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Human Brain Cells Make Mice Smart

The views expressed are those of the author and are not necessarily those of Scientific American.


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Study shows that intelligence derives from brain cells other than neurons

White cell is human astrocyte with the unique long tendrils that penetrate multiple layers of grey matter (yellow arrowheads)

White cell is human astrocyte with the unique long tendrils that penetrate multiple layers of grey matter (yellow arrowheads). Image from Oberheim et al., J. Neurosci, March 11, 2009, p. 3276.

A team of neuroscientists has grafted human brain cells into the brains of mice and found that the rodents’ rate of learning and memory far surpassed that of ordinary mice.  Remarkably, the cells transplanted were not neurons, but rather types of brain cells, called glia, that are incapable of electrical signaling.  The new findings suggest that information processing in the brain extends beyond the mechanism of electrical signaling between neurons.

The experiments were motivated by a desire to understand the functions of glia and test the intriguing possibility that non-electric brain cells could contribute to information processing, cognitive ability, and perhaps even the unparalleled cognitive ability of the human brain, which far exceeds that of any other animal.

Current thinking about how the brain operates at a cellular level rests on a foundation established over a century ago by the great Spanish neuroanatomist and Nobel Prize winner, Ramon ý Cajal, who conceived the “Neuron Doctrine.” This doctrine states that all information processing and transmission in the nervous system takes place by electrical signals passing through neurons in one direction, entering through synapses on the neuron’s root-like dendrites and then passing out of the neuron through its wire-like axon as high-speed electrical impulses that stimulate the next neuron in a circuit through points of close apposition called synapses.  All thinking of how the brain receives sensory input, performs computational analysis, generates thoughts, emotions, and behaviors, rests on the Neuron Doctrine.

The possibility that glia, which lack any of the tell-tale attributes of neurons (dendrites, synapses, or axons) could contribute to information processing and cognition is well beyond traditional thinking.  Glia are understood to be cells that support neurons physically and physiologically and respond to neuronal disease and injury. In recent years, however, some neuroscientists have begun to wonder whether these neuron support functions, together with other aspects of the poorly understood glial biology, could participate in learning, memory and other cognitive functions.

Human glia are different

Human+mouse cells, from the Cell Stem Cell paper.

Human+mouse, from the Cell Stem Cell paper.

Looking through a microscope at a type of glial cell called an astrocyte, neuroscientist Maiken Nedergaard, was struck by a peculiar observation.  “Steve [Goldman] and I were culturing human brain cells many years ago and noted that the cultured astrocytes were much, much larger than in cultures [of astrocytes] prepared from rodent brain,” she says recalling the moment of inspiration for these human-mouse transplant experiments.  Nedergaard is a pioneer in research on neuron-glia interactions working together with Steven Goldman, an expert in neural stem cells.  Both are members of the Center for Translational Medicine at the University of Rochester Medical Center.  “Human glia, and astrocytes in particular, are substantially different from those of rodents,” Goldman explains. “Human astrocytes are larger and more varied in morphology, features that accompanied evolution of the human brain.”

The researchers observed that human astrocytes were 20 times larger in volume than rodent astrocytes.  This was far greater than the proportionate increase in size of human neurons relative to rodent neurons.  Human astrocytes looked different too–the shape of human astrocytes is far more complex.   Some human astrocytes extend cellular extensions that penetrate deep through several layers of grey matter in the cerebral cortex, something not seen in the mouse brain.  Argentinian neuroanatomist, Jorge Colombo, who was not involved in the new study, had reported in 2004 that astrocytes with such deep-penetrating cellular processes were not only missing in the mouse brain, but that they were unique to the brain of primates.  In fact, according to neuroscientist Alfonso Araque, a neuroscientist at the Cajal Institute in Madrid, this difference between astrocytes in animals and humans had not escaped the notice of Ramon ý Cajal, but this anatomical curiosity had been cast into the dustbin of history, absent from all modern texts on the subject.

