I'm Jeremy Nathans. I'm a professor at the Johns Hopkins Medical School and an investigator of the Howard Hughes Medical Institute. This lecture is called "One Amazing Second in the Life of Your Brain," We're going to describe a very simple task, one so simple that it takes only a second to perform, and seems almost effortless, and yet, as we look at the processes that happen in our heads as we perform this task, I think we'll agree, I hope we'll agree by the end, they're most amazing. So, let's look at our simple task. I will say "Three plus two" and you say what that sum equals. I think you've all said "5" by now, it's a simple thing to do, and let's just dissect piece by piece what has happened inside your heads as you've gone from the 3+2 instructions to the answer 5. We can break it down into various parts. These would be, to first approximation, detecting sounds, decoding the meaning of the sounds, holding the numbers in your short term memory, performing the calculation, formulating your linguistic response, the word 5, and then generating a complex set of commands to the muscles that control speech. Let's take these one at a time. Consider the sound waves that have come from my mouth and have eventually arrived at your ear. Sound consists of alternating compressions and rarefactions of the air. Air is like a spring, it can be compressed and it can expand. And that arrives at your ear as a complex series of waves. These are diagrammed here. We can see a series of vibrations, this is human that we're looking at, and a series of changes in intensity over time and when they arrive at the ear, they enter through the outer ear canal and they cause this very thin membrane, it's really like the drum, head of an acoustic drum, to vibrate back and forth. That vibration is transmitted to a series of bones, there are three little bones. In the middle ear, a central cavity, and the third of the bones connects to yet a smaller drum, which is at the base of this snail shell looking object called the cochlea. Let's just look at the last of those bones just for fun in a little more detail. This one is called the stapes. It and the other two bones are the three smallest bones in the body. You can see if's just a few millimeters in size. It's sitting next to a coin here. And that base of the stapes, the flat part, is what is pressing back and forth against that inner membrane at the base of the cochlea. Now, the cochlea, as we saw, is a snail shell shaped object, it twists around and around and it's actually a hollow cavity that is twisting around and around. That cavity, shown in cross section here we see is divided actually into three chambers. There's an upper chamber, there's a middle chamber, and there's a lower chamber. All the chambers are filled with fluid. The drum head, the one that's vibrating back and forth, is connected to the upper chamber, it's at the base of the upper chamber, and as it pushes into the chamber, it pushes on the fluid, and that fluid pushes downward on these connecting dividers between the other chambers. And those are flexible and they vibrate up and down in synchrony with the vibration from that external drum head. How do you detect the sound waves? That is, those vibrations, now fluid vibrations. There's a very sensitive detector apparatus that is mounted in this central chamber, it's called the organ of Corti. It has a series of delicate sensory cells and if we look on the next slide at the organ of Corti at high power, we see a series of cells, this is cut in cross section, it's taken through a microscope, these are the cells at high magnification, they're sitting underneath this tectorial membrane, this lid, essentially, on top of the cells, and as the membrane fluctuates up and down, the lid, which is connected to the top surface of the cells, moves back and forth just a little bit, a back and forth motion, coupled to the up and down motion of the entire apparatus. That back and forth motion is the thing that is detected by the sensory cells. Here we see the V-shaped sensory apparatus of each of these hair cells. The tips of the little cilia that constitute the V-shapes touch this roof, the tectorial membrane, which lies on top of this sheet of cells. And as that membrane vibrates back and forth, it pulls these little v-shaped objects back and forth with it. Let's look at even higher power at one of these sensory cells. This is actually from a different part of the inner ear, the part that detects motion of the head, rather than sound, but the operating principles are the same, and here we see that the bundle is consisting of a series of individual cilia, these delicate rods that stick up. They can pivot at their bases, and the tip, when it's pulled back and forth causes the entire bundle to swivel back and forth. How is that swiveling motion detected by the individual cell underneath? This is a very beautiful mechanism, we have to look at even higher power to see what its origin is. If we look at the individual elements of that bundle, and here they are at extremely high magnification, this is an electron micrograph, taken with an electron microscope. It uses electrons, rather than light, to amplify the image and it