Okay, so let's go to structural plasticity. I mentioned that when I say structural plasticity, I mean that there are some anatomical morphological structural changes that are correlated with learning. And we already discussed that Cahal already realized that there must be some structural changes. And actually, later on, recently, not so recently, we, there are, there were several experiments. And this only one out of many that showed that when you do something dramatic. For example, to a kid, when you deprive the vision of one eye of a kid for enough time, early on, for example. Then you'll start to see changes in the density of spines. So here is a change in the structure of an undeprived kid and a deprived kid following, closing of an eye. So here is an example of something about learning to see or the experience of seeing, by closing your eye or opening it, may change the structure of a, a neuron individual system, for example. There were also other examples in the literature of comparing a tissue before and after learning. For example, people show that there is an increase in number of stable new spines following a behavioral improvement of a mouse, of a rat. So we saw correlation between structure and function. Number of spines, number of synapses, and capability to improve behavior. But these were not really direct in, in, in a, in a living behaving brain. Okay, so really much of our understanding until very recently about this structural underpinning of learning and memory came from old techniques in fixed brain tissues, comparing a brain that learned to a brain before learning, another brain of course so statistically showing differences, but today with new technologies we can view miracles. And here is one of the relatively new technology, the 2-photon microscope. So, of course, I'm not going to get into the optics of the 2-photon microscope, but it's a microscope that enables to view, in a very, very fine resolution, a particular region of the brain. In the living behaving brain, asking in real time while look at the cell what are the changes that may underlie particular learning in this living brain, not in dead tissue but in the living brain. So this is the 2-photon microscope which really enable a jump in our capability to look at neurons during behaviors and changes. So again, so this is the mouse that I want to look at the brain of, and I'm really zooming in using this 2-photon microscope. Into dendritic spines. In living behaving brain, and I'm trying to really look at these spines and count or see whether there are changes, at the level of spines due to learning, due to activity, due to behavior, due to enrich environment. Challenging environment, either it changes or not. So the group of Karel Svoboda from Janelia farm near Washington, they zoomed in, the cortex of mouse in this region. Zoom and zoom and zoom using the 2-photon microscope, and they could really see something very interesting at the level of dendritic spines. So you can use, and that's fantastic, because you can zoom into the same region again and again, day after day, day for one, day two, day three, day four, and follow a particular spine, dendritic spine. So look at this spine that is highlighted with a yellow arrow here. Day one there is a spine, day two there is a spine, day three there is a spine and so on. So this is a stable spine. It appears in all days, eight days. But look at another one. For example, look at this Blue spine. So in day number five, suddenly you see a spine that did not appear here. In day number four there was no spine, and suddenly there is a new spine, but in day number six this spine disappeared. This is a transient spine. It appears and disappears. So releases a structural change something grows, and then disappear. There are this other spines, the red spines, that appear in day number five, and stay to them day number six, day number seven, and then disappear. So this is semi transient spines. So there are spines, apparently synapses that are stable probably through all your life. There are spines that appear or disappear, they are trying to find a mate, a friend, a connection. Probably they don't. They dissolve. They disappear. Some of them find maybe a friend for a few days. Then they disappear. We don't completely understand the rules underlying this structural plasticity, but I'm showing you that there is this structural plasticity, that some spines are stable, some spines are very transient, some spines remain for a few days and then disappear. So there is a change in the brain constantly all the time. The question is does it relate or not to learning in plasticity. And that's of course the question. And the answer is yes. Let me show you a real, so to speak, ongoing movie of spine changes in the brain, in the living brain. Day after day, day after day, so I'll show you it again, so just to highlight what you have to see, what you must see, so this is, this is a dendrite of the postsynaptic cell. This is a spine, and this is an axon, of the presynaptic cell. And I want to show you these two cells, at least in this region, sometimes are not connected and sometimes are connected day after day. So this is day after day movie in the living brain. Look at it again. Day after day. First day, no connection, no connection, boom. There is a connection. This, the axon and the spine probably, we have to see whether there is a synapse there. But probably are connected. So this spine was really jittering and sadly, we established a connection. So we have a new connection apparently, here, ongoing connection, maybe stabilized for a long time if it's a persistent spine and connection, or maybe transiently, we don't know. Let me show you another movie. That following stimulation of the system, you can see really, a spine growing during stimulation. So here is the stimulation of the presynaptic cell. Zoom in and suddenly you see, a new spine is growing here. A whole new spine is growing. In this piece of dendrite, this is the work of Tobias Bonhoeffer from the Max Planck Institute in Munich. So we have today a direct proof just by looking in vivo on the behaving brain using 2-photon microscope, that there are these new structure, spines. Growing disappearing, dissolving, popping up, again and again, and sometimes establishing a synapse. And the outcome of this is that the synapse, the strength of the synapse, is becoming stronger when you have new spines, because there are new synapses or because existing synapses become stronger due to SDTP. Eventually, after enough stimulation here, you get, after enough pairing, pre and post, pre and post, either due to the generation of new synapses. Or due to generation of enhanced efficacy of a given synapse. You see that the synapse, before it was with this control normalized strength, and here it becomes stronger. And when it becomes stronger, it persists, as you see, for many, many minutes. Many, many minutes. Half an hour, and more. And this happens relatively fast. After several stimulations, suddenly, a new spine or the existing synapse becomes stronger. So let me summarize what I said until now, an interim summary. About structural plasticity, we know that new spines are born constantly, again and again, constantly in your brain now. During learning more spines are grown, I didn't show it to you but I'm telling you that we know that learning challenging environment generates new, more spines, new synapses, new connections. And these new synapses apparently, that's what we believe today. Generate functional networks that are, that together code for a new item. So clearly, the brain is using structural plasticity in addition to functional plasticity. In this case, at the level of dendritic spines, not new cells, but dendritic spines to generate new functional networks. And these new functional networks are related to challenging environment, to learning in plasticity. Let's go to the third possibility.