“Perhaps part of what makes us human resides in astrocytes,” Araque conjectures.    The increase in number and complexity of astrocytes in the human brain contributes more than neurons do to the large increase in cerebral volume in humans and primates.  “During evolution of the human brain, its volume expanded by about 300% with respect to their ancestral primates; in contrast the estimated number of neurons is only 25% higher than in other primates,” Araque says.    By contrast, neurons from the brain of mice and men are not very different.  How might astrocytes contribute to the quantum leap in human brain power?  Such colossal astrocytes spanning large numbers of neurons and millions of synapses might contribute another level of integration to neural networks.  “Astroglia ‘nets’”, says Colombo, could provide “a potential non-neuronal dimension” of information processing, in which glia couple neurons and synapse in to functional ensembles.  By regulating the concentration of ions and neurotransmitters that neurons depend upon for synaptic communication, glia could modify the transmission of information through neural networks.  The larger scope of influence provided by gigantic human astrocytes might provide humans with a higher degree of integration.  “A single human astrocyte encompasses 2 million synapses compared to 100,000 in rodents,” Nedergaard says.

Human astrocytes are distinguished not only by their large size, but also by far superior high-speed communication.  Rather than generating electrical signals, astrocytes communicate with other astrocytes and with neurons using neurotransmitters.  Signals inside astrocytes are often carried by rapid waves of calcium ions that respond to neurotransmitters stimulating receptors on their cell membrane.  Nedergaard and her colleagues found that these waves of calcium signals travel 3 times faster in human astrocytes than in mouse astrocytes.

Testing the hypothesis with a human/mouse chimaera

Rat neurons (blue) astrocytes (red) other glial cells (oligodendrocytes, green) in cell culture. Photo: Jonathan Cohen

Rat neurons (blue) astrocytes (red) other glial cells (oligodendrocytes, green) in cell culture. Photo: Jonathan Cohen

An experiment to replace a significant number of astrocytes in the mouse brain with human astrocytes may be the ideal “thought experiment” to test the theory, but the practicalities of such an approach are daunting.  Would human astrocytes maintain their unique properties inside the mouse brain where the cellular environment and mix of growth factors are different from those in the human brain?  Would the astrocytes not only retain their human properties, but also integrate themselves properly into neuronal networks or might they instead grow wildly, disrupt the mouse brain or form tumors?  Professor Alcino Silva, from the Brain Research Institute at UCLA, who is an expert on learning and memory and one of the co-authors of the study, was surprised by the outcome.  “This is a profoundly surprising and unexpected finding,” he says.  “It is possible to replace mouse astrocytes with human astrocytes and not only get a live mouse, but [get] one that learns and remembers better than normal counterparts.”

The researchers isolated human glial progenitor cells (cells in the early stages of development before maturing into astrocytes) and labeled them with a fluorescent protein so that the transplanted cells could be identified unambiguously.  A suspension of these cells was then injected into the forebrain of newborn mice under anesthesia.  Examination of the brain 2 weeks to 20 months later revealed that mature human astrocytes had apparently inserted themselves into the rodent brain properly, while maintaining their unique human size and shape, including sending long twisted cellular processes deeply through the layers of cortical grey matter just as they do in the human brain.

Further tests showed that these transplanted astrocytes formed functional channels of communication between mouse astrocytes and other human astrocytes (gap junctions) that enabled them to communicate with adjacent cells and form a large inter-cellular network.  Next the researchers tested whether neurotransmitter signaling between neurons was affected by calcium signaling inside astrocytes.  Over the last 15 years, researchers from many laboratories have found that such astrocytic calcium signals can affect synaptic transmission between neurons, by manipulating the release or take up of neurotransmitters or other substances acting on neurons.  This influence on synaptic transmission is significant, because the basis of learning and memory is the formation and breaking of connections between neurons in networks that encode different sensory experiences.  The ability of astrocytes to boost or diminish the strength of synaptic transmission provides the opportunity for these glial cells to participate in learning and other cognitive processes.  Using electrodes to measure the voltage generated by a synapse in several well-established tests used by electrophysiologists who study learning and memory, the researchers observed that human astrocytes increased the strength of the synaptic signal; that is, the voltage in the postsynaptic neuron generated when a synapse fires rose faster and to higher voltages in mice grafted with human astrocytes.  Human astrocytes strengthen synaptic connections in the mouse brain.