can see extraordinary detail. We see that there are these very thin connectors, the so-called tip lengths that connect one rod to the one adjacent to it. And the rods, as they pivot at their bases, my two arms now are those two rods, they swivel back and forth such that the motion of one rod and the rod next to it creates a shear force. You can see that the alignment of my hands changes as they pivot back and forth, as my elbows, being the pivot points and the result is that those tip links, those little rubber bands that are connecting one rod to its neighbor are stretched as the rod tilts to one direction and they're relaxed as it tilts to the other direction. And that stretching motion, as the rods tilt in this diagram, to the right side, is connected to the opening of a channel in the membrane, the surface membrane, of these cells. So, let's just look at this in detail. At the bottom are pictures of a pair of these cilia in which they are either relaxed, in the sense that they are tilted towards the direction that relaxes that spring. In the middle, they have been tilted a little bit to the right and so they're stretching that spring, and as a result of the stretching, the channel door, the gate of the channel, is opened. That is, the spring is connected to the door. We see this at higher magnification in the upper part of this image. Here's the channel on the left, with the spring connected to the door, the spring is not being pulled. But when we pull on the spring, in the middle panel, that tends to open the door, as shown on the right panel. So, this is a way in which mechanical motion, a back and forth motion, can in one direction favor channel closure and then the cell remains inactive, or in the other direction, it favors opening of the channel and the cell becomes active. A very beautiful mechanism. And these cells are exquisitely sensitive to motion. So, for example, the tip of these cilia can move a distance about the diameter of an atom, that is about 5 or so angstroms, 5 times 10 to the -10 meters, about half a billionth of a meter, and that is sufficient to detectably open the channel of the hair cells. That's a movement that is equivalent to say a one hundred story building moving at its tip about half a meter. A very tiny motion. And yet detectably sensed by these cells. Now, in any system as complex as this, as you might imagine, things can go wrong and they do, unfortunately, for a number of people, and for those individuals who are profoundly deaf, as a result of any of a variety of defects in the inner ear, there is a beautiful bioengineering solution. It's called the cochlear implant, which for many individuals can restore substantial hearing and just as an aside, I just want to tell how this works. The cochlear implant takes advantage of the fact that different regions within the cochlea vibrate preferentially to different pitches of sound. That is, if we look along the length of the cochlea, of course, it's coiled up like a snail shell, but if we were to stretch it out, and look along the length of the cochlea, we would find that vibrations of low frequency, that is low pitch sounds, deep sounds, cause the membranes to vibrate up and down at one location, near one end of the cochlea, and high pitched sounds, high frequency sounds, cause the membrane to vibrate at the far end of the cochlea, with intermediate pitches laid out along the length of the cochlea in between. So, the cochlea, in a sense, is like a piano. The keys of a piano are laid out in space from one end of the keyboard to the other and the location of a key is an indication of the frequency of sound that will be activated when you hit that key. In the same sense, the positions along the cochlea of the vibrations of those membranes, and then of the organ of Corti, are correlated with the frequency of the sounds. So, the sound waves are divided up into their various frequencies along the length of the cochlea and the pattern that the brain is then required to see is the pattern of hair cells at different locations, which are activated by a given sound. Now, the engineers have taken advantage of that design feature, if you will, of the cochlea, and in building the cochlear implant, they have done the following. They have set it up with two separate components. There is a microphone on the outside, this is worn outside of the head, which senses the sounds and converts those sounds into a radio frequency signal which is sent to a little receiver that is implanted inside the head, within the bone, this is the surgical part, and from that receiver, comes out a bundle of wires which are threaded through the cochlea around the snail shell of the cochlea such that each wire ends at a different location within the cochlea. The wire that transmits the low frequency sounds touches the part of the cochlea that normally responds to low frequency sounds. The ones that transmit the medium frequency are in the central part and the high frequency wire touches the high frequency part of the cochlea. So, in this way, the stimulation of the cochlear cells is very much in line with the natural analysis of sound frequencies that would be performed in the normally functioning ear. And