Mar 26 2010

Neural Stem Cells and Plasticity

New research is expanding our knowledge of the nature of plasticity in the brain, creating the potential to treat a variety of neurological diseases and injury with transplanted stem cells.

At present the research is mostly in the proof of concept stage – doing animal studies to understand plasticity and the fate and function of neural stem cells. Plasticity is the ability of the brain to form new connections and pathways, even to change the pattern of its hardwiring. Plasticity is maximal when we are developing, and progressively declines with age. Although, even adults retain some plasticity and this likely results from the presence of neural stem cells (young cells capable of developing into new neurons) present even in the adult brain.

Further, all brain regions have a window of intense plasticity during which they are forming the majority of their connections. This development is closely tied to use, and if the brain is deprived of the appropriate sensory input or stimulation during this critical window of development, permanent deficits will develop. For examples, if children are not exposed to language by the age of 4 or so, their language window will close and they will never fully develop their language cortex. Or, if one eye is patched in young children, during the critical window in which binocular vision develops, they will never develop binocular vision.

University of California at San Francisco (UCSF) researchers, studying neural stem cell transplantation in mice, have been exploring the nature of these windows of high plasticity and have made some potentially useful discoveries. They isolated stem cells from the brain of embryonic mice and allowed them to age for various numbers of days. Meanwhile they patched one eye of other mice during their critical window of visual development, which results (due to the high degree of plasticity) in the visual cortex forming more connections to the open eye and fewer connections to the patched eye (called ocular dominance plasticity). This plasticity does not happen in more mature mice, after the critical window closes.

They then transplanted neural stem cells of various ages into mature mice, who were too old to display ocular dominance plasticity, to see if this would create a new period of such plasticity. They found that stem cells that were 33-39 days old (but not younger or older) resulted in ocular dominance plasticity. They also demonstrated that the stem cells distributed themselves throughout the cortex, matured, and formed connections.

What this likely means is that the period of increased plasticity is determined by the age of the neurons themselves, specifically inhibitory neurons that release the neurotransmitter GABA. If there are 33-39 day-old GABA producing neurons present, there is plasticity.

There are several important proofs of concept here: neural stem cells can be transplanted and will survive and make meaningful connections; the window of maximal plasticity is largely determined by factors intrinsic to the neurons themselves (rather than some other mechanisms of signaling); and the window of plasticity can be recreated by transplanting stem cells of the appropriate age.

This all bodes well for the potential of neural stem cells to treat a variety of conditions – traumatic brain injury, Parkinson’s disease, stroke, cortical blindness, and maybe even Alzheimer’s disease. Any traumatic, developmental, or degenerative neurological condition in which the problem is dying or damaged neurons could potentially benefit.

Of course, we need to extend this research to humans. The method of obtaining neural stem cells in this research would not be possible in humans, and so other methods would need to be developed. But there is already extensive and growing research showing the potential to derive stem cells from adult tissue.

Extrapolating technology is always tricky, but with the various proofs of concept already established by research we can easily imagine a future (once all the pesky technical details are worked out) in which a patient with one of the diseases I listed above or similar condition will have some of their fat cells (or some other cells) removed and then turned into stem cells. These stem cells will then be coaxed into forming neural stem cells and allowed to mature to the optimal age, and then transplanted back into the brain of the patient (either in a specific damaged location or more diffusely, as appropriate). Perhaps this treatment would have to be given multiple times. The stem cells will make connections, and due to plasticity will form the needed pathways, restoring function.

How long these new neurons will survive, and if they will fall prey to the original disease are important questions that later research will have to answer. Ideally, this type of treatment will result in young and vigorous brain cells that will last another lifetime.

This raises some further interesting, if speculative, questions. Would such treatments be useful for the brain atrophy and decline of function that most people (but interestingly not all) experience with normal aging? Will this technology make the “senior moment” a thing of the past?

Further, will such treatments be useful in making healthy young individuals smarter? Can an injection of neural stem cells before engaging in study or training enhance the benefits? Want to learn to speak a new language without an accent – no worries, just get an autologous transplant of neural stem cells in your language area and you are 3 years old again, ready to soak up a new language complete with all the phonemes.

Another interesting question is this – what if someone with severe Alzheimer’s disease, in which the brain steadily atrophies until more than half of the brain cells are lost (and this would continue if the patient did not eventually die first), were treated with neural stem cells. The new cells replace the old, making connections, and restoring and maintaining cognitive function. After years of such treatment, most of the brain’s original neurons will have died and been replaced by new neurons. Will this still be the same person?

Of course, the simple answer is yes. But I am interested in neurological function. It’s possible that if the process were slow enough there could conceivably be no cognitive changes – all the memories, personality, and talents will still be present. But that is the question – could this process slowly change the person neurologically, so that after 10 years and most of the brain being replaced the patient will actually be a different person in some meaningful respects. Will they have still lost some of their memories, will their personality and abilities change? Will they be almost like a newborn person (although with a very slow birth process)?

I don’t think we will know unless and until we achieve this kind of treatment.

In any case, the research into neural stem cells is consistently moving in a very encouraging direction. So far, so good. It certainly would be a good thing if this technology ushers in a new age of restoring damaged brains. Right now treatments are mostly limited to treating symptoms, compensating for damage, or maybe slowing down the progression of degenerative diseases. In some cases we can support the limited self-repair potential of brains (relevant to injuries but not degenerative disorders). But there is no way to directly repair damaged brains.  That would be a welcome addition to our repertoire.

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