Long-term potentiation (LTP) is the widely-studied strengthening of synaptic connections that is observed after a neuron is stimulated repeatedly.  This fundamental phenomenon of repetitive firing strengthening synaptic connections is thought to be the cellular basis for memory, just as repetition in learning helps form lasting memories.  In mice engrafted with human astrocytes, much less stimulation was needed to cause the synapse to suddenly increase the voltage it produced in signaling to the postsynaptic neuron and this amplified signal was maintained long after the stimulus was delivered (LTP).  When these mice were given standardized behavioral tests of learning and memory, the mice engrafted with human astrocytes outperformed mice injected with astrocytes from other mice as a control.

This changes everything

Rat neurons (blue) astrocytes (red) other glial cells (oligodendrocytes, green) in cell culture

Rat neurons (blue) astrocytes (red) other glial cells (oligodendrocytes, green) in cell culture

Commenting on this report, Pritzker Professor at Stanford University School of Medicine and an expert on LTP, Robert Malenka, says that “It is certainly possible that via several different mechanisms, differences in the number and/or properties of astrocytes could contribute to the greater intellectual capacity of humans compared to other species.  This work is an important first step in exploring this possibility.”

Colombo notes that in experimental cell transplantation experiments to treat Parkinson’s disease, substances released from the transplanted cells were found to contribute to the therapeutic effect without the cells necessarily becoming integrated into functional connections.  In the present studies, Nedergaard and colleagues found that one such substance released from astrocytes (TNFalpha) was increased after transplantation, and counteracting TNFalpha with drugs erased the enhanced performance of these chimeric mice in learning tests and LTP response.  Previous research by Malenka and Stellwagen has shown that TNFalpha can enhance synaptic transmission in mice.  Nedergaard and colleagues believe the human astrocytes could enhance learning by multiple mechanisms and that the cells inserted themselves properly into the mouse tissue.  “There is a carefully choreographed synaptic signaling dance between astrocytes and neurons, and I find it absolutely amazing that synaptic function was not only not disrupted, but plasticity was actually enhanced by the human astrocytes,” says Silva.

These new findings raise many new questions for future research, and as is often the case with a new scientific advance, the issues can expand beyond the laboratory.  Professor Helmut Kettenmann, at the Max-Delbrück Center for Molecular Medicine in Berlin,  and expert on glia, agrees that this is “a really surprising finding,” that builds on previous research from Nedergaard’s laboratory showing that human astrocytes are much more complex than their mouse counterparts.  “Of course, one is always concerned about the ethical aspect,” Kettenmann observes.  “If human astrocytes enhance the capacity of mouse brains, how far is one allowed to go?”

Goldman notes, however, that the development of mouse models containing human cells enables better experiments to understand how the human brain functions and how to treat human neurological and psychiatric disorders.  “This may permit a significant advance in how both the mechanisms and potential treatments of human-selective brain disorders are evaluated, in that a disease-specific human glial chimera may permit potential therapeutic strategies to be evaluated.” He points to disorders such as schizophrenia, which seem to appear in parallel with the human brain and its more complex glial and neuronal architecture.  The cellular basis for such human disorders is difficult to study in animal models.  “Similarly, we have established mice chimerized with human glia derived from patients with Huntington’s disease, to assess the relative contributions of diseased human glia to the neuropsychiatric symptoms and cognitive deterioration noted in patients with late-stage Huntington’s Disease,” he says.

This paper marks a departure from the past century of exclusive focus on neurons as the only important cells in information processing and cognition.  “When considering how the brain works, we need to analyze and understand all the different types of cells in the brain and how they interact,” Malenka concludes.

