WEBVTT 00:00:01.000 --> 00:00:05.000 Good morning. All right. So, it was a lot of fun to tell you 00:00:05.000 --> 00:00:10.000 last time about the work that's going on here at MIT in genomics. 00:00:10.000 --> 00:00:16.000 It's, it's just fun. I mean it's fun to share what's going on and 00:00:16.000 --> 00:00:21.000 it's fun that you guys can understand what's going on already 00:00:21.000 --> 00:00:27.000 with simply one semester of biology, which I think is really cool. 00:00:27.000 --> 00:00:30.000 What I would like to do today is talk about another exciting area, 00:00:30.000 --> 00:00:34.000 one I don't work in, but one that I know many people are interested in. 00:00:34.000 --> 00:00:38.000 And I would like to lay the foundations for neurobiology. 00:00:38.000 --> 00:00:42.000 Neurobiology is an incredibly interesting area. 00:00:42.000 --> 00:00:45.000 I confess it's the subject that got me interested in biology in the 00:00:45.000 --> 00:00:49.000 first place, even though I don't work on it itself. 00:00:49.000 --> 00:00:53.000 And, I mean, who can't be interested in the brain. 00:00:53.000 --> 00:00:57.000 But if you want to take on the brain, you really have to understand 00:00:57.000 --> 00:01:01.000 its working components in some retail detail. 00:01:01.000 --> 00:01:06.000 And so what we're going to focus on in this course for the next three 00:01:06.000 --> 00:01:11.000 lectures is the specific molecular mechanism by which nerve cells are 00:01:11.000 --> 00:01:16.000 able to transmit signals down their length, how they're able to transmit 00:01:16.000 --> 00:01:21.000 signals from one cell to the next, and then how they're able to change 00:01:21.000 --> 00:01:27.000 their properties over time, that is learn and remember. 00:01:27.000 --> 00:01:34.000 So, the fundamental unit of neurological processing is a nerve 00:01:34.000 --> 00:01:42.000 cell which goes by the name a neuron. You have approximately ten to the 00:01:42.000 --> 00:01:51.000 twelfth neurons. 00:01:51.000 --> 00:01:53.000 How many bases are in the human genome? 00:01:53.000 --> 00:02:00.000 About three times ten to the ninth. 00:02:00.000 --> 00:02:04.000 So, you have a lot more nerve cells than bases in the genome. 00:02:04.000 --> 00:02:08.000 So, it's unlikely that all of the wiring diagram is completely 00:02:08.000 --> 00:02:13.000 specified in the sequence of the genome simply because we have a lot 00:02:13.000 --> 00:02:17.000 of them here. That's just a minor side point. And what does a typical 00:02:17.000 --> 00:02:22.000 neuron look like? So, neurons and connections. 00:02:22.000 --> 00:02:30.000 So, a neuron. Well, 00:02:30.000 --> 00:02:38.000 a typical neuron, your ten to the twelfth neurons makes contacts with 00:02:38.000 --> 00:02:47.000 other neurons. It might receive contacts. 00:02:47.000 --> 00:02:56.000 It might get contacts from, oh, ten to the third other neurons. 00:02:56.000 --> 00:03:05.000 And sends signals to ten to the third other neurons. 00:03:05.000 --> 00:03:09.000 So, that's a lot of connections if you figure ten to the third times 00:03:09.000 --> 00:03:13.000 ten to the twelfth. Ten to the fifteenth connections in 00:03:13.000 --> 00:03:17.000 this circuit diagram. Here's sort of a, kind of a picture 00:03:17.000 --> 00:03:24.000 of a nerve cell -- 00:03:24.000 --> 00:03:34.000 -- making connections to another nerve cell. Making connections to 00:03:34.000 --> 00:03:44.000 maybe a muscle. 00:03:44.000 --> 00:03:48.000 Oh, and what activates this nerve cell? Well, maybe in your eye we 00:03:48.000 --> 00:03:54.000 have a photoreceptor cell. 00:03:54.000 --> 00:03:58.000 And that photo receptor cell will synapse upon a first neuron which 00:03:58.000 --> 00:04:02.000 will synapse on a second neuron which will synapse on your muscle. 00:04:02.000 --> 00:04:06.000 So maybe you'll see something, send a signal, send a signal, 00:04:06.000 --> 00:04:10.000 activate your muscle to pick it up. Needless to say, it's pretty much 00:04:10.000 --> 00:04:14.000 more complicated than that because it will take more than those two 00:04:14.000 --> 00:04:18.000 neurons to figure out this is a piece of chalk and how to coordinate 00:04:18.000 --> 00:04:22.000 that whole motion and all, but you get the idea. So, let's 00:04:22.000 --> 00:04:26.000 just take a look at some of these pieces here. What kinds of 00:04:26.000 --> 00:04:31.000 receptors might we have? We might have receptor neurons that 00:04:31.000 --> 00:04:43.000 receive light -- 00:04:43.000 --> 00:04:49.000 -- called photoreceptors. 00:04:49.000 --> 00:04:54.000 And these photoreceptors in your eye are an extraordinary piece of 00:04:54.000 --> 00:05:00.000 engineering. Do you know how sensitive a photoreceptor can be? 00:05:00.000 --> 00:05:05.000 What's the absolutely minimum possible detectable unit of light? 00:05:05.000 --> 00:05:11.000 One photon. It turns out your photoreceptors can, 00:05:11.000 --> 00:05:16.000 under appropriate circumstances, detect a single photon. Not in the 00:05:16.000 --> 00:05:22.000 bright right but in dark adapted conditions, you actually have on 00:05:22.000 --> 00:05:28.000 photon sensitivity. Very impressive. 00:05:28.000 --> 00:05:32.000 Under appropriate conditions, mind you. Sound receptors. You've 00:05:32.000 --> 00:05:36.000 got sound receptors in your ear and they are beautiful. 00:05:36.000 --> 00:05:40.000 We're not going to talk about them at any length, 00:05:40.000 --> 00:05:44.000 but there's little flappy, these little spiky things going 00:05:44.000 --> 00:05:49.000 along in your ear and they can translate vibrational energy coming 00:05:49.000 --> 00:05:53.000 from your ear, hurting your eardrum, 00:05:53.000 --> 00:05:57.000 being translated into a vibration into the fluid in your ear into a 00:05:57.000 --> 00:06:01.000 physical motion of these little receptors there into an electrical 00:06:01.000 --> 00:06:06.000 motion, into an electrical signal that goes into your ear. 00:06:06.000 --> 00:06:09.000 So, all of that, all of that's pretty impressive 00:06:09.000 --> 00:06:12.000 stuff. We're not going to talk about the details of it, 00:06:12.000 --> 00:06:15.000 but I invite some of you who want to learn more about this, 00:06:15.000 --> 00:06:18.000 particularly MIT students I think find receptors really quite 00:06:18.000 --> 00:06:21.000 remarkable kinds of devices. We're going to focus, though, 00:06:21.000 --> 00:06:24.000 more on this intermediate step here of a generic neuron. 