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1997 LECTURE SERIESUse It or Lost It: Brain Plasticity Across the LifespanDr. William T. Greenough If you understand the material in this first slide, you can leave. The rest is just the data that backs it up. The points that I'm going to make are first that the structure of the brain reflects its experience. That is, your brain, our brains, change their structural organization as a result of experience, as they incorporate information from experience. Some of you may feel that this is true for a developing brain because it starts little and it grows big, therefore its structure has to change, but what I'm also going to tell you is that this, as close as we can tell, is a life-long process. There is probably not a point in life where brain structure can't be modified by experience, by what you do, by what you learn. Both mental and physical activity seem to be important, both affect the brain. Of mental activities, learning seems to cause, probably among many other things, the formation of new connections between nerve cells. That is, learning seems to embellish the wiring diagram of the brain. Physical exercise also affects the brain. One of the most predominate effects that we know about is that it increases blood flow to the brain. This is particularly true of areas that are directly involved in mediating the exercise, but there's reason to believe that the effects go beyond that and as a result--and this is the title that Jim and I together chose for the lecture-- a good bottom line is that use it or lose it is a good rule for your brain. Nerve Cells and Their Connection Now, if you take this little tiny piece of this dendrite and blow it up again, as you might in a very high-powered microscope, then you can see what the connections between nerve cells look like. So here we have this dendrite from this cell and the axon from another cell terminates on this dendrite. This is the point of communication, perhaps the atom of the nervous system in the sense that this is as small as you can break it down and still have a functioning unit, so that the way in which information moves here is from this termination point of this nerve cell across a gap between them into the other nerve cell. This is the basic mode of communication in the nervous system. And in effect, the way in which you think involves the firing of these cells and the carrying of nerve impulses in axons and transmission across the synapses. Now this is what a real nerve cell looks like, more or less. In this particular case, it's been made visualizable or stained. And since the stain doesn't stain any of the other neurons in the field, the delicate details of this neuron are revealed. If all of the neurons that were here, since the brain is packed with neurons and support tissue, if all of them stain like this one, the picture here would be jet black. Everything would be stained. You wouldn't be able to see anything. But since we have just one neuron that's been visualized with stain, you can see again the cell body that's common to all cells, and this tree-like structure that goes out in all directions which is again, the receptive portion of the nerve cell. This is where the excitatory inputs, the synapses from other neurons terminate and it's a little harder to find here, but you can see the axon that goes out. The axon can be conceived as a sort of a telephone wire that's going out from the neuron. It doesn't go to just one other neuron. In fact, it breaks itself up, bifurcates many, many, many times so that an axon from a neuron like this can easily make 10,000 synaptic contacts with other neurons and likewise, a cell like this, this is a layer five paramatiamal cell and visual cortex. A human cell of this sort might receive up to 17,000 inputs from other cells. You know, presumably, that the brain, contains on the order of many billions of nerve cells. And if you multiply that by the numbers of synapses that exist on each nerve cell, we are into the medium to high trillions of synaptic connections that make up your brain. So, we are dealing with an extraordinarily complex system capable, obviously as you are well aware of, in coding and storing a great deal of information in roughly three pounds of tissue. Again, a synapse now visualized in three dimensions, this is the synapse as it would appear in the high-powered microscope. Here is a reconstruction of it, just showing that this is a dendrite, and here is the specialized synapse with the input coming from another cell and communicating across a tiny gap between them. A chemical neurotransmitter released from here activates the beginnings of the nerve impulse in the cell to which it or with which it communicates. So these are the players. This is what we are going to be talking about in terms of the elements of brain that are affected by experience. A Complex Now we have a contrast group. These are one example of a contrast group. This is the kind of experiment that I use, or the kind of cage that I use for the experiments that I'm going to talk about first. We have subsequently gone to cages that are somewhat less prison-like for the rats. In fact, the results don't vary very much with cage type. The point is these animals are housed either individually or socially with another rat in a relatively sterile cage, a cage that doesn't have toys or anything to really interact with, entertain the animal, anything the animal can learn from. Now, one of the ways in which growing up like this affects the rat is in its behavior. If one tests a rat's intelligence in a maze like this where the animal has to follow this kind of a pattern to reach a goal box that has a sweetened water reward, you can measure how quickly they learn not to go into these error zones (you can also actually time them and get other measures of how fast they learn). Generally, what we do is to count how many times they enter each of these blind alleys, these cul-de-sacs, and of course a rat can enter them more then once if it gets lost in the maze. And so, the next slide