now at this point, about 200,000 people world wide have a cochlear implant. And I'll just show you what that looks like from the outside. Here's a young lady wearing one of these implants. This is the part that has the microphone and the radiofrequency transmitter. Of course, you can't see the internal part here. Now, back to our task. So, how is the information transmitted from the cochlea inward to the brain? Nerve cells, or neurons, transmit information by a mixture of electrical signaling and chemical signaling. For long-range transmission, along wires that we call axons, the signaling is basically an electrical wave that propagates down the axon. We won't go into the details of that but we will mention something about how signals are transmitted from one neuron to another. Let's look at the transmission of information at synapses. This is a synapse shown in cartoon form. It's the connection between two neurons. There's a presynaptic side, that is the side for the sending cell, and there's a post-synaptic side, the side of the receiving cell. At the synapse, neurotransmitter molecules are released from the sending cell onto the receiving cell and they are detected by the receiving cell at specific receptor sites. These are protein molecules in the membrane of the receiving cell that bind the neurotransmitter with high specificity and high affinity. Now, if we look in a transmission electron micrograph at the appearance of a typical synapse, we're impressed with how amazingly small the space is between the presynaptic and postsynaptic cells. So, this pair of lines, this pair of black lines, indicates the adjacent membranes of those two cells. You can see the space in between is extremely tiny, it's on the order of tens of billionths of a meter in size. And so synaptic transmission is, partly because of this small size, extremely rapid. It takes a very short time for that neurotransmitter to go from one cell to the other. About a millisecond or less. But synapses are more amazing than just this still image would indicate. And one of the most remarkable things about synapses is their ability to change over time. This is what we call synaptic plasticity. And that plasticity appears to be a central mechanism and most likely the central mechanism for learning and memory. This was first worked out using this beautiful little organism, a sea slug, about 40 years ago. Sea slugs, Aplysia is the official name, have a very simple nervous system. They don't have very many neurons. But they can learn things, they can remember things, and they can forget things. And the activity of those neurons, the electrical activity of those neurons, can be monitored during those processes, while the animal is learning, while it's remembering and while it's forgetting. And what one sees when that analysis is performed is that the strength of the synapse changes and it changes in a way that underlies those various learning and memory processes. There are two particular kinds of changes that I want to discuss and these appear to be universal. They're true of sea slugs, they're true of us. One is a change in the strength of pre-existing synapses. So, here we see an example of some experimental data in which a series of stimuli, that is pre-synaptic cell activity which is sensed by the post-synaptic cell, is diagrammed in the upper panel, and we see a series of 7 individual stimuli that have arrived at the post-synaptic cell. And if there was no plasticity, we would expect the response of the post-synaptic cell to be identical to each of these stimuli. But, it is not. You can see on the bottom, as we monitor the post-synaptic response, that with each successive stimulus, the response is getting stronger and stronger. That is, the cell has somehow remembered what has come before. A very simple form of plasticity. But in a number of cases, a number of neurons, this memory can last for an extended period of time, for hours or days. There's a second phenomenon which is of relevance here, and that is the change in the number and location of synapses. Now, this is a longer-term phenomenon. We see it here in this pair of photographs of the same neuronal process, it's in the brain of a mouse. In panel A, we see an image of this process at one time, and in panel B, it's a couple of months later. And we can see that some of these little projections, these are the places where the synapses are located, have newly appeared, for example, this arrow down here indicates a couple of new ones, and others have disappeared over time, you can see the open arrows on the panel A, are at places where in panel B, the synapses have been withdrawn. So, this is a kind of plasticity which almost certainly mediates memories on a timescale of weeks or months or even years and as I mentioned, this is a universal phenomenon. It's seen throughout the animal kingdom. Now, we humans generally believe that our brains being larger than those of most other animals have powers that other animals do not have. Certainly that's true in various realms, but I'd like to just cast a little bit of doubt on that assumption in the realm of memory with a video of a chimpanzee performing a task that I think you will agree