00:06:24.000 --> 00:06:28.000 So, here's my generic neuron. And the first thing that has to be 00:06:28.000 --> 00:06:32.000 said is there are no generic neurons. Neurons are all very specific, 00:06:32.000 --> 00:06:37.000 but I'm just going to use a generic neuron for the moment. 00:06:37.000 --> 00:06:41.000 And the important features of a generic neuron here, 00:06:41.000 --> 00:06:45.000 it has these funny little processes on its cell body that are called 00:06:45.000 --> 00:06:50.000 dendrites. That's where it's going to receive signals. 00:06:50.000 --> 00:06:54.000 Processes are the name for things that stick out. 00:06:54.000 --> 00:06:59.000 So, these processes are called dendrites. 00:06:59.000 --> 00:07:05.000 Here's our nucleus of our cell. Here's our cell body. We will 00:07:05.000 --> 00:07:11.000 label this your cell body with a nucleus in it. 00:07:11.000 --> 00:07:17.000 Then we have this very long process here called an axon. 00:07:17.000 --> 00:07:23.000 The axon is the wire here. This region here is called the axon 00:07:23.000 --> 00:07:29.000 hillock and it looks like a little hill. That's what hillock means, 00:07:29.000 --> 00:07:35.000 it's a little sort of hill-like region here. 00:07:35.000 --> 00:07:39.000 And it's where all the electrical signals from the cell body are 00:07:39.000 --> 00:07:43.000 integrated and a, quote, decision is made about 00:07:43.000 --> 00:07:47.000 whether to fire. And the neuron will then fire a 00:07:47.000 --> 00:07:51.000 signal down the length of its axon and then it will get to the end here 00:07:51.000 --> 00:07:55.000 where we have these terminal processes that'll be synapsing on 00:07:55.000 --> 00:08:00.000 other cells here. These are called nerve terminals. 00:08:00.000 --> 00:08:04.000 And each will make connections either with other dendrites or maybe 00:08:04.000 --> 00:08:08.000 with a muscle, although you wouldn't see both of 00:08:08.000 --> 00:08:12.000 those occurring, so I'm just drawing this for 00:08:12.000 --> 00:08:17.000 illustration purposes here. And it will send a signal. And 00:08:17.000 --> 00:08:21.000 these points of contact are called synapses. So, 00:08:21.000 --> 00:08:25.000 nerve or muscle. OK? So, that's your general 00:08:25.000 --> 00:08:30.000 picture there. You have a synapse which transmits. 00:08:30.000 --> 00:08:35.000 This is an electrical signal. This is typically a chemical signal. 00:08:35.000 --> 00:08:40.000 And, as you might imagine, the pre-synaptic cell is this guy, 00:08:40.000 --> 00:08:46.000 the post-synaptic cell is that guy. So, I'll say pre-synaptic and 00:08:46.000 --> 00:08:51.000 post-synaptic. And what neurobiologists want to do 00:08:51.000 --> 00:08:57.000 is understand how does this all work? How does the initial signal impinge 00:08:57.000 --> 00:09:01.000 upon the dendrite from a synapse? How does that signal get collected 00:09:01.000 --> 00:09:04.000 and integrated into a decision about whether to fire an action potential 00:09:04.000 --> 00:09:08.000 that runs along the nerve? And then how does that get 00:09:08.000 --> 00:09:11.000 transmitted from an electrical signal back into a chemical signal 00:09:11.000 --> 00:09:14.000 which then restarts an electrical signal in the next cell, 00:09:14.000 --> 00:09:18.000 etc., etc., etc? Those are some of the kinds of questions we want to 00:09:18.000 --> 00:09:21.000 ask. Now, I said generic neuron. Of course there's really nothing 00:09:21.000 --> 00:09:24.000 generic about it. Some neurons are very tiny. 00:09:24.000 --> 00:09:28.000 Some neurons are very big. What's the typical size of an ordinary 00:09:28.000 --> 00:09:32.000 eukaryotic cell in a liver cell? Ballpark. Ten microns. 00:09:32.000 --> 00:09:37.000 So, a typical eukaryotic cell might be -- 00:09:37.000 --> 00:09:49.000 -- and ten microns. 00:09:49.000 --> 00:09:56.000 But a neuron can be anywhere from that size, ten microns, 00:09:56.000 --> 00:10:02.000 all the way up to three meters. Where's the longest neuron known? 00:10:02.000 --> 00:10:06.000 Squid giant axon. That's possible, actually. I'm not sure how big 00:10:06.000 --> 00:10:11.000 squid, I mean there are these giant squids and they may qualify. 00:10:11.000 --> 00:10:15.000 The longest one that I know of is in a similar sort of setting. 00:10:15.000 --> 00:10:19.000 It's in the giraffe. It's a motor neuron in the neck of the giraffe 00:10:19.000 --> 00:10:24.000 which runs three meters, a single cell. But these monstrous 00:10:24.000 --> 00:10:28.000 squids that, at least in stories, glom onto boats might actually get 00:10:28.000 --> 00:10:33.000 up there. Will somebody check the squid, 00:10:33.000 --> 00:10:37.000 the largest squid on record here? I might need to revise that. But 00:10:37.000 --> 00:10:41.000 the largest one I know about definitively is the giraffe that has 00:10:41.000 --> 00:10:45.000 single neurons three meters long. Ten foot long single cells. So, 00:10:45.000 --> 00:10:49.000 it's really very impressive what a cell can do there. 00:10:49.000 --> 00:10:53.000 So, I'll put down the giraffe but we'll check out on the squid there. 00:10:53.000 --> 00:10:57.000 Giraffe neck. OK. So, what are the kinds of questions that 00:10:57.000 --> 00:11:02.000 we might want to ask? Well, the kinds of questions we 00:11:02.000 --> 00:11:07.000 might want to ask about this process, and I'm not going to be able to 00:11:07.000 --> 00:11:12.000 answer all of them but I'll get them up here. So, how do receptors 00:11:12.000 --> 00:11:19.000 transduce signals -- 00:11:19.000 --> 00:11:26.000 -- from the outside world? 