Max Cynader: Enhancing The Plasticity of The Brain at TEDxStanleyPark (Transcript)

And this is a lesson that has been learned in the last 20 or 30 years of neuroscience research. I’m going to tell you a little bit about just how that actually works.

So let’s focus at the beginning on one part of neuroplasticity, the plasticity that we think of as memory. So what’s a memory, anyway? What is a memory? Well, I submit to you that a memory is nothing more than your ability to reconstruct the whole from a degraded fragment. Nothing more than that. So what do I mean by that?

Let’s talk about a specific memory. How about the memory of, I don’t know, your grandmother? OK. You see all these points of light behind you. Imagine that they’re all points of activity inside your brain. So if you look at this part of the brain here in the back, the visual cortex, imagine that this is what your grandmother looked like, the activity that your grandmother evokes in your visual cortex, during your interaction with her.

Here’s the auditory cortex, and this is the sound of her voice, or the things, the wise things she said to you. You know, this is the parietal cortex, the somatosensory cortex, this is the touch of her skin, the texture of her clothes. Up here in the smell cortex is the smell of her perfume, things like these. So all of these points of light represent activity that occurs in your brain while you’re interacting with your grandmother.

And now remember the slogan: “Neurons that fire together wire together.” So as you interact with your grandmother over the years, the sound of her voice, the texture of her clothes, what she looks like, the smell of her perfume, the taste of her cookies, all those things associate. They come together, they’re active at the same time, and neurons that fire together wire together.

Many of you have probably not seen your grandmother for a very long time. She may be dead. So what happens? You’re walking, I don’t know, along Robson Street, and you walk past the store, and you smell the perfume. Out of that store comes the perfume. And what happens? Your grandmother is right there. All of her is right there: the sound of her voice, what she looks like, the texture of her clothes, all the other attributes of your grandmother can be evoked just by stimulating one part of it. And that’s because neurons that have been firing together for years have now wired together. You can enter the circuit at any point. A piece of music that your grandmother liked is enough to activate that circuit as well. A picture of her is enough to activate it. And that’s what we think is a key part of the memory process, and that’s why neurons firing together are so important.

So in neuroscience now we can actually make neurons — Here we have two neurons, and these neurons are in a mouse brain, but what we’ve done is we’ve taken two neurons, and we’ve stuck into them a gene that we borrowed from jellyfish. It’s the gene that makes jellyfish glow green at night, and we’ve stuck it into these two neurons, and now they too are glowing green, and you can see two neurons connected to each other. The soma is the cell body, the axon is the sending end of the neuron, the dendrite is the receiving end of the neuron.

And what we can do is we can take these two neurons, and force them to associate. We can take the neuron on the left and tickle it with an electrical stimulus, zap! zap! zap!, we make it fire. And if we make it fire hard enough, we can get through the axon, we can activate the next neuron, the neuron on the right. Neurons that fire together wire together. So we go prrp! prrp! prrp! and after a time, what we find is if we make those two neurons associate that the connection between them will get stronger, and we’re understanding the mechanisms by which that works.

Now the way in which the two neurons connect to each other is right over here at a place called the synapse. And over the last decades, neuroscience has really understood the synapse in ways that were just not possible before. So the next slide gives you an illustration of what the synapse looks like. Those little blue dots on the top are the transmitters released by the axon, and then they activate all of these receptors, and all of that machinery in the next neuron, and ultimately that causes the neuron to fire.

But you know there is much more to it. It’s these receptors that are actually very important. You see this receptor? It’s called an AMP receptor. It’s kind of boring. If you put more in, more comes out. In other words, if you give it a weak stimulus, it gives a weak response, if you give it a stronger stimulus, it gives you a stronger response, if you give it a really strong stimulus, it gives you a really strong response called linear.

Look at this kind, the NR receptor, and NMDA receptor it’s also called. It’s very interesting. Very undemocratic receptor. It hates weak inputs: you give it a weak input not only does it not respond, but it actually goes negative. You give it a slightly stronger input; still not very interesting. You give a strong input; it goes crazy. And when it goes crazy, what it does is it activates all this machinery down here, and the effect of all that machinery is to put in more of these ordinary boring receptors.

So what that means is if you can tickle the fancy of this NMDA receptor, you’ll put in more of these ordinary AMPA receptors into the synapse, and then the synapse will become stronger. And that actually seems to be the core mechanism of memory, of strengthening connections between two neurons, of how strong inputs and contiguity can result in a stronger synapse. And that’s actually how we think you remember today’s lecture.

“So OK, Max. That’s all been great biochemistry. I’m all excited. Fine. Good. Well, what have you done for me lately? How’s my memory going to improve from all this?” OK. So I can tell you that scientists are working very hard. All of this understanding is leading to new strategies and therapies. If you actually look here, it turns out that if you block this, this is very important in getting this whole process to happen. We’re working on drugs that will tickle this pathway to give you a better memory. But we’re not there yet.

OK, it turns out that there’s a crucial structure in your brain that seems to be actually very important for your memory. It’s called the hippocampus. So they’re all these points of light on the outside of your cortex. They all funnel down to the hippocampus which again represents the memory trace in a compressed and higher form. We can now record the activity of hundreds of points in the hippocampus, hundreds of cells, as animals, for instance, run through a maze.