is most remarkable. This chimp, we're going to see this in a second, has learned two rather difficult things. First, she has learned to distinguish the numbers 1, 2, 3, 4, 5, 6, 7, 8, 9. And second, she's learned to play a little video game which involves remembering the locations of those numbers when they appear simultaneously on a computer screen and then to point to the locations where the numbers were after they have disappeared. The part that is most remarkable about this little video game is that the chimp can do this task even if the numbers have appeared on the screen for a very brief time, a fraction of a second. And so let's just look at this. Initially, we'll see it in a freeze frame. Here she is, looking at the numbers on the computer screen. You can see that they're all there. And she is going to point to them and there she is, pointing to the correct locations in the correct order, and getting her reward. Now, let's look at this in slow motion. So, she has remembered where each of the numbers is and she's pointing to them in order, 1, 2, 3, 4, 5, 6, 7, 8, 9. And if she gets it right, which she has, she gets a little snack as a reward. We'll now look at this in real time. Have you been able to memorize the locations of those numbers? It's not so easy. And in fact, this chimp performs better at this task than almost any human. And if you think about that, that's a most remarkable accomplishment because not only has she learned the task, learned the numbers, learned to play the video game, but she's learned it without any linguistic communication, without any explanation of what she's supposed to do, except that if she gets it right, she gets a snack, and if she gets it wrong, she doesn't get the snack. And I would invite you just to see how difficult that sort of process is to try with one of your friends teaching some sort of complex task without using language at all, just use a reward or no reward and see how long it takes to learn that task. Now, at this point, let's return to our task, we're about halfway through. The numbers 2 plus 3 have entered our heads, they're on their way to regions of the brain that are involved in language processing and here, the details get a little murky. We don't know nearly so much about how language is processed as we do about how the basics of sounds are registered. But we know something about where the processing takes place. And we've learned about that using techniques like the one shown here, magnetic resonance imaging. This requires a very big magnet. The subject lies down on the bed, they put their head in the plastic head-holder, they're pushed in the magnet, and the kind of image we see is shown here, for example. So, this is a cross-sectional image of the human head, you can see the extraordinary detail that can be obtained with magnetic resonance imaging. As you might guess, this has revolutionized neurosurgery, nowadays, the neurosurgeon very rarely is left wondering what he or she will see after she enters the brain. At this point, I want to introduce a variation on magnetic resonance imaging technology. It's called functional magnetic resonance imaging and it's a way of monitoring blood flow to different regions of the brain. In the same way that muscles get an increase in blood flow if they work hard, for example, if you're running, your legs will experience an increase in blood flow, so those regions of the brain which are working harder get more blood flow. And that can be monitored in a living person who's doing a task. So, here, for example, we see a series of different regions of the brain that are involved in language. For example, if you're hearing words, if you're seeing words, if you're speaking words, or if you're thinking about words, each of those tasks ends up calling on different regions of the brain to perform it. We can see that by looking at the amount of blood that is flowing to one region or another in the brain. And that's shown by the colors here. The bright colors show where most increases in blood flow have taken place. Now, that tells us something about where language processing events occur. It doesn't really tell us what is happening at the level of individual neurons and I would say at this point, that's still not well understood. But, by following the locations of events, we can learn some things, and let's just follow that, especially in respect to two important regions of the brain, these are called Broca's area and Wernicke's area. Wernicke's area is a region towards the back, it's involved in hearing words and in understanding the meanings of those words, and in formulating the meanings of words as part of our speech. Someone with damage to Wernicke's area speaks in what appears to be fluent sentences but the words don't come out in the right order, or their meaning is inappropriate. A person with damage to Broca's area, by contrast, has good understanding of language, but their ability to express themselves is compromised. They have difficulty speaking, they have difficulty coming up with the word, and articulating it. Now, the location of Broca's area, this output region for language, is not haphazard. It turns out to be right next to the principle