00:11:26.000 --> 00:11:35.000 Light, sounds, touch, etc. 00:11:35.000 --> 00:11:40.000 That's a good question. People know a lot about it. 00:11:40.000 --> 00:11:45.000 How do electrical signals propagate along the neuron? 00:11:45.000 --> 00:11:52.000 Along an axon? 00:11:52.000 --> 00:11:55.000 People know a lot about that one, and that's what we're going to 00:11:55.000 --> 00:12:02.000 discuss today. 00:12:02.000 --> 00:12:05.000 How do signals transmit across a synapse? 00:12:05.000 --> 00:12:12.000 We'll talk about that, 00:12:12.000 --> 00:12:17.000 some today and some next time. And how do they transmit them to 00:12:17.000 --> 00:12:22.000 effector cells? So how do signals transmit 00:12:22.000 --> 00:12:28.000 specifically to effector cells like a muscle? 00:12:28.000 --> 00:12:36.000 We'll talk about that. 00:12:36.000 --> 00:12:44.000 Then how does the pattern of connections -- 00:12:44.000 --> 00:12:50.000 -- give rise to a computation? 00:12:50.000 --> 00:12:58.000 That's pretty tricky. 00:12:58.000 --> 00:13:03.000 We'll talk just a teeny little bit about the simplest kind of 00:13:03.000 --> 00:13:08.000 computation, but the complex computations of recognizing that 00:13:08.000 --> 00:13:13.000 that's somebody's Volkswagen or that that's your grandmother or something 00:13:13.000 --> 00:13:18.000 are still beyond us today. But we know things in between that. 00:13:18.000 --> 00:13:23.000 How does this pattern of connections arise during development? 00:13:23.000 --> 00:13:28.000 That's a fascinating question. And a lot is known about it, but 00:13:28.000 --> 00:13:33.000 we're not going to talk about it in this course. 00:13:33.000 --> 00:13:40.000 How does this pattern of connections get modified by experience? 00:13:40.000 --> 00:13:47.000 That's something that we'll mention briefly on Friday that a colleague 00:13:47.000 --> 00:13:54.000 of mine who's very knowledgeable about this is going to give. 00:13:54.000 --> 00:14:01.000 And that's learning and memory. And then how does this all give 00:14:01.000 --> 00:14:12.000 rise to consciousness? 00:14:12.000 --> 00:14:16.000 And we haven't got the first clue. We have no idea. It's fascinating. 00:14:16.000 --> 00:14:20.000 I digress for a second. A famous biologist, J.B. 00:14:20.000 --> 00:14:24.000 . Haldane in the mid-century, middle of the 20th century wrote a 00:14:24.000 --> 00:14:28.000 final exam to be given in the year 2000 or so. And on the final exam 00:14:28.000 --> 00:14:31.000 he had about 20 odd questions. And if you go through the exam 00:14:31.000 --> 00:14:35.000 virtually all of those questions could indeed be answered by a 00:14:35.000 --> 00:14:39.000 student in the year 2000, except for the question that says 00:14:39.000 --> 00:14:43.000 consciousness arises on embryonic day 18, example. 00:14:43.000 --> 00:14:46.000 And we have no progress toward that particular question. 00:14:46.000 --> 00:14:50.000 That was one that he completely was way off in terms of being able to 00:14:50.000 --> 00:14:54.000 predict that we'd make any progress on. Maybe he meant it as a joke. 00:14:54.000 --> 00:14:58.000 Anyway. So, let's now dive into the specifics. 00:14:58.000 --> 00:15:04.000 So, electrical signals in axons. Here is an axon. We're going to 00:15:04.000 --> 00:15:10.000 give a very close up view. Here's the lipid bilayer. I'm just 00:15:10.000 --> 00:15:16.000 going to take a cross-sectional view of my axon here. 00:15:16.000 --> 00:15:22.000 That's the lipid bilayer. It turns out if I stick an 00:15:22.000 --> 00:15:28.000 electrode into an axon and I measure the voltage gradient from the 00:15:28.000 --> 00:15:34.000 outside of the cell to the inside of the cell, what I'm going to find is 00:15:34.000 --> 00:15:40.000 that the inside of the cell is negative compared to the 00:15:40.000 --> 00:15:45.000 outside of the cell. There is an electrical potential 00:15:45.000 --> 00:15:50.000 across the plasma membrane of this axon. This plasma membrane you 00:15:50.000 --> 00:15:55.000 remember, you know, you all remember about this. 00:15:55.000 --> 00:16:00.000 This is, what, three nanometers wide. There's an electrical 00:16:00.000 --> 00:16:05.000 membrane, electrical potential across this equal to about 00:16:05.000 --> 00:16:14.000 minus 70 millivolts. 00:16:14.000 --> 00:16:17.000 Now, come on, minus 70 millivolts is pretty trivial, 00:16:17.000 --> 00:16:21.000 right? You go to the store, you buy a battery, what has it, 00:16:21.000 --> 00:16:24.000 what's it got like one and a half volts or something? 00:16:24.000 --> 00:16:28.000 It's minus 70 millivolts like who cares, right? Except it's minus 70 00:16:28.000 --> 00:16:34.000 millivolts across three nanometers. What's the electrical field of minus 00:16:34.000 --> 00:16:44.000 70 millivolts across the incredibly tiny distance of three nanometers? 00:16:44.000 --> 00:16:53.000 Well, the electrical field strength minus 70 millivolts over three 00:16:53.000 --> 00:17:03.000 nanometers is about 200, 00 volts per centimeter. 00:17:03.000 --> 00:17:08.000 That's a very impressive number, 200,000 volts per centimeter. 00:17:08.000 --> 00:17:13.000 Suppose I could arrange to change the electrical potential of a cell 00:17:13.000 --> 00:17:18.000 from minus 70 millivolts inside to, I don't know, minus 70 millivolts 00:17:18.000 --> 00:17:24.000 outside. That would be a swing of 400,000 volts per centimeter. 00:17:24.000 --> 00:17:29.000 Do you think that a protein which had an alpha helix that had a dipole 00:17:29.000 --> 00:17:35.000 moment on it could feel a change of 400,000 volts per centimeter? 00:17:35.000 --> 00:17:39.000 You bet. Some alpha helix that had some dipole moment on it would swing 00:17:39.000 --> 00:17:44.000 wildly in the presence of a change of 400,000 volts per centimeter. 00:17:44.000 --> 00:17:48.000 That's the key to how things work down there is this tiny little minus 00:17:48.000 --> 00:17:53.000 70 millivolts. It's a huge potential gradient. 