1 00:00:16,540 --> 00:00:18,550 ADAM MARTIN: All right, let's get started. 2 00:00:18,550 --> 00:00:21,670 So I'm starting with this video here. 3 00:00:21,670 --> 00:00:24,710 What's happening here is there's this mouse, 4 00:00:24,710 --> 00:00:27,700 and you see there's like this fiber optic cable going 5 00:00:27,700 --> 00:00:29,580 into its brain. 6 00:00:29,580 --> 00:00:32,170 And the mouse is asleep right now. 7 00:00:32,170 --> 00:00:36,070 And now the researchers are shining light 8 00:00:36,070 --> 00:00:39,040 into its brain, a specific region of the brain, 9 00:00:39,040 --> 00:00:41,710 to activate specific neurons in order 10 00:00:41,710 --> 00:00:44,620 to test whether they function in arousal. 11 00:00:44,620 --> 00:00:48,237 And here, you see the mouse is going to wake up. 12 00:00:48,237 --> 00:00:48,820 There it goes. 13 00:00:48,820 --> 00:00:49,510 It's awake now. 14 00:00:52,570 --> 00:00:54,860 So for today's lecture, we're going 15 00:00:54,860 --> 00:01:00,010 to work towards understanding how this experiment works. 16 00:01:00,010 --> 00:01:03,040 And we're going to talk about how neurons function 17 00:01:03,040 --> 00:01:07,510 and how researchers are able to control that function in order 18 00:01:07,510 --> 00:01:09,670 to modify behavior-- 19 00:01:09,670 --> 00:01:12,400 in this case, the arousal of this mouse. 20 00:01:15,670 --> 00:01:19,570 OK, so this is going to involve a particular type of cell 21 00:01:19,570 --> 00:01:21,700 in our body, which is the neuron. 22 00:01:21,700 --> 00:01:25,060 And neurons are highly specialized cells 23 00:01:25,060 --> 00:01:28,510 that have a function to transmit information from one 24 00:01:28,510 --