant than neurons. TLRS are pattern recognition receptors, which recognise conserved molecular motifs in pathogens and are central to innate immunity. The TLR family recognise conserved motifs known as pathogen-associated molecular patterns (PAMPs). There are currently ten known human TLRs. Recognition of PAMPs by TLRs results in signalling cascades with activation of transcription factors and cellular responses including the production of inflammatory mediators such as interferons (IFNs) and cytokines. This helps initiate the innate immune response.

In the CNS glial cells, including microglia, astrocytes and oligodendrocytes, act as sensors for neuroinflammation. Activation of TLRs on glial cells results in activation of pro-inflammatory mediators and hence in increased expression of membrane pores that allow ATP release and Ca(2+) influx. As a consequence of this, activated glial cells release ATP and glutamate, affecting myelinisation, neuronal development, and survival. It is hypothesised that occurrence of inflammatory responses in pregnancy could pre-dispose children to psychiatric and neurological disorders such as autism and schizophrenia. It has also been suggested that innate immune responses may be implicated in lowering seizure threshold in experimental models of epilepsy. A study from the University of Colorado in the USA implicated TLR4 signalling on glial cells as a potential contributor to acute seizures, which could be ameliorated by pre-application of interleukin-1 receptor antagonist. They suggested that inhibition of TLR4 signalling on glial cells could be a potential therapeutic target in human seizure disorders such as epilepsy. However, TLRs on glial cells may also recognise endogenous molecules released from damaged tissue, suggesting that TLRs on glial cells may be involved in initiation of an inflammatory response to tissue damage in the nervous system important in repair, for example in strokes and peripheral nerve injuries.

Sources

AGUIRRE, A. et al., 2013. Possible Involvement of TLRs and Hemichannels in Stress-Induced CNS Dysfunction via Mastocytes, and Glia Activation. Mediators of inflammation, 2013, pp. 893521-893521

LEE, H. et al., 2013. Toll-like receptors: sensor molecules for detecting damage to the nervous system. Current Protein & Peptide Science, 14(1), pp. 33-42

MAJDE, J.A., 2010. Neuroinflammation resulting from covert brain invasion by common viruses - a potential role in local and global neurodegeneration. Medical hypotheses, 75(2), pp. 204-213

RODGERS, K.M. et al., 2009. The cortical innate immune response increases local neuronal excitability leading to seizures. Brain: A Journal Of Neurology, 132, pp. 2478-2486
#3
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Glia Cells in Human Brain Can Improve Cognitive Functions of Mice00