This is something the father of the Neuron Doctrine, Ramon ý Cajal would have no doubt endorsed.  In 1913 Cajal wrote “The human cortex differs from that of animals not only by the huge amount of astrocytes that it contains, but also by their smallness [in animals] and by the rich interstitial glial plexus [glial networks penetrating multiple layers of grey matter].” (Translation provided by neuroscientist Alfonso Araque.)

These results are reported in the March 7, 2013 issue of the journal Cell, Stem Cell.

R. Douglas Fields About the Author: An internationally recognized authority on neuron-glia interactions, brain development, and the cellular mechanisms of memory, Douglas Fields serves on the editorial board of several neuroscience journals and is the author of over 150 articles and the book The Other Brain.

The views expressed are those of the author and are not necessarily those of Scientific American.






Comments 13 Comments

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  1. 1. jtdwyer 3:19 pm 03/7/2013

    Don’t glia produce the myelin sheaths that insulate axons from electrical signal cross-talk and noise, improving the reliability and performance of electrical signal transmissions between neurons?

    I have an anecdote… I once underwent chemotherapy for 9 months. Having a heart condition as well, the result was severe anemia. Recovering afterwards (having gained back some of the 40 lbs. I’d lost, for example), I was feeling much better when my cardiologist prescribed 4 grams of omega-3 to treat very high triglycerides, starting at 1 G, increasing weekly.

    Within a week I suddenly became markedly interested in some specific issues in astrophysics (I’d only had a very casual interest in the past, as an IT professional). I began to keep a journal and research these issues. It seemed obvious to me that I was not only able to think much more clearly but much faster now than I had for a very long time.

    It was apparent that, while I’d been feeling OK, my intellectual capabilities had unknowingly been severely impacted by my condition & treatment, and was now, suddenly, been greatly restored to prior levels. Having coincidentally just begun the omega-3 treatment, I found that it has been associated with improved intellectual performance and restoration of myelin sheaths.

    My conjecture is that my prolonged anemia had resulted in the slow deterioration of the myelin sheath insulation between neurons, generally degrading signal propagation and performance of neuronal networks. The omega-3 treatment suddenly supplied large quantities of precursors necessary to repair the myelin sheaths – with the quick restoration of signal performance my inherent intellectual capabilities suddenly returned.

    Based on this personal perspective, I have to speculate that the performance of inter-neuronal electrical transmissions improved significantly with the transplanted human glial cells…

    Link to this
  2. 2. R. Douglas Fields 3:46 pm 03/7/2013

    Yes, but the cells that make myelin are a different type of glial cell called an oligodendrocyte. The third major type of glial cell in the brain are microglia. All of them have very different functions, but they can all respond to neural activity and influence neuronal communication in different ways.

    Link to this
  3. 3. jtdwyer 3:54 pm 03/7/2013

    R. Douglas Fields,
    Thanks for explaining. Might not neuronal communication performance be the most likely source of processing improvements? Could this be directly evaluated somehow?

    Link to this
  4. 4. Tanmay 4:27 pm 03/7/2013

    jtdwyer Thank you for that insight. I don’t know if it has any relevance, but it was a wonderful discovery on your personality.

    I always did wonder who this jtdwyer guy was, who comments on every article I read. I just assumed he was another science junkie, like me :)

    Link to this
  5. 5. jtdwyer 4:49 pm 03/7/2013

    Tanmay,
    Thanks for your kind remarks. I probably just have too much time on my hands in my retirement, but I am still taking 2 G of Lovaza daily…

    Link to this
  6. 6. leggedfish 7:04 pm 03/7/2013

    “several well-established testes” Might want to edit that line :P

    Link to this
  7. 7. jtdwyer 7:27 am 03/8/2013

    Having taken my potshot, after more carefully reading the article, I find this study to be very interesting indeed! Briefly, the research report is freely available at:
    “Forebrain Engraftment by Human Glial Progenitor Cells Enhances Synaptic Plasticity and Learning in Adult Mice,” Han, et al., Cell Stem Cell 12, 342–353, March 7, 2013, http://dx.doi.org/10.1016/j.stem.2012.12.015
    - which includes a nice video discussion of their results by the principal researchers. The research report itself contains many helpful images, charts and illustrations.
    Also see http://news.sciencemag.org/sciencenow/2013/03/human-brain-cells-boost-mouse-me.html

