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A brain part mouse, part human


Researchers placed human cells into the brains of mice. The human brain cells began to replicate and take over much of the mouse brain, and the effects on mouse behavior were bizarre.  True.  Not science fiction.

Researchers at the University of Rochester in New York figured out a way to put human brain cells into mouse brains, taking steps to ensure that the mouse immune system wouldn't reject the human cells.   The mice they created are 'chimeric', their brains are part mouse, part human. (Chimera were mythical hybrid creatures with body parts from more than one animal.)

In order to appreciate what the researchers did, and what they found, it helps to know about the kind of human brain cells they introduced into the mouse brain.  Like mice, we have two basic types of brain cells: neurons and glia.  The cells they implanted into the mouse brain were human glial cells.

Most people have heard a lot about neurons, but not much about glia.  Glia are sometimes described as the brain's 'support staff'. Some glial cells clean up the debris from neurons that have been injured (the microglia), others provide nutrients to nearby neurons (they're called astrocytes, the type that were implanted into the mice), other glial cells play other roles that help neurons survive and function.

So it was surprising that mice implanted with human glial cells became smarter, or at least faster learners, than other mice. Glia aren't normally thought of as playing a key role in learning.  If you've seen the movie Good Will Hunting, you may remember Matt Damon's character working as a janitor in the halls of Harvard University.  His mathematical mind far surpassed that of the Harvard faculty.   The genius in the Harvard math building was the guy sweeping the floors.  The fact that human glial cells, our brain's support staff, would power-up the learning abilities of the mouse brain was surprising, very much in that way.

Here are some of the details:

The experimenters aimed to implant the mouse brain with a particular kind of human glial cell called astrocytes ('astro' because it's shaped like a star).
An astrocyte is a star-shaped glial cell. The image above shows an
astrocyte with its many thin processes radiating out from a round center.

Instead of implanting fully formed human astrocytes, they implanted an immature form of the astrocyte that exists in the brain during late stages of embryonic development. They're called glial progenitor cells or GPCs. The GPCs turn into astrocytes at some point during brain development. Experimenters placed human GPCs into the brains of newborn mice (Goldman, Nedergaard, & Windrem, 2015), taking steps to ensure that the mouse immune system wouldn’t reject the human cells.  This allowed the human astrocytes to develop and take their places within the mouse brain as it developed.

The brains of newborn mice were
implanted with human GPCs, immature
cells that eventually turn into astrocytes.
The immature human cells traveled throughout the mouse brain and increased in number. They soon developed into human astrocytes, which competed with and replaced most of the mouse astrocytes. Within about 10 months, most of the astrocytes in the mouse brain were human in origin! In the  figure below, the human astrocytes are stained red. As you can see, they spread to virtually all parts of the mouse brain. Researchers sometimes refer to this procedure as “glial humanization,” or more specifically, “astrocytic humanization” of the mouse brain.

The front of the mouse brain is to the left, the
back is to the right. The red dots are human  astrocytes.
They multiplied throughout the mouse brain.
The neuroscientists presented the mice with tones a few seconds before a mild shock was delivered to the floor of the cage. Once mice learned the tone-shock association, they would ‘freeze’, immobilized in their place, as soon as they heard the tone.  The more experience they had with tones followed by shock, the more time they spent freezing when the tone came on.  The black line below shows the behavior of a group of mice that was not transplanted (not grafted) with foreign cells. Over the course of 4 days of training, they increased the time they spent freezing when the tone came on. The purple line shows the behavior of another group of mice that received a graft containing astrocytes from other mice (allografted control mice). These mice gradually learned the tone-shock association as well. However, the mice with human astrocytes (the red line) were by far the fastest learners. After one day of training, they showed better learning than the other groups of mice showed after four days’ training.

The long, thin processes that radiate out from the center of the astroctyes often wrap around synapses between neurons. Evidence suggests that astrocytes enhance synaptic plasticity, the ability of neuronal connections to strengthen, and thereby enhance learning (Han et al., 2013). What is the precise role that these astrocytes, the supposed 'support staff' for the neurons, play in learning?  Do some people with learning disorders have a lack of, or dysfunction in, astrocytes? If so, can we do something to enhance their astrocyte activity? And what is going through the minds of these unusually smart mice with human astrocytes as an experimenter walks into the room?  I imagine an experimenter noticing a look of intelligence in the eyes of the chimeric mouse. Then I imagine the experimenter quickly looking away.