00:17:53.000 --> 00:17:57.000 And if we can change that we can swing the shapes of proteins 00:17:57.000 --> 00:18:02.000 quite dramatically. OK? That's the principle. 00:18:02.000 --> 00:18:08.000 Now, it turns out that if you take this electrode and use it to change 00:18:08.000 --> 00:18:14.000 the electrical gradient, what you will get is the following 00:18:14.000 --> 00:18:19.000 bizarre and fascinating behavior. So, take my axon here, I use this, 00:18:19.000 --> 00:18:25.000 and what I do is I start off, here's zero, at minus 70, 00:18:25.000 --> 00:18:31.000 minus 70, this is the electrical potential. 00:18:31.000 --> 00:18:41.000 If I use the electrode to change this to about minus 50 or so then 00:18:41.000 --> 00:18:51.000 all by itself, with no further input on our part, 00:18:51.000 --> 00:19:01.000 the cell wildly shoots up to plus 50 before rapidly coming back down and 00:19:01.000 --> 00:19:09.000 reestablishing itself at minus 70. So, this depolarization slightly 00:19:09.000 --> 00:19:15.000 shifting it away from being as polar as it is, it has a polarity of minus 00:19:15.000 --> 00:19:21.000 70, if we depolarize it, make it less polar, make it less 00:19:21.000 --> 00:19:28.000 negative, all by itself the cell executes something called an action 00:19:28.000 --> 00:19:34.000 potential. This action potential involves rapidly changing to being 00:19:34.000 --> 00:19:41.000 positive inside the cell instead of negative and then restoring itself. 00:19:41.000 --> 00:19:45.000 And, as you would imagine, this massive change in the field has 00:19:45.000 --> 00:19:50.000 a huge effect on proteins in the membrane. This is called 00:19:50.000 --> 00:19:54.000 depolarization phase. Not shockingly this is the 00:19:54.000 --> 00:19:59.000 repolarization that occurs there afterwards. So, 00:19:59.000 --> 00:20:04.000 it goes from minus 70 millivolts up to about plus 50 millivolts there. 00:20:04.000 --> 00:20:09.000 All right. How does this happen? That's my job to explain right now. 00:20:09.000 --> 00:20:14.000 Well, the way this happens, what kind of a beautiful piece of 00:20:14.000 --> 00:20:19.000 engineering explains this? Well, the first thing you need to 00:20:19.000 --> 00:20:24.000 know is that there are some concentration gradients set up in 00:20:24.000 --> 00:20:29.000 the cell. So, the concentration gradients in the 00:20:29.000 --> 00:20:35.000 cell are as follows. There are certain ions, 00:20:35.000 --> 00:20:42.000 sodium. Sodium happens to be low inside the cell and high outside the 00:20:42.000 --> 00:20:49.000 cell. The concentration of sodium inside the cell is about 12 00:20:49.000 --> 00:20:56.000 millimolar. Whereas, outside the cell is about 145 00:20:56.000 --> 00:21:04.000 millimolar. By contrast, potassium ions are high 00:21:04.000 --> 00:21:12.000 inside the cell, 139 millimolar. Whereas, 00:21:12.000 --> 00:21:20.000 only four millimolar on the outside of the cell. Calcium ions also have 00:21:20.000 --> 00:21:28.000 a gradient across the cell. They are virtually rare. 00:21:28.000 --> 00:21:33.000 0.1 micro, not milli, micromolar inside the cell and 2. 00:21:33.000 --> 00:21:38.000 millimolar outside the cell. So there are very big differences in 00:21:38.000 --> 00:21:43.000 the concentrations. Let me try to write these 00:21:43.000 --> 00:21:48.000 concentration gradients. If this is the outside and this is 00:21:48.000 --> 00:21:53.000 the inside, sodium has a concentration gradient higher on the 00:21:53.000 --> 00:21:58.000 outside than the inside. Potassium has a concentration 00:21:58.000 --> 00:22:03.000 gradient that's higher on the inside than the outside. 00:22:03.000 --> 00:22:07.000 Calcium has a concentration gradient higher on the outside than the 00:22:07.000 --> 00:22:12.000 inside. This turns out to be the force that drives this action 00:22:12.000 --> 00:22:17.000 potential, is that energy has been stored up in these concentration 00:22:17.000 --> 00:22:22.000 gradients. A concentration gradient is a form of energy. 00:22:22.000 --> 00:22:27.000 Why is that? Well, if there was no membrane there, 00:22:27.000 --> 00:22:32.000 what would be the concentration on the inside and the outside? 00:22:32.000 --> 00:22:35.000 The same. There wouldn't be an inside and outside but, 00:22:35.000 --> 00:22:38.000 you know, so let's imagine. Suppose I just drilled holes in the 00:22:38.000 --> 00:22:41.000 membrane. I get in there vrm, vrm, vrm, drill a lot of holes, 00:22:41.000 --> 00:22:45.000 it will equilibrate and, you know, because just by diffusion there, 00:22:45.000 --> 00:22:48.000 we'll go to the entropy, you know, entropy will set in and it 00:22:48.000 --> 00:22:51.000 will be equal concentrations. If I want to establish a 00:22:51.000 --> 00:22:54.000 concentration gradient then, I have to work against entropy. 00:22:54.000 --> 00:22:58.000 That takes energy here. And that is a form of energy then. 00:22:58.000 --> 00:23:04.000 I had to put work into moving ions around in order to establish a 00:23:04.000 --> 00:23:10.000 concentration gradient. Well, who's in charge of carrying 00:23:10.000 --> 00:23:16.000 out that work? Who is it that sets up these 00:23:16.000 --> 00:23:22.000 concentration gradients in the cell? Membrane proteins. Certain 00:23:22.000 --> 00:23:28.000 membrane proteins. In particular, membrane 00:23:28.000 --> 00:23:34.000 transporters are involved. So, we're going to talk about 00:23:34.000 --> 00:23:40.000 transporters and then we'll talk about some channels. 00:23:40.000 --> 00:23:51.000 All right. The first one. 00:23:51.000 --> 00:24:04.000 There is an ATP-driven sodium potassium pump. 00:24:04.000 --> 00:24:12.000 Any ideas what an ATP-driven sodium 00:24:12.000 --> 00:24:18.000 potassium pump does? It sets up, how does it set up a 00:24:18.000 --> 00:24:24.000 concentration gradient? So, what does it pump? It pumps a 00:24:24.000 --> 00:24:29.000 sodium. Does it pump a sodium in or out? 00:24:29.000 --> 00:24:33.000 It pumps a sodium out. It pumps potassium in. And it does it as an 00:24:33.000 --> 00:24:37.000 even exchange. Why would it like to do it as an 00:24:37.000 --> 00:24:41.000 even exchange, one sodium for one potassium? 