motor area of the brain, the part that controls muscle movements and if we look at that region and this is shown schematically on this brain up here, it's a long strip of the cerebral cortex, which controls at different points along its length, different parts of the body, different motor systems, we see that the region of Broca's area, which is just in front here, and is immediately adjacent to that part of the motor area that controls the mouth, the lips, the tongue and the vocal chords, is perfectly situated to send its message downstream to that motor region. Just as an aside, the map of different motor groups onto the motor area in the cerebral cortex has an interesting history. This mapping was determined by a surgeon named Penfield about 60 years ago and it was through a series of surgical operations in which he was able to stimulate very locally different regions of the brain that he could map out which regions controlled which muscle groups and the map that he obtained is shown in cartoon form at the bottom here. You can see it's a very much distorted map of the human body. The hand, for example, is very large, the mouth and the tongue are large, but other parts are quite small. And this makes sense, if you think about it, because there are certain parts of the body, for example, the fingers, the lips, the tongue, which have very fine motor control. They require many neurons in the brain to effect that fine control and therefore, they map to large regions of the cortex. Other muscle groups, for example, the muscles of the legs, the feet, and so on, are much less finely controlled, they are far fewer neurons required to control those muscle groups, and therefore, a much smaller territory on the brain is used, hence this distorted map. If it weren't for this enlargement of the region controlling the hands and the fingers, we wouldn't be able to type, play a violin, do surgery and so on. All of those fine motor tasks that we can do with our fingers. Now what happens to the signal from the motor cortex? Well, a complex program, for speech in the present case, the act of speaking the word 5 that you did, is put together and that information is sent to the appropriate motor groups in the vocal cords, the lips, the tongue and so on. It's transmitted along axons from the motor neurons and is transmitted to the muscles in very much the same way that information is transmitted from one neuron to another. That is, there's a synapse, in this case from a nerve onto a muscle fiber and at that synapse, a neurotransmitter is released, it's acetylcholine in this case, and it binds its receptor, again very much like the signaling between nerve cells, and the acetylcholine receptor, it turns out, is a membrane embedded ion channel. It is normally closed, but if acetylcholine binds to it, it changes its shape and it opens up, allowing the sodium ions outside of the cell to flow into the cell. And it's that flow of ions, positively charged ions, from out to in which signals the muscle that it should contract. How does that signal cause muscle contraction? It's a series of steps of which that's just the first. The next is the opening of a second set of channels, which admit calcium ions. That second set of channels is sensitive to the voltage change that was induced by the first set of channels. The calcium ions admitted by the second set act on a series of calcium binding proteins, which regulate the contractile apparatus, and then the muscle twitches. And so, we've come to the end of the task. So, we've gone from hearing the sounds, processing it internally, where, admittedly we don't know much about the mechanistic details, but we know a little bit about where the processes happen, we've formulated a linguistic response, we've activated the muscles for speech, and out has come the word '5'. So, let's just step back and look at the big picture. The human brain, taken as a whole, and ask ourselves a few very simple questions. First, how complicated is the brain? How complex is it as a machine? This is a question an engineer might ask. From the outside, perhaps, it doesn't look that complex. But as soon as we take a look inside, and here is, for example, a slice through the brain, we're struck by its enormous complexity. So, this is an image from yet another kind of magnetic resonance imaging technology called diffusion tensor imaging which shows the long-range connections between different brain regions. We're looking at just a single slice, and we're looking at connections, each of which represents thousands of individual axons and I think you can appreciate that the wiring is very complicated. In fact, if we look at just some basic numbers regarding the complexity of the brain, we can't help but be impressed as an engineer might perhaps, in looking at how sophisticated this machine is. So, let's just ask, for example, how many neurons there are in a brain? Well, in a human brain, there are about 100 billion neurons. The average neuron, in the cerebral cortex, for example, has about 10,000 connections to other neurons. So, that is two hundred trillion connections total in the cerebral cortex. If we ask, for example, what the total length is, of all the