http://blogs.scientificamerican.com/guest-blog/2013/03/07/human-brain-cells-make-mice-smart/
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Human Brain Cells Make Mice
Smart<http://blogs.scientificamerican.com/guest-blog/2013/03/07/human-brain-cells-make-mice-smart/>
By R. Douglas Fields | March 7, 2013 |
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*Study shows that intelligence derives from brain cells other than neurons *
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*
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*
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 testes 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*
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
cellsinserted 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.)"
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