00:24:41.000 --> 00:24:46.000 Charge conservation, exactly. So, there's no electrical work to 00:24:46.000 --> 00:24:50.000 be done if it swaps them one for one. And is there work, 00:24:50.000 --> 00:24:54.000 though, to be done? Yes, there is, because if I'm going to 00:24:54.000 --> 00:24:58.000 pump sodium out of the cell, I'm doing it against the 00:24:58.000 --> 00:25:03.000 concentration gradient. Or at least once I get going I'm 00:25:03.000 --> 00:25:07.000 doing it against a concentration gradient. So, 00:25:07.000 --> 00:25:11.000 energy is needed to move a sodium out of the cell against its 00:25:11.000 --> 00:25:15.000 concentration gradient. Energy is also needed to move a 00:25:15.000 --> 00:25:19.000 potassium into the cell against its concentration gradient. 00:25:19.000 --> 00:25:23.000 And where do we get the energy? ATP. So, an ATP is burned in order 00:25:23.000 --> 00:25:29.000 to do that. This guy gets called an anti-porter 00:25:29.000 --> 00:25:36.000 sometimes because it's an anti-transporter or something like 00:25:36.000 --> 00:25:43.000 that. OK. The pump then is ATPA as it uses the energy from an ATP to 00:25:43.000 --> 00:25:50.000 exchange this. Good. Next. There is an 00:25:50.000 --> 00:25:57.000 ATP-driven calcium pump or transporter. 00:25:57.000 --> 00:26:05.000 And, as you might imagine, what does it do? It transports a 00:26:05.000 --> 00:26:13.000 calcium ion out of the cell, and it happens not to do that in 00:26:13.000 --> 00:26:21.000 exchange for any other ion. And it, too, is driven by ATP. 00:26:21.000 --> 00:26:30.000 So, we go pump, pump, pump, pump, pump, pump, pump, pump, keep going. 00:26:30.000 --> 00:26:35.000 Will this thing be able to keep going forever, 00:26:35.000 --> 00:26:40.000 set up arbitrarily large concentration gradients? Why not? 00:26:40.000 --> 00:26:46.000 Well, what is nothing leaked back in? 00:26:46.000 --> 00:26:49.000 Could we, could we keep going? It gets harder and harder to put 00:26:49.000 --> 00:26:53.000 stuff out because you're working up against a bigger and bigger 00:26:53.000 --> 00:26:56.000 concentration gradient. And the ATP is only going to give 00:26:56.000 --> 00:26:59.000 you so much energy. So, at a certain point, 00:26:59.000 --> 00:27:03.000 the burning of that ATP or however many ATPs it uses for its specific 00:27:03.000 --> 00:27:06.000 mechanism won't suffice. So, there's going to be some natural 00:27:06.000 --> 00:27:09.000 upper bound to how far it could go in setting up a gradient because 00:27:09.000 --> 00:27:12.000 there's a nature amount of energy it can spend. OK. 00:27:12.000 --> 00:27:15.000 It's useful to think about these gradients as, you know, 00:27:15.000 --> 00:27:19.000 work that you've got to do and the hill gets steeper and steeper. 00:27:19.000 --> 00:27:22.000 All right. So that could, in principle, set the electrical 00:27:22.000 --> 00:27:25.000 gradient, the concentration change across the cell. 00:27:25.000 --> 00:27:28.000 But there's one other important component that we have 00:27:28.000 --> 00:27:34.000 to think about. And that is something called a 00:27:34.000 --> 00:27:42.000 resting potassium channel. So, what is a resting potassium 00:27:42.000 --> 00:27:51.000 channel? The resting potassium channel is a protein that sits in 00:27:51.000 --> 00:28:00.000 the membrane and it's got a hole in it, a pore. 00:28:00.000 --> 00:28:04.000 And that pore here is designed so that while a sodium can't escape 00:28:04.000 --> 00:28:09.000 through that pore, and you can imagine there's some 00:28:09.000 --> 00:28:13.000 little bit of cleaver molecular architecture to make the sodium atom 00:28:13.000 --> 00:28:18.000 not be able to, sodium ion not be able to get out 00:28:18.000 --> 00:28:23.000 but a potassium ion be able to get out, a potassium ion can get out. 00:28:23.000 --> 00:28:27.000 This is a completely open door that allows potassium ions to escape. 00:28:27.000 --> 00:28:32.000 Now, isn't this stupid? We just spent all this ATP getting 00:28:32.000 --> 00:28:36.000 potassium in and sodium out, and here I go opening the door for 00:28:36.000 --> 00:28:41.000 potassium saying you're free to leave despite all the work we put 00:28:41.000 --> 00:28:45.000 into bringing you into the cell. That makes no sense. All the 00:28:45.000 --> 00:28:50.000 potassium is just going to rush out. 00:28:50.000 --> 00:28:58.000 Can all the potassium rush out? 00:28:58.000 --> 00:29:02.000 The concentration gradient goes which way? It's more inside, 00:29:02.000 --> 00:29:06.000 more potassium inside, less outside, so the potassium is going to rush 00:29:06.000 --> 00:29:10.000 out. Yes. Ooh, electrical gradient. 00:29:10.000 --> 00:29:15.000 If there's an electrical, so maybe at the beginning there's no 00:29:15.000 --> 00:29:19.000 electrical gradient, so potassium rushes out. 00:29:19.000 --> 00:29:23.000 What does it do? It makes it more positive on the outside. 00:29:23.000 --> 00:29:28.000 Now the next potassium wants to rush out. 00:29:28.000 --> 00:29:32.000 It's going to, it's going down its concentration 00:29:32.000 --> 00:29:36.000 gradient but it's going up a teeny weenie little electrical gradient. 00:29:36.000 --> 00:29:40.000 Now that gets out there, and what does it do to the outside? 00:29:40.000 --> 00:29:45.000 Makes it more positive. So, the third potassium makes it even 00:29:45.000 --> 00:29:49.000 more positive. And as more and more potassiums 00:29:49.000 --> 00:29:53.000 rush out, the outside becomes more positive. And every potassium now 00:29:53.000 --> 00:29:58.000 has to do work to get up that electrical gradient. 00:29:58.000 --> 00:30:02.000 But, of course, it's still got a concentration 00:30:02.000 --> 00:30:07.000 gradient pushing it out. So, will they keep going forever? 