    Also interestingly, in 1985 UC Berkley prof. Marion C. Diamond produced a disputed study of tissue samples from 4 specific regions of Einstein’s brain, compared to 11 other men. The comparative sampling methods were questionable, but most significantly, a greater proportion of glia (both astrocytes and oligodendroglia cells) to neurons was found in Einsteins brain – _only_ in the left inferior parietal region (associated with mathematical thought, visuospatial cognition, and imagery of movement). It seems unlikely that if the comparative samples were invalid as some charged that the proportion of glial cells would only be differentiated in this one of 4 brain regions studied (assuming the cell counts were correct).

    There is some evidence that Einstein’s brain was missing a nearby structure associated with speech production and that his inferior parietal region simply expanded to fill the void. In this case, the increased proportion of glial cells to neurons may have nurtured the expansion or even simply provided spatial ‘filler’.

    The findings of the Diamond et al. study may support the findings of this study – that astrocytes are involved in information processing…
    MC Diamond, et al. (1985), “On the brain of a scientist: Albert Einstein”, http://www.ncbi.nlm.nih.gov/pubmed/3979509
    http://en.wikipedia.org/wiki/Albert_Einstein's_brain#Glial_cells
    http://science.howstuffworks.com/life/inside-the-mind/human-brain/einsteins-brain1.htm
    http://education.jhu.edu/PD/newhorizons/Neurosciences/articles/einstein/

    Link to this
  8. 8. R. Douglas Fields 9:24 am 03/8/2013

    Thanks Leggedfish. It is a funny typo. Many folks may not know that blogs are generally not copyedited so these things are bound to happen as a consequence of this new form of direct communication with readers. Just pointing this out so you don’t blame SciAm. The typo is mine.

    Link to this
  9. 9. greenhome123 4:54 pm 03/8/2013

    I am curious if there have been studies to see if humans with high IQ have larger or different glia cells than humans with average IQ. If that is the case, then it would be cool to have the glia cells extracted from the high IQ individuals and implanted into baby humans to increase their intelligence.

    Link to this
  10. 10. rshoff 8:02 pm 03/8/2013

    And I have been keeping my brain as empty as possible lest it overfill. Now we’re finding out that its capacity is near unlimited (well, maybe not mine)! Shucks.

    And jtdwyer always has a good perspective to introduce. A good contributor.

    now back to my empty brain….

    Link to this
  11. 11. hungry doggy 5:24 pm 03/13/2013

    Jtdwyer, your comments were interesting. I hadn’t read that before about Einstein’s brain.

    Greenhome, I had similar thoughts to what you wrote. As I was reading the article I was wondering if you couldn’t boost human intelligence by injecting a new born human baby with the same mix of glia and astrocytes as were injected in the mice. (Please, I’m NOT suggesting this actually be done – just a thought experiment.)

    I was also wondering what implications this may have had in human evolution. Developing a second network of astrocyte cells working in parallel to the neural network might have been a way to increase the brain’s intelligence without increasing the brain’s size. The human brain is already about as large as it can be and still fit through the birth canal. Maybe this was a way around the size limitations on the brain? Just a thought.

    Link to this
  12. 12. jgrosay 9:05 am 03/23/2013

    I’d say it’s: “Ramón y Cajal” and not “Ramon ý Cajal”, I’d say also that Neuron activity is not of an electrical nature, even when the electrical changes that follow the synaptic signals, that rely on membrane exchanges of neurotransmitters, are among the easiest things to detect, assess and measure, but all this may be just epiphenomena, many things go along with the activation of neurons, that in some way may act as transistors do, with collector, base and emisor, base controlling the flow between collector and emisor, that in the end, is not very different from the good old triode.

    Link to this
  13. 13. bozz5674 1:57 pm 10/13/2013

    If this was done for a cat, would it be more likely to come when you call its name? Or would it just ignore you more intelligently?

    Link to this

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