presents a learning curve. Here we're presenting the number of errors, the number of cul-de-sacs the animals went into as a function of trials in the maze. They get one trial a day for each of five days. This curve is for the animals from the Disneyland environment, the complex environment, and you can see that relative to animals from individual cages on day one when they don't have a clue about what the maze looks like, what characterizes the complex-environment animals is that they typically make the number of errors that is possible to make in that maze. You'll recall there were eight cul-de-sacs. They make about eight errors, they enter each error, each cul-de-sac, once, which makes sense. That's a great strategy when you don't know about the maze, to find out all of the various possibilities and then of course, by day two, they're making very few mistakes, essentially none by the third day. By contrast, the animals that are from individual cages make repeat errors on the first day and approach perfection more slowly. They certainly learn okay. This is actually a task that's very well designed for a rat to learn, but you can see there's an effective experience that you can see in behavior. The animals have presumably stored some kind of information from their rearing that aids them in performing this task. Now, in research that I began with Fred Volkmar which has continued since, we've measured the properties of nerve cells in animals that grow up under these circumstances and, as you'll see later, in animals that are placed under these circumstances at various points across the lifespan. This just gives an idea of how we measure neuronal size. In the experiments that I'm going to talk about first, we measured dendrites, the receptive surface of the cell. We're looking essentially at how much space there is for synapses to be made from other cells. How much other space is there for the wiring diagram to be complex? The way in which we measured this involved either measuring the length and counting the number of individual branches, we order them, as you can see, away from the cell body so that a branch from the cell body is called a first order branch. When it fabricates into two daughter branches, those are called second order and so forth on out. You can imagine, then, if a new branch were to be added out here, all of these numbers would increment by one, so there's a tendency to get especially pronounced effects at higher numbers in this hierarchy if one counts things in this way. Another way in which we measure the overall size, how much dendrite is there, is by putting an overlay of concentric spheres. This is a three-dimensional object, and just counting the number of times the dendrite penetrates the spheres and that gives you a notion of how much dendrite there is and also how it's distributed in three-dimensional space. These are results for animals that were reared from weaning, essentially the first time that they could live without their mothers in individual cages, social cages, or in the complex or enriched environment. The first measure here, and the only one I'm going to spend much time on, is total dendrite, how much total dendrite if you just put it end to end is there on each nerve cell and what you can see, this is, the length is in microns, a millionth of a meter, these neurons are still pretty small, but the animals that grow up complex have about 20 to 25% more dendrite on the average nerve cell than the animals that grow up in individual cages, so there really is a complexity effect. The complexity of the structure of nerve cells and hence the complexity of the wiring diagram organization of the brain is embellished really rather dramatically, I mean 20% is a big change if you think about it, as a function of this experience. If you grow up with lots of information processed, lots of opportunities for learning, you have a brain that is more complex, that has more wiring, more connections between nerve cells. A Life-Long Process It is true that there are advantages to having this experience early. The signs of the effect that you see, the speed with which the effects occur, both are greater in the younger animal. As a matter of act, in general, the younger an animal is, the more rapidly and more completely that animal seems to benefit from these environments, and that's certainly compatible with a lot of things that we know and believe about the effects of early experience in humans as well. But the brain doesn't stop being able to respond to experience. It remains capable of incorporating information from its experience in brain structure throughout life, measuring again branching of dendrites in animals that were placed in a complex environment at 450 days of age, which is more or less early middle age for the rat. What we find is that in these cells, these are in the visual cortex of these rats, there is a clear cut difference between the animals that are placed into the complex environment and the animals that are left in their standard laboratory cages. There are parts of the brain, notably the cerebellum, that actually show some deterioration with increasing age. That is, both in humans and in rats, there are some parts of the brain, it's actually fairly rare, most parts of the brain don't show deterioration in healthy aging but some do and one that does is the cerebellum cortex. The neurons there actually shrink in very elderly humans and in very elderly rats and as they shrink, they're actually losing connections. Even under this condition, however, experience can play a beneficial role. Even where the brain is sort of running down where the structure is failing, you can see positive off-setting effect of experience. Mental vs. Physical Activity: Which is More Important? So this rat is learning to traverse an elevated obstacle course. Pylons are joined by pathways which the rats have to negotiate. They have to go from one end of it to the other, both because they want what's at the end, which is a little tiny piece of a candy bar, and because the experimenter is encouraging them