00:30:07.000 --> 00:30:11.000 No, they're going to balance each other. There will come a point when 00:30:11.000 --> 00:30:16.000 the concentration gradient, the force driving potassium out due 00:30:16.000 --> 00:30:20.000 to the concentration gradient is offset by the electrical gradient 00:30:20.000 --> 00:30:25.000 pushing potassium in, or keeping potassium in. 00:30:25.000 --> 00:30:33.000 So, what happens is potassium goes out, rushes out, 00:30:33.000 --> 00:30:41.000 or goes out, leaks out, potassium leaks out which now sets 00:30:41.000 --> 00:30:51.000 up an electrical gradient. 00:30:51.000 --> 00:30:56.000 And what happens is the cell becomes more positive on the outside, 00:30:56.000 --> 00:31:02.000 more negative on the inside, and an equilibrium potential is reached, 00:31:02.000 --> 00:31:09.000 equilibrium is reached. 00:31:09.000 --> 00:31:12.000 So, an equilibrium electrical potential -- 00:31:12.000 --> 00:31:22.000 -- is reached when the concentration 00:31:22.000 --> 00:31:30.000 gradient exactly offsets, when it balances the electrical 00:31:30.000 --> 00:31:39.000 gradient. 00:31:39.000 --> 00:31:43.000 Any guesses to what that electrical concentration gradient is? 00:31:43.000 --> 00:31:48.000 Minus 70 millivolts. That's where minus 70 millivolts comes from. 00:31:48.000 --> 00:31:53.000 It comes because that's the concentration gradient at which 00:31:53.000 --> 00:31:58.000 potassium going up that gradient just offsets the, yes? 00:31:58.000 --> 00:32:11.000 Well, because, 00:32:11.000 --> 00:32:14.000 oh, it doesn't. The electrical potential wants to 00:32:14.000 --> 00:32:17.000 keep it in. The concentration wants it out. The electrical wants it in. 00:32:17.000 --> 00:32:20.000 That's why we have an equilibrium. Exactly. It's those two balancing 00:32:20.000 --> 00:32:23.000 forces. Very good. So, how much potassium, 00:32:23.000 --> 00:32:26.000 by the way, has to rush out to set this up? It turns out 00:32:26.000 --> 00:32:30.000 a trivial amount. It turns out that about ten to, 00:32:30.000 --> 00:32:34.000 one part in ten to the sixth of all the potassium ions leaving sets up a 00:32:34.000 --> 00:32:39.000 gradient of about minus, of about five millivolts, 00:32:39.000 --> 00:32:43.000 minus five millivolts. One part in a million of the potassium ions will 00:32:43.000 --> 00:32:48.000 suffice to set up a concentration gradient of minus five millivolts. 00:32:48.000 --> 00:32:52.000 So, all I've got to do is set up about, let's see, 00:32:52.000 --> 00:32:57.000 I don't know, less than, I don't know, maybe about one part 00:32:57.000 --> 00:33:02.000 in ten to the fifth of all the potassium ions leaving. 00:33:02.000 --> 00:33:05.000 A tiny contribution of the concentration. 00:33:05.000 --> 00:33:08.000 Changing the concentration by one part in ten to the fifth will get me 00:33:08.000 --> 00:33:11.000 minus 50 millivolts already. So, what's very interesting is 00:33:11.000 --> 00:33:15.000 teeny amounts of ions set up a very big electrical gradient and have no 00:33:15.000 --> 00:33:18.000 real effect on the concentration, but they have a big effect on the 00:33:18.000 --> 00:33:21.000 electrical gradient. So, when I say potassium leaks out, 00:33:21.000 --> 00:33:25.000 it only takes a teeny bit of potassium to leak out in order to 00:33:25.000 --> 00:33:29.000 accomplish this. OK, guys. Now let's get ready to make an 00:33:29.000 --> 00:33:35.000 action potential. Here it goes. So, 00:33:35.000 --> 00:33:45.000 the action potential mechanism. 00:33:45.000 --> 00:33:51.000 We've set up our resting potential by transporters, 00:33:51.000 --> 00:33:57.000 by this open channel. Now, the first thing we have is a 00:33:57.000 --> 00:34:03.000 new kind of membrane channel. We have a voltage gated 00:34:03.000 --> 00:34:19.000 sodium channel. 00:34:19.000 --> 00:34:26.000 Check this out. This guy here is a channel that's 00:34:26.000 --> 00:34:35.000 closed. It's closed. Except, so at minus 70 millivolts 00:34:35.000 --> 00:34:45.000 it's closed. But if I can transiently depolarize the cell to 00:34:45.000 --> 00:34:56.000 minus 50 millivolts it opens and it admits sodium. 00:34:56.000 --> 00:35:04.000 So, when I get to minus 50 it opens. Now, what will sodium do when that 00:35:04.000 --> 00:35:10.000 door opens? Let's see. Electrically what would sodium, 00:35:10.000 --> 00:35:20.000 what would sodium do? 00:35:20.000 --> 00:35:23.000 So what, well, how about concentration? 00:35:23.000 --> 00:35:26.000 From the point of view of concentration what would sodium, 00:35:26.000 --> 00:35:30.000 oh, what did I just draw here? Ooh, forget my error. 00:35:30.000 --> 00:35:34.000 Electrically what would sodium like to do? It would like to come in, 00:35:34.000 --> 00:35:38.000 wouldn't it? Because it's negative inside and sodium is positive. 00:35:38.000 --> 00:35:42.000 But from a concentration gradient what would it like to do? 00:35:42.000 --> 00:35:46.000 Come in also. So what's stopping it? Nothing. We've got the ion 00:35:46.000 --> 00:35:50.000 that would like to come in electrically and would like to come 00:35:50.000 --> 00:35:54.000 in from the point of view of concentration. 00:35:54.000 --> 00:35:58.000 So what happens? It comes in. And it comes rushing 00:35:58.000 --> 00:36:02.000 in. Now, what happens as it comes 00:36:02.000 --> 00:36:06.000 rushing in? What will it do to our electrical potential? 00:36:06.000 --> 00:36:11.000 We went from minus 70, we got it transiently up to minus 50, 00:36:11.000 --> 00:36:15.000 and as it comes in what does it do to our electrical gradient? 00:36:15.000 --> 00:36:20.000 Brings in positive charge. The electrical gradient goes towards 00:36:20.000 --> 00:36:24.000 zero. Does it stop at zero? No, because now, even as the cell 00:36:24.000 --> 00:36:29.000 becomes positive in the interior, sodium still wants to keep coming in 00:36:29.000 --> 00:36:34.000 because of it's concentration gradient. 00:36:34.000 --> 00:36:39.000 It now has to do some work against the electrical gradient that's set 00:36:39.000 --> 00:36:44.000 up, but it keeps going and going and going. Does it go on forever? 