So I thought, for the first time, when we introduce each other, to each other, and I introduce you the

brain, I want to introduce you, what I see today, and this is a choice, five, very exciting things that are happening today, in terms of science of the brain. This will be the Connectomics, which is a buzz word that you should know. The Brainbow technology, which is a beautiful new technology. I want to talk a little bit about the interface between Brain and machines. I want to discuss a beautiful technology, the Optogenetics, and eventually I want to show you just a glimpse just the teaser for the 'Blue Brain Project" in terms of simulating the brain mathematically, building models for the brains in the Computers. So, I want to just hightlight five of the recent excitments in brain research. [COUGH] So, we start with Modern neuroanatomy. We need to have the wiring diagram, we need to have the roadmap, or the blueprint of the brain. This is of course something very fundamental that actually started many, many years ago. Not so many, 120 years ago. This is what I see as the begining of Modern neuroscience. So when I say the Beginning of Modern Neuroscience in a systematic way in a scientific sense, I'm talking about these two characters, Camillo Golgi, the Italian, Harmonica Hal Santiago, Amonica Harl, a Spaniard, both great anatomists, really are giants. They are working very systematically to develop methods. Both optical met, methods, or microscopes, but also staining methods. To be able to look at the brain, to stain the brain, and to see what are the elements that build the brain. And so these are drawings, 120 years old drawings. In this case from Harmonica Hal in Spain and you can see that after using the technology that was developed by Golgi pouring so to speak into pieces of brain, dead tissue, a, a particular dye, the Golgi stain, the Gorge dye. You can suddenly see these kind of elements popping up. So, some kind of elements. Now, we call them neurons, but then, they

did not call them neuron. They saw some kind of things that looked like cells in the brain. This is the first systematic study by Ramonica Hal about the, the, the different parts of the brain in terms of the elements, the anatomy, the building blocks, the units that build the system. Lucky for them, the gorgeous stain, the Golgi staining method was very, very sparse. So it didn't stain everything, because if you would stain the brain and everything would be colored, it would become completely dark. Black. Because it's so packed, it's so dense, this jungle of nerves in there. So, so packed that if everything would have been stained, you could not see individual elements. It will look dark. So about less than 1%, or 1% of the cells for some unknown reason, pick up the dye and then you'll see this beautiful structure. They got a noble prize in 1906 but they did not agree with in , with each other at all. They actually did not agree with each other on the most fundamental thing. So, Golgi thought that it cannot be that the brain, unlike other regions, are built from individual cells. This did not fit his view about this beauty of the brain. He can, he could not think that the brain like any other system is built from one cell, and another cell, and another cell individually. Harmonica Hal thought no, these aren't like any other living tissue, are built from units. So here are the units, he says. But they don't really know if they are connected physically to each other or not, at this resolution. They don't know if this element, and this elements are not really physically a continuum, or not. So they fought. It was a big fight. It was a very big fight, and we know today that Harmonica Harl was right. These units typically do not touch each other, they are separate elements, there is a gap between them. These elements, we later call them neurons. And so this is a later term, not by them.

And, but today we do a new kind of anatomy, and you should see that this, old type of anatomy, which was the foundation of understanding the circuit, at different regions in the brain, we are now doing more than anatomy, which is called the connectomics. So here is Connectomics. The idea of Connectomics is to cut very, very, very thin slices of the brain, slice after slice after slice, very, very thin, at the nanometer scale. So nanometer is 10 to the power of minus, it's a it's a thousandth of million of a meter, very, very thin slices. You detect the structure within each slice separately, and then you put the slices back, so to speak. You align them back, one on top of the other, one after the other, after the other, after the other at a very fine resolution and then you can reconstruct a piece of the brain. A very small piece of a brain in this case but the you can really, really see whether they touch each other or not touch each other. This is the electron microscope system. And eventually you can see that cell number two is making contact, synaptic contact. We'll talk about this. And which part of the brain is touching which, sorry, of the cell, touching another part of the cell. So you really start to develop a very systematic method, to really map the whole brain, in 3-D. This is the Connectomics. It's a big endeavor. We did not yet succeed to reconstruct the whole brain but we did succeed to reconstruct, pieces of brain, and really, really learn and study who are, who are the elements that build the brain, who is connected to who, and who is not connected to who. So we ge, start to get the road map at the level of cells and snyapses, the connection between the cells. This is a big, big endeavor. It is done at several central location in the world, very expensive one, to have this huge microscope, and to cut, cut, cut, cut, and reconstruct. But we are getting, for the first time ever, the full 3-D anatomy, of the whole brain tissue. The Connectomics. Let's look at it.

How does it look when you reconstruct it? And in this case I'm going to show you a piece of the cortex of a mammalian, of a mouse, that is reconstructed in the way that I showed you. This is done in MIT. So you see piece, by piece, by piece, by piece, you put them together as I explained before, you of course, artificially dye the cells because the cells in the brain are not blue or purple, but you artificially, while you reconstruct, you dye the separate cells, and suddenly you see the network. This is the network in your brain. In this case of a, of a smaller mammal but it looks very similar and you see all these wires that we talk a lot about them. We'll talk about axons and we'll talk about dendrites, and we'll talk about the connection between them. But just to see, to show you the jungle within your brain. This is what we have. And this is the foun atomical foundation, on top of which, you can see also, blood vessels going through. So you see really, a very small piece of your cortex, mammalian cortex. and that's what we need to understand. So, we are going to go into the details, but we completed understanding what is the connectomic project for now. Why is it so important, why is it so important to understand, to get the details of, of, of the brain structure? What is the prospect, prospect? What is the future of this, of this Connectomics endeavor? Where are we heading? So just to give you a few points, some points, some prospects about Connectomics. As I said before, we will, for the first time, we will have a complete full, what we call blueprint wiring diagram of a network. So if I want to understand the city, if I want to understand the, the globe I need to know where are things and who is connected to who. So this is the road map of a circuit and this is very fundamental. When I say I understand a circuit I really need to know how it is structured. So that's very fundamental, very basic. But the main thing is that because we have a particular structure, which is not random, and it has a particular

principles underlying it. We will need, we will be able eventually and that's the hope to connect how this structure subserve a particular function. How is structure of my retina in the eye subserve my capability to see, or at least to start to see? So the connection between the structure and the function. Which is actually will be, specifically highlighted, but in lecture number six is what we need to do. You have a structure. You have a function. I move my hand, and I want to understand how this particular structure that controls my hand, is operating. But, so I need to know the structure, but on top of the structure I need to know something about the activity that gives rise to behavior. So this connection between structured function is the most fundamental thing. And finally, when one get's sick, let's say with Alzheimers, or Parkinson, something about the structure, not only, but something about the structure. But also, something about the activity, both may go, go wrong. So if something with the structure goes wrong, I may become autistic, I may become schizophrenic or I may become a genius. So we want to connect the structure to the function. This will be, this will be the focus of lecture number seven.