Bill Richardson - Piano-playing mice

14 January 2015

Interview with

Bill Richardson, UCL

Kat - This month I'm reporting back again from the Genetics Society autumn meeting, held at the Royal Society at the end of November, which focused on the genetics and neurobiology of learning and memory. One of the most interesting talks, if only for the cute videos of mice running round on wheels, was from Bill Richardson from University College London. He's investigating the role of myelin - the fatty white insulating material that coats our nerves - and how it's involved in learning.

Bill - We and others have discovered relatively recently that new myelin continues to be formed in the brain of a mouse long after embryonic development and early postnatal development into young adulthood. That was quite unexpected because you would expect for the brain to work normally that everything should be set up early in order to be able to be programmed later.

Kat - You kind of think you've made enough, you don't need to make anymore.

Bill - Exactly, yeah. By finding that it continues to be made from these immature cells called oligodendrocyte precursor cells that raised the question of what is the function of the newly adult born myelin. Also, there's an increasing body of evidence in humans that people who learn complex motor tasks - that means complex sequences of movements like juggling or using the abacus or playing the piano - they develop changes, structural changes in their brain which are not necessarily to do with neurons.

They have structural changes which can be detected by MRI in the white matter tracts. The white matter is those parts of the brain which are called the information superhighways. They don't contain the neurons themselves. They just contain the connections between the neurons. So, it's where all the traffic occurs. Those superhighways contain myelin. And so, this was another link suggesting that new myelin might be formed in response to training or learning.

Kat - So, how do you go about discovering if making new roads in this superhighway for myelin is the key to learning?

Bill - Well, it's a very simple concept. We try and prevent the formation of new myelin and see if that impacts the ability of a mouse to learn complex motor task.

Kat - Now, a mouse can't learn to play the piano. So, how do you challenge a mouse to learn something complicated?

Bill - Well, we'd like the mice to play the piano, but we devised a task which is a little akin to playing the piano for a mouse, which to take a running wheel with rungs and remove some of the rungs so that it's irregularly spaced rungs. We call that the complex wheel.

Kat - So, it has to kind of figure out, "Ooh! Miss one, miss two, miss a few."

Bill - That's correct! It's like running up a staircase and some of the steps are taller than others and you have to remember where the trip steps are, so to speak. For some reason that I don't understand, they seem to enjoy it. So, you don't have to give them a reward. They will persevere and become very proficient at running on those wheels.

Kat - Just for the joy of running.

Bill - Just for the joy of running, yes.

Kat - So then how do you test whether it's this myelin growth that's involved in their learning?

Bill - We have to somehow prevent the production of new myelin and see if that affects the ability of the mice to learn to run on this complex wheel. So, how do we affect the production of myelin? Well, that's where the genetics comes in. We used genetic tricks to delete a specific transcription factor, a crucial protein or the gene encoding that protein that is required to elaborate the structure which is known as myelin. That genetic switch that we introduce into the mice is activated by a drug, tamoxifen, so that if we inject tamoxifen into the mice, it doesn't affect their pre-existing myelin, but it prevents any new myelin from forming after that point.

Kat - So, what happens then if you get a mouse and you treat it in this way and you try to make it learn something?

Bill - So, we injected tamoxifen, we showed that we can effectively prevent 95 per cent of the new myelin forming and then we give them the complex will and find that they're pretty poor at learning the complex will compared to their littermates that still have the gene.

Kat - So, that seems to be pretty strong confirmation that it is the growth of this new myelin that's involved in their learning.

Bill - It's a very good clue, but of course, that on its own, that one experiment doesn't necessarily tell us it's learning per se. It could be that knocking at that gene has unexpected effects on fitness. It may have reduced cardiovascular tone or reduced muscle tone. So, we have to do a control, and the control was to allow the mice to learn to run on the wheel before we knocked out the gene. When we did that, of course, during the learning phase, while the gene was still present, they could learn normally like their wild type or normal littermates. Then we knocked out the gene and put them back on the wheel and they were now able to remember what they had previously learned. And that shows that they don't need new myelin to remember something that they previously learned, only to lay down the new skill.

Kat - I mean, this makes sense if you use the analogy of a highway - once you've laid down the tarmac, it's there.

Bill - Well, that's a pretty good analogy. We've also started to look at other learning and memory tasks. Still sticking with motor learning, we're training mice to pick up food pellets with one hand which they can do. Pretty clumsy at first, but they get better at that. After training with one hand, we can detect cellular changes in the white matter and the grey matter on the contralateral side - the opposite side of the brain to the hand that they're using because as we know, the pathways in the brain cross. That's rather useful because it means that we can compare the trained side of the brain with the untrained side and that would comprise a very nice internal control. We can compare one side of the same mouse with its opposite side if you see what I mean.

Kat - So now, we have these really nice clues that the growth of new myelin is really important for learning. This is in mice. How do we know that similar pathways may be at work in humans when we're learning things like playing the piano or running on a complicated wheel?

Bill - There is MRI evidence that there are structural changes in the white matter - the information superhighways. And that's what originally got us thinking about this whole question of adaptive myelination. But at the same time, it has recently been shown or reported at least that myelin production in humans does not extend throughout adult life as it does in mice. Most myelin production in humans is completed by age 10 or so. Although there is a small trickle that carries on into young adulthood into the early 20s. Maybe learning new tasks requires a relatively small proportional change in the myelin which cannot be detected so far.

Kat - So, could this explain how old dogs can learn new tricks that you do still need a little bit of myelin when you're older?

Bill - Dogs do learn new tricks but much more slowly than they would have done if they were younger and everyday experience tells us the same thing about humans. Another thing about myelin is, since it's a sheath that wraps around the axon, it has a kind of protective role and it preserves the circuit. As we know, if you learn to ride a bicycle, you can put the bicycle in the shed for maybe 20, 30 years and get it out at the end of that time and you can still ride the bicycle. So, motor skills are a very long lived thing. That also smacks of some kind of structural support by myelin in my opinion.

Kat - I always find it amazing. I'm a musician and sometimes if I haven't played a piece for ages, I sit down and I play and it's there.

Bill - Well, the very first MRI studies in humans were to do with pianists in fact, showing that the amount of time a professional musician practised before age 11 in fact was reflected in the amount of myelin in his or her white matter.

Kat - That was Bill Richardson, from UCL.

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