00:36:44.000 --> 00:36:49.000 No, because eventually it reaches a point where the electrical gradient, 00:36:49.000 --> 00:36:54.000 positive now inside the cell, offsets the concentration gradient 00:36:54.000 --> 00:36:59.000 and it'll stop and it'll reach a new equilibrium potential which turns 00:36:59.000 --> 00:37:04.000 out to be at about plus 50. Amazing. Opens the door. 00:37:04.000 --> 00:37:08.000 Sodium comes rushing in down its concentration electrical gradient, 00:37:08.000 --> 00:37:13.000 shifts the electrical gradient from being negative to positive, 00:37:13.000 --> 00:37:17.000 and eventually it slows itself down because it's now going against an 00:37:17.000 --> 00:37:22.000 electrical gradient. But that's not the end of the story 00:37:22.000 --> 00:37:27.000 because what there also is, there are two other interesting 00:37:27.000 --> 00:37:31.000 functions. One, after a certain amount of time, 00:37:31.000 --> 00:37:39.000 after a very brief time interval -- 00:37:39.000 --> 00:37:42.000 -- this channel also has the property that it closes. 00:37:42.000 --> 00:37:49.000 So now when it closes, 00:37:49.000 --> 00:37:53.000 what's going to happen? The pumps will start working again 00:37:53.000 --> 00:37:57.000 and reestablish our negative 50. It's going to take too long, though. 00:37:57.000 --> 00:38:02.000 I mean it'll happen. You'd get back to minus 50, 00:38:02.000 --> 00:38:06.000 but it's going to take a long time. So it's good that the channels, 00:38:06.000 --> 00:38:11.000 that the voltage gated sodium channel closed, 00:38:11.000 --> 00:38:15.000 but even better nature has arranged to have a voltage gated 00:38:15.000 --> 00:38:25.000 potassium channel. 00:38:25.000 --> 00:38:31.000 And what happens to this voltage gated potassium channel is around 00:38:31.000 --> 00:38:37.000 plus 30 millivolts it opens and admits potassium. 00:38:37.000 --> 00:38:45.000 Now, instead of having to wait for the relatively slow ATP-driven pumps, 00:38:45.000 --> 00:38:53.000 what happens when I admit potassium? Well, if the cell is positive on 00:38:53.000 --> 00:39:01.000 the inside, negative on the outside, what happens to our potassium? 00:39:01.000 --> 00:39:08.000 Potassium starts coming out because there's more potassium on the inside 00:39:08.000 --> 00:39:15.000 and there's also a favorable electrical gradient. 00:39:15.000 --> 00:39:22.000 So, potassium explosively starts rushing out and rapidly 00:39:22.000 --> 00:39:30.000 reestablishes the resting potential. All this happening in a millisecond. 00:39:30.000 --> 00:39:34.000 It's very impressive. So, in something like one 00:39:34.000 --> 00:39:38.000 millisecond we open up the potassium channels. Now, 00:39:38.000 --> 00:39:42.000 you have to ask how did it happen that the channels got open in the 00:39:42.000 --> 00:39:46.000 first place? How did we get to minus 50? That's the work of these 00:39:46.000 --> 00:39:51.000 dendrites. The dendrites integrating a signal from all the 00:39:51.000 --> 00:39:55.000 things impacting on it will get the cell to minus 50, 00:39:55.000 --> 00:39:59.000 but once the cell gets to minus 50 at its axon hillock, 00:39:59.000 --> 00:40:03.000 bingo, the action potential fires, the cell zips up to plus 50 in a big 00:40:03.000 --> 00:40:07.000 rush of sodiums and then zips down to minus 70 again in a big rush of 00:40:07.000 --> 00:40:16.000 potassiums. Yes? 00:40:16.000 --> 00:40:19.000 Yup. Remember I said it was only like one part and ten to the fifth 00:40:19.000 --> 00:40:22.000 of the ions? It's a trivial actual, the number of ions necessary to set 00:40:22.000 --> 00:40:25.000 up these electrical things is such a tiny fraction of the concentration 00:40:25.000 --> 00:40:29.000 that through this whole thing those concentrations don't 00:40:29.000 --> 00:40:32.000 noticeably change. That's what's so cool, 00:40:32.000 --> 00:40:36.000 is there are different regimes, right? And they do change. They 00:40:36.000 --> 00:40:39.000 change by one part and ten to the fifth of those numbers. 00:40:39.000 --> 00:40:42.000 It's really cool, isn't it? We haven't screwed up our 00:40:42.000 --> 00:40:46.000 concentration gradient? We moved tiny numbers of ions to 00:40:46.000 --> 00:40:49.000 accomplish all this. This is very cleaver engineering. 00:40:49.000 --> 00:40:53.000 It's very cleaver engineering. Now, how do we manage to transmit this 00:40:53.000 --> 00:40:56.000 signal down a cell? Well, let's talk about how we 00:40:56.000 --> 00:41:00.000 propagate. I think this is really cool. 00:41:00.000 --> 00:41:04.000 This is one of the truly great mechanisms that was invented. 00:41:04.000 --> 00:41:19.000 Transmitting an action potential. 00:41:19.000 --> 00:41:27.000 Suppose I transmit my action. Suppose I have a neuron here and 00:41:27.000 --> 00:41:35.000 over here, at the axon hillock, I transiently depolarize to minus 50. 00:41:35.000 --> 00:41:43.000 Then I fire and fire. 00:41:43.000 --> 00:41:49.000 Well, what happens is this part of the cell was originally minus, 00:41:49.000 --> 00:41:55.000 minus, minus, plus, plus, plus, it becomes positive temporarily, 00:41:55.000 --> 00:42:04.000 right? It now becomes -- 00:42:04.000 --> 00:42:10.000 -- plus, plus, plus. So, let's go minus along the 00:42:10.000 --> 00:42:16.000 whole cell here. Plus, plus, plus, 00:42:16.000 --> 00:42:23.000 plus, plus. Now, some little patch of membrane at the beginning of the 00:42:23.000 --> 00:42:29.000 axon has become positive inside, right? Because whatever local 00:42:29.000 --> 00:42:35.000 affect here caused this to flip. If this becomes positive at this 00:42:35.000 --> 00:42:40.000 part of the membrane, what happens to the negative charges 00:42:40.000 --> 00:42:46.000 over here a little bit further down the axon? Some of them will be 00:42:46.000 --> 00:42:51.000 pulled over to the positive. Ho-ho. Some negative charges get 00:42:51.000 --> 00:42:56.000 pulled over. Well, what happens when some of those 00:42:56.000 --> 00:43:02.000 negative charges get pulled over to my minus 70 millivolts? 