What we can do now is we can understand the functions of the hippocampus so well that we can actually, without knowing where the animal is, we can say: “OK, these are the cells that are active now — the animals of the first choice point — Now is at the second choice point. Now is at the third choice point.” And we can hear all this simply by recording the activity of all these neurons inside the hippocampus.

I want to tell you about an experiment that was done at MIT about ten years ago by Matt Wilson. He was studying the hippocampus as the rat was learning the maze, he was going through the first choice, blah, blah, blah. The experiment ends. He closes up the apparatus, the animal sitting in the vestibule of the maze now, not in the maze, and he starts to write up his lab notes. He’s still listening to all these neurons. What he finds is while he’s writing up the notes, he hears the neurons, you can hear them on loudspeaker. The animals running through the maze. How could that be?

Well, it turns out he goes over, he looks at the animal, the animal is asleep, but the hippocampus is still running through the maze while the animal is asleep. And there is now overwhelming evidence that what actually happens at night, every night, after you learned stuff during the day is that during sleep you replay and rebroadcast the memories of the day back out from your hippocampus to the rest of your cerebral cortex, rehearsing those memories again, strengthening the association among all those points of light.

So what’s my advice if you want to improve plasticity? Get a good night’s sleep. It’s very important.

Here’s another thing you can do if you want to improve your memory capabilities and your brain plasticity, and that is do physical exercise. Do physical exercise. It used to be thought that we already had all the brain cells we’re ever going to have; that’s not true. We’re actually making thousands of new brain cells every day, and you can double or triple the number of brain cells that you make next week by doing physical exercise.

Here’s an experiment which we did, again, in rats, where we can paint the new baby brain cells red, the ordinary cells are green. We take animals, we put them in an enriched environment. We have other animals in an impoverished environment, we find the enriched environment animals make more cells, and we fractionate the environment; we consider social cues, cognitive stimulation, physical stimulation. What’s important? Physical exercise. More important than having friends, more important than playing Sudoku, more important than all that stuff; do physical exercise.

So what we’re trying to do is to understand what actually happens in the brain when you do exercise. And we’re understanding there’re growth factors that go on, parts of these NR2B receptors are turned up, and the entire plasticity machinery is turned on along with these new baby cells.

We have a very good target now, and we’re actually working to develop a drug that will enhance your neurogenesis, your ability to produce new brain cells. And, by the way, this happens most in the hippocampus that I told you about. And we’re working very hard to basically develop that drugs, so you won’t have to do all that messy exercise, or hopefully, it will be synergistic with exercise. So if you can make three times as many more brain cells with physical exercise, maybe three times as many, again, with the drug and physical exercise.

So, there’s been a lot of work on understanding — I’ll skip this — There’s been a lot of work on looking at what happens in humans who do exercise, and this is a longitudinal study that we’re involved with. As you get older, your hippocampus shrinks along with everything else in your brain. But if you look at the red group, what you can see is that in a one-year longitudinal study, the controlled group is doing stretching, the experimental group is doing physical exercise, the volume of the hippocampus doesn’t shrink, and in fact, it even gets bigger.

So what’s my message? Do exercise. We’re trying to understand what kind of exercises you should be doing. Here’s a study by Teresa Liu-Ambrose from our center, working with a group of women in Dunbar. What she finds actually is that cardio is important, but actually doing weights is also surprisingly important. So do both cardio and resistance training, because that will actually enhance your cognitive performance.

So one of the things we’ve been able to achieve in the last few years in the field of brain imaging, is that not only we can see what parts of the brain are active, but we can now actually see the pathways in the brain. And we can see how they change as a function of usage. And this slide shows you this.

Now, what we’re learning then is under certain circumstances, pathways can be too weak or perhaps even too strong. And we’re learning how to modulate the strengths of brain pathways. There’s a new technology, called Transcranial Magnetic Stimulation that Lara Boyd is using in our Center. We put somebody in this apparatus, and we can stimulate one place in the brain, or several places in the brain. And what we can do again now, is to literally arrange — remember, neurons that wire together fire together — we can arrange the contiguities to be such that we strengthen a pathway from A to B in the brain. And when we do this, over time we strengthen the pathway.

How do we do it? We stimulate one place, the other place. We can stimulate lots of places. We got all these electrodes now, arrays are being developed. We’re going to be able to imagine the locus of neural points that represents your grandmother versus your grandfather. We should be able to strengthen the memory of your grandmother by just stimulating the right connection of points inside your head.

So we’re pretty excited about what’s going on now. I can’t tell you everything that we’re doing, but I just want to close with a quote from that great Canadian philosopher, Wayne Gretzky: “Skate where the puck is going to be.” And what Wayne is telling us in this quote is that here’s a tremendous challenge and opportunity in association with what is now going on in understanding how the brain works.

I’ve been doing brain research, I hate to tell you, 50 years now, and it has never been as exciting as it is today. It is moving so fast, it sits right at the confluence of genetics, imaging, cell signaling, electrophysiology. And combining all of these technologies is going to give us unprecedented capability to change the brain for the better. I look forward to the next 50 years.

Thank you again.

 

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