during the early learning phase to move right along. Eventually, they get to the point where they don't need an experimenter, and they happily run along something like the Indiana Jones Bridge, or even more surprisingly, a loosely hanging chain. Now, those of you who have tried to protect a bird feeder from squirrels will not be surprised that rats can learn these sorts of things. They learn them very, very well. They get to extremely high levels of performance. So this is our learning test. To compare, we want a task that has lots of opportunity for exercise, but little opportunity for learning. One way to do that is to attach the animal's cages directly to what are called activity wheels. It's a little hard especially with people behind me over here to see it, but basically on the far side of this wall is a wheel just like a large version of the wheels that you might have had if you had hamsters or other kinds of pets, activity wheels that you could put in their cages where they could run and run in place. The wheel spins, they don't move essentially, and they can do this any time they want. That is, the wheel is available. All they have to do is hop in and run. It turns out just because of the activity patterns of rats, most of the running is done at night. But they run a lot. As a matter of act, these animals ran so much that at the end of the 30 day experiment, the weight, not rate, the weight of their heart was elevated statistically over weight of the controls, which is a criteria variable for having engaged in aerobic exercise. The third group of rats, since we wanted to equate for the fact that we had to force rats through the acrobatic learning paradigm, was forced to run on the treadmill. Each of these lanes has a moving belt at the bottom of it, it's moving at a pace that makes the rat have to keep walking at roughly a jog. They do this for about a half an hour, they get five minutes of rest, they get another half hour of jogging. For what it's worth, rats like this, for those of you who have stair masters and other things in your basement. If you're not careful when you're bringing them to this apparatus, they will launch themselves from your hand onto the treadmill in order presumably to get the process started as quickly as possibly and they also protest, you know, when you take them out they're upset, they don't want to leave. Probably at this point I should come back and tell you why we used female rats. Those running wheels I showed you, if you put a male rat in a cage with free access to a running wheel, in a 300 day old rat, he says uh uh. Won't touch it. But females will hop in and run, you know, and enjoy it. Aren't you glad we're human and not rats. Where of course both females and males love to exercise. And then finally, our control group, caged potatoes. They simply sit in their cages, they're handled to control for the handling that we have to do with the other groups, but that's it. They don't do anything. So we're looking at the number of synapses, these are called precengy cells, that doesn't really matter, the output cell of this particular frame and they have there the acrobats, the animals that learned the obstacle course. They have the forced exercise in the treadmill, voluntary exercise on the running wheel, and the inactive condition, the caged potatoes. Now what you can see is that the animals that learned new skills increased numbers in synapses. The animals that merely exercised and didn't learn anything didn't increase the number of synapses. They look statistically no different from the inactive animals. So what this says is that when you learn, the way in which, or a way in which you change the structure of your brain is to add new synaptive connections. Again, it's not a small effect, it's around 20% with a month learning and learning at a very high degree of skill compared with what would be characteristic of the inactive laboratory rat. So that's in a sense the result of thinking and learning. Changing the numbers and presumably the patterns and actions. That is, the connections are the wiring diagram of the brain and what these animals have done is to embellish their wiring diagram in the process of incorporating the skills. Well okay, so I said I would tell you both mental and physical activity are important. So what does physical exercise do and the answer is, it increased brain blood flow. Now I'm going to prove this to you in two steps. Here's the first. What we're dealing with is a network of capillaries. So here is what happens to capillaries, the density, the number of the capillaries per unit area of section through the brain. You see a quite different pattern from what we saw before. Now the acrobats, the animals that learn are no different from the inactive animals. These animals are not adding extra capillaries. But by contrast, the exercise animals, the voluntary exercisers in the wheels, the forced exercisers on the treadmill, are adding capillaries. This was actually fairly revolutionary when we first reported it, because it was not believed that adult animals could add capillaries and adults of any species, including us, could add capillaries to their brain. There now have been some other people that have repeated it. It's a reliable finding. So you can see that there are important and complementary effects of learning and of exercise upon the brain with learning affecting, more or less, the connections between the cells and the brain's wiring diagram, and exercise affecting, among other things, the blood supply to the brain. You need both, and obviously these complementary effects would ideally be something that you would generate by being engaged, both in the appropriate amounts of physical activity and appropriate amounts of mental activity. Now, I said that I would prove that flow is actually altered. That's because at this point, we know that there are extra capillaries but we don't have any real evidence that they're being used, so that this is a further experiment that post-doctoral Rodney Swain conducted in my laboratory in collaboration with