00:43:02.000 --> 00:43:08.000 Is it as negative as it was before? No. It becomes minus 50 millivolts. 00:43:08.000 --> 00:43:14.000 Oh. What happens when this becomes minus 50 millivolts? 00:43:14.000 --> 00:43:21.000 Fires an action potential. So, what happens is, here's my axon, 00:43:21.000 --> 00:43:27.000 I fire an action, I have an action potential here, 00:43:27.000 --> 00:43:34.000 and in the course of that I pull over some negative charge. 00:43:34.000 --> 00:43:38.000 That, of course, transiently depolarizes here and 00:43:38.000 --> 00:43:42.000 causes an action potential to fire. Then, of course, this becomes 00:43:42.000 --> 00:43:46.000 positive which pulls over some negative charge which causes the 00:43:46.000 --> 00:43:50.000 action potential to fire here, etc., etc., etc. So, if I can 00:43:50.000 --> 00:43:55.000 manage to get the thing started with my dendrites causing a transient 00:43:55.000 --> 00:43:59.000 depolarization from minus 70 to minus 50 then the action potential 00:43:59.000 --> 00:44:03.000 itself will draw over some charge and start the process at the next 00:44:03.000 --> 00:44:07.000 patch of membrane, the next patch of the next membrane, 00:44:07.000 --> 00:44:12.000 the next patch of the next membrane and the next patch of membrane. 00:44:12.000 --> 00:44:17.000 And it gets all the way down to the end. It's a brilliant mechanism. 00:44:17.000 --> 00:44:22.000 You can calculate, based on the diffusion coefficient of ions, 00:44:22.000 --> 00:44:28.000 how long it will take to transmit that signal. And it's OK 00:44:28.000 --> 00:44:33.000 but not good enough. I'd like it to go faster. 00:44:33.000 --> 00:44:40.000 How can I make it go faster? 00:44:40.000 --> 00:44:46.000 How about put an insulator around it? It turns out that with one little 00:44:46.000 --> 00:44:52.000 trick, I can speed this up dramatically. Oh, 00:44:52.000 --> 00:44:58.000 sorry. Sorry about that. The trick is suppose I were to wrap 00:44:58.000 --> 00:45:04.000 some insulator around the axon that would make this such that it could 00:45:04.000 --> 00:45:10.000 not, that it was not an electrical contract outside, 00:45:10.000 --> 00:45:16.000 that it was only an electric contact with the outside solution 00:45:16.000 --> 00:45:22.000 here, here, here. Then, when the action potential 00:45:22.000 --> 00:45:27.000 fires here, it's going to pull charges over, not from the tiny 00:45:27.000 --> 00:45:31.000 little patch of membrane here, but the charges are going to have to 00:45:31.000 --> 00:45:36.000 come from here, it turns out, because that's where 00:45:36.000 --> 00:45:41.000 I'm going to next feel my action potential. And so what'll happen is 00:45:41.000 --> 00:45:45.000 that the action potential, if this stuff is electrically 00:45:45.000 --> 00:45:50.000 insulated, will only be happening at this little gaps between the 00:45:50.000 --> 00:45:55.000 insulation. And I can dramatically speed up the electrical transmission 00:45:55.000 --> 00:46:00.000 if I'm willing to insulate the wire. 00:46:00.000 --> 00:46:04.000 Because then there's much less leakage along the way. 00:46:04.000 --> 00:46:09.000 So, it turns out that there are special cells that wrap themselves 00:46:09.000 --> 00:46:14.000 around the axon that are called Schwann cells. 00:46:14.000 --> 00:46:19.000 The Schwann cell wraps itself around and around and around and 00:46:19.000 --> 00:46:24.000 squeezes out all of its cytoplasm leaving only a lipid bilayer. 00:46:24.000 --> 00:46:29.000 Lipid bilayers wrapped around and around and around make 00:46:29.000 --> 00:46:35.000 great insulators. This is called the myelin sheath of 00:46:35.000 --> 00:46:41.000 a nerve. These myelin sheaths allow the transmission of this action 00:46:41.000 --> 00:46:48.000 potential to proceed about a hundred times faster. Very cleaver. 00:46:48.000 --> 00:46:54.000 Now you ask me how do I know this matters? I mean you can calculate 00:46:54.000 --> 00:47:01.000 that it should go about 100 times faster. 00:47:01.000 --> 00:47:07.000 But how would you really know that it mattered. Try taking them off. 00:47:07.000 --> 00:47:13.000 Unfortunately, there is a disease that takes them off. 00:47:13.000 --> 00:47:20.000 Some human patients make autoimmune reactions against their own myelin. 00:47:20.000 --> 00:47:26.000 It attacks their own myelin and leads to the demyelination 00:47:26.000 --> 00:47:32.000 of the nerves. This disease is called multiple 00:47:32.000 --> 00:47:38.000 sclerosis. Multiple sclerosis involves an autoimmune attack on 00:47:38.000 --> 00:47:44.000 your very own myelin sheaths, and the effects, the very serious 00:47:44.000 --> 00:47:50.000 effects that multiple sclerosis can have on an individual come from the 00:47:50.000 --> 00:47:56.000 greatly diminished, hundred-fold diminished conduction 00:47:56.000 --> 00:48:02.000 velocity of electrical signals down motor neurons along these 00:48:02.000 --> 00:48:07.000 large distances. So, this is, in fact, 00:48:07.000 --> 00:48:11.000 the basic electrical setup. We have taken a situation where we 00:48:11.000 --> 00:48:15.000 don't have electrical wires at all but have concocted, 00:48:15.000 --> 00:48:19.000 through chemistry, a powerful way to create signals. 00:48:19.000 --> 00:48:23.000 First, by setting up a resting potential using pumps and an open 00:48:23.000 --> 00:48:27.000 potassium channel. Then by setting up this explosive 00:48:27.000 --> 00:48:31.000 mechanism where a little change in voltage which, 00:48:31.000 --> 00:48:36.000 of course, has a huge change in field, swings open a sodium channel, 00:48:36.000 --> 00:48:40.000 shuts it, swings open a potassium channel, and then cleverly recruits 00:48:40.000 --> 00:48:45.000 charges from down the neuron and sends the signal. 00:48:45.000 --> 00:48:49.000 Next time we shall talk about what happens when the signal gets all the 00:48:49.000 --> 00:48:54.000 way to the other end and it has to talk to the next neuron. 00:48:54.000 --> 00:48:59.000 Till next time.