axons, the long distance wires that connect one cell to another, one brain region to another, the answer is for a single human brain, it's about one and half times ten to the five kilometers. That is, about 5 times the circumference of the earth. That's a lot of wires to pack into one brain. But that in fact doesn't tell the whole story. These numbers, impressive as they are. If we look at even a single neuron, we see that it is enormously complex. So, here is one neuron that has been made fluorescent with a special dye that's been injected into it and we see this enormously complex branching pattern with hundreds and hundreds of branches. This sort of pattern is stereotypical for a given kind of neuron. Other neurons will have different branching patterns. And furthermore, if we look at the packing of neurons, it's extraordinarily precise. So, there's very little wasted space. Here's a picture from a mouse brain, a genetically engineered mouse, I should say, in which different neurons have been labeled with different colors. You can see they're very tightly packed. Their branches, which are coming out to the right side, are also very tightly packed. They're packed in with other branches that are not fluorescently labeled here. There's virtually no wasted space. If we were to compare the brain to devices that we humans have made, and this might be the sort of comparison an engineer would like to make, we can ask how does the complexity of the brain compare to the complexity of our manmade objects. So, let's take the most complex thing that we humans have made: a computer chip. This is a typical computer chip. There are perhaps a billion different elements that have been manufactured on its surface, it's very tiny, it's smaller than a coin, and if we look at high power, this is now an electron micrograph of the surface of the chip, we see that the elements, the individual elements on the chip, are about 50 billionths of a meter in diameter. So, that's about the size of a synapse. So, we humans have done pretty well, we've got the miniaturization of our devices down to roughly the size scale of the brain's devices. But I want to remind you that computer chips can only be manufactured in two dimensions. They're on flat surfaces. Whereas, the brain packs all of the machinery into a 3-dimensional space and very efficiently at that. So, the brain can pack a lot more circuitry into a little volume than a computer can by many, many orders of magnitude. An engineer might also ask a question about how the brain is built, compared, for example, to the building of our man-made devices. Now, when we build something, we typically design it and draw out a blueprint, so that we can have an image of the thing we want to build. Here's a piece of metal that's been machined, we can see that this is certainly a logical way to encode the information for the object that we're going to build, encode it essentially as a picture, with commentary written on it, and if we have something that's very complex, like a brain, we might imagine that having blueprints, wiring diagrams, essentially, would be very helpful but in fact nature does not use images to encode the information for building anything. The information is encoded, it turns out, in a long, one-dimensional string of letters. It's along the DNA, our genetic material. So, this is much more like text, where, here, in this case, the alphabet of DNA has four letters, four chemical groups, which we abbreviate A, C, G and T. And it's the order of those groups along the DNA chain which is the information. How information that is encoded in this one-dimensional form, along a strand of DNA, is used to produce objects as complex as synapses or whole neurons, or whole brains, is very much an area of active research. There are a number of advances that have been made, but I think it's fair to say that most of the story still lies ahead of us. And I therefore want to close with three open questions, questions that we neuroscientists are intrigued by, questions that are still largely unanswered, but, in principle, are answerable. And let's look at those one at a time. Question one: how is brain structure and plasticity encoded in the DNA? It is encoded in the DNA, in the sense that each organism, whether it's a person, or a sea slug, has a particular kind of nervous system, and that nervous system is largely a product of their genetic inheritance. It is also a product of their environment in the sense that changes to the nervous system change the nervous system itself, and that, of course, brings us to the second question, which is, what those changes are? What are the cellular and molecular representations of memories and thoughts? What happens inside your head when you hear a new phone number, or a new name, or see a new face. These are still largely unknown. And finally, how do genetics and experience interact to make each brain structurally and functionally unique? And this really gets at the heart of our own sense of ourselves as unique individuals and I think the answer to each of these three questions, and especially this last question, is going to shape our view of ourselves, both as individuals and as a species. Thank you.
