The adolescent brain, with its neurons constantly birthing and killing its axons and synapses, is like a cauldron of old and young octopuses. Its developing and dying tentacles are constantly slithering into existence and withering away. It is exquisitely reactive to the electrical and hormonal hurricanes of adolescence, which it both thrives on and promotes, as life’s first memories are created, captured, engulfed or ejected, time and again.
Neuroscientists have apparently been drawing on vestigial remnants of all that brilliant brain-storming. For, stunningly, two labs reported last week making mice smarter, in two different ways, one of which “changes everything,” according to top neuroscientist Douglas Fields.
In adolescence, billions of neural connections, which exuberant childhood brains make in amazing over-abundance, are either permanently preserved or drastically pruned. It is a vibrant stage of life and evolution when we are, in the words of writer David Dobbs, “creatures optimally primed to leave a safe home and move into unfamiliar territory”; our “most fully, crucially adaptive” selves.
Left behind, when the neural carousing ends, is us. Stable, sane, rigid adults whose brain cells will forever turn over—and react to change, learning, or injury—far slower, for life.
But in last week’s Neuron1 Yale University scientists showed how the flip of one molecular switch can make old brains young again in terms of dendrite and axon turnover. “We caused a two-fold acceleration in turnover of neural connections in the middle-aged somatosensory cortex,” says neurobiology researcher Feras Akbik. “Plasticity was returned to the level of juvenile brains.”
The immediate result was mice completing a cognitive task twice as fast. They also shed fear faster, possibly getting emotionally smarter (this needs further study). And by flipping the same switch, the Yale lab earlier created mice who recovered “significantly better” from stroke and spinal cord injury than normal mice—as adolescents do.
“No one has ever demonstrated before that a single gene can return adult brains to juvenile levels of anatomical plasticity,” says Akbik.
That gene codes for a molecular receptor on neurons called Nogo Receptor 1. It suppresses growth of neurites—dendrites and axons—when triggered by some glial proteins. Yale study leader Stephen Strittmatter characterized the receptor in 2001. He has since studied how it inhibits axon regeneration in the adult central nervous system to prevent instability. The Yale team knocked out the Nogo Receptor 1 gene in mice to get many of their results.
The “aha” moment came when, after laboriously counting turnover in the knockout mice, they started un-blinding results, Akbik says. “The moment it was clear the knockout mice were stuck in adolescence was striking.”
Human drugs to mimic this are being tested at Axerion Therapeutics.
But smart mice have also overrun another lab. Last week, Rochester University neuroscientists Steven Goldman and Maiken Nedergaard reported in Cell Stem Cell2 that immature human glial cell injections created smarter mice—who outdid normal mice on four cognitive tasks.
Human brains are dominated by two kinds of cells: neurons, and glial cells called astrocytes. Human astrocytes are 20 times larger than mouse astrocytes. Human astrocytes are also far more varied in shape, and extend processes deeper into brains, than mouse astrocytes.
It was once thought astrocytes just support neurons, as they do not conduct electricity like neurons. But recently it has become clearer astrocytes are involved in critical human cognition. For one thing, it has been found that during evolution they expanded in humans 300%, compared to 25% in other primates. And while human/mouse neurons are barely divergent, human astrocytes possess 2 million connecting synapses, compared to 100,000 for mice. Then there is Albert Einstein, who had two glial cells for every one neuron. Most of us possess only one glial cell per two neurons.
Astrocytes had to be a key reason human brains are advanced.
After Goldman and Nedergaard infused newborn mouse brains with immature human glial progenitors, those progenitors—and the mature astrocytes they became--overwhelmed the hosts. Human glial cells hooked properly to mouse glial cells. After a molecule called tumor necrosis factor was released by new cells, mouse/human glial networks emitted calcium ion signals—astrocytes’ mode of communication—three times faster.
Importantly, human glial cells also strengthened electrical impulses between neurons in the hippocampus, the seat of learning and memory.
The result was smarter mice with more plastic brains, as in the Yale study. (A major difference: Strittmatter blocked one receptor from interacting with specific repressive glial proteins, while Goldman/Nedergaard added multi-potent stem cell-like (progenitor) glial cells with more diverse skills.) As Fields put it in an email: “Both papers highlight the importance of glia in learning and nervous system plasticity, but each study concerns entirely different kinds of glia operating through different cellular mechanisms.”
The upshot is the Goldman/Nedergaard study dramatically illustrates the notion that glial cells are partly responsible for our higher cognitive abilities: our humanity, says Fields, who is Chief of the Section on Nervous System Development and Plasticity at the National Institutes of Health. “This is the first paper to show in such a compelling way that glial progenitors are important for learning and cognition.”
More accurate human brain learning, memory, and disease model mice may now be created to test drugs—and to learn more about how we learn, says Fields. “This changes everything,” he wrote recently3, adding via email: “It is only the beginning.”
Questions may soon be raised regarding just how human we should be making those mice.
But for now, beyond the pitter patter of smart-mouse feet, neuroscientists are listening for the faint sound of another paradigm shifting, that of the tyranny of the neuron in the human brain.
1. Akbik, F.V., et al, “Anatomical Plasticity of Adult Brain Is Titrated by Nogo Receptor 1,” Neuron, March 6, 2013, Vol 77, Iss 5: 859-866.
2. Han, X., et al, “Forebrain engraftment by human glial progenitor cells enhances synaptic plasticity and learning in adult mice,” Cell Stem Cell, March 2013, Vol 12, Iss 3: p342-353.
3. Fields, R.D., “Human Brain Cells Make Mice Smart,” Scientific American guest blog, March 7, 2013.