Dr. Paul Lauderberg, in which again we have activity wheels attached to the cages of animals and we have cage potatoes but not the other two groups. So we're just looking at effects of exercise in this case. And we used the technique, a fairly new technique that allows you to measure the amount of blood that's in the brain at any point in time. You're not actually measuring blood. You're measuring the molecule of blood, the protein that carries oxygen. It's called hemoglobin, and it turns out when it gives up its oxygen, you can detect that and measure that using what's called functional magnetic residence imaging. This is a rat size MRI. So you have a big magnet, a lot more powerful actually than anything that you could get in the hospital, and deep down inside of here is a rat with a machine that provides an anesthetic to him, not because it's painful, but because we don't want the rat to move while we're taking this reading on its brain. So the rat is asleep, he gets pushed back in here and essentially we do a brain scan on this rat and it turns out that the oxy hemoglobin, the thing we're trying to measure, it's a more or less an estimator of blood volume, subtracts from the image that you would normally get if you were having your brain or some other part of your body examined for clinical purposes. A question that one might ask is, "Does exercise effect performance?" And now here I have to go to other people's data. We have not done a behavior performance on our exercising rat. This is a study performed by a very eminent exercise physiologist, where she's looked at rats that were subjected to an exercise program essentially to the equivalent of our treadmill for a period of about four months. She tested both old animals, elderly animals and young adults that were either subjected to this exercise program or were cage potatoes, and you can see number one that there's an aging effect here, what she's measuring is in a task where the animals have to respond to a signal in order to avoid a mild electrical shock, how many, what percentage of the time they are able to do that and here it's just how long a warning, how long a period there was between the warning stimulus and the opportunity or the time that they had to avoid the shock. The response is a fairly minimal one. Essentially what you see is younger rats are better than old rats. They make more avoidances and that's good. They get fewer electric shocks, but then within these groups you can see that the exercise training enhances the performance, both in this case of the young adults and of the elderly rats. So again, here is an effect of exercise that you now can see in behavior, so it's not just that it's affecting the brain, it clearly is affecting the animal's ability to perform in the situation. So now we're back to fitness. This is a combination of a study and a review. These are humans, and this is a compendium of various published studies of the relative body fitness of athletes versus ordinary people. What's being measured is called BO2 maxis, it's essentially under optimal, or peak exercise conditions how much oxygen can your body consume, and it's a very standard measure of physical fitness in general. What you can see is that the athletes in some of these studies out to their 70s have a higher level of fitness by this measure than non-athletes either lean or overweight in their 20s. So it makes clear that physical fitness can be maintained through exercise or through training. Most of these athletes were involved in track of various sorts, but this is particularly interesting. Among young people, whether you're fit or not doesn't seem to make that much difference If you're young, fortunately, your brain works pretty well no matter how badly you abuse your body. If you're old, that doesn't hold so that the high fit people are down here not statistically different from the young people. Whereas the low fit older people have a much longer latency for the ah ha wave to appear in the brain. Correspondingly, this is a series of tests of cognitive or mental function, a test of how well you can think across a number of different sorts of tasks, all put into a single factor score and you see correspondingly then in thinking ability, young people, it doesn't matter too much how fit you are, but with people, with older people, those who keep fit at least 10 in the direction higher cognitive performance, those who don't fall behind. So fitness, clearly, is positively related to mental ability. The studies that I showed you so far were done with men. Here's a study that shows essentially that the same thing pertains for females, although you have statistical effects of activity both in the young group and in the old group. So, what I think I've tried to argue here is that both for humans and the work that other people have done and for animals, we really do see effects of experience on the brain. Effects that exist throughout the lifespan so that the structure of the brain reflects this experience and behavior. That is, the ability to do things well goes along with the recorded history of experience in brain structure. We've seen that it is a lifelong process, that certainly there are advantages to being early in development. The brain is more plastic, behavior is more plastic early in development than later on, but nonetheless, the ability to incorporate information into brain structure is a lifelong process, and both mental and physical activity are important. We saw especially in the case of the human studies, the importance of physical activity as you grow older. We don't know that all of the human effects are due to blood flow kinds of manipulations. We can really only get some of these answers in animals although I will say that if the funding agencies are with us, we will be looking at exercising human's brain blood flow at Illinois within the next six to nine months. And so bottom line, both mental and physical activity are ways of using your brain and as I said at the outset, use it or lose is a rule for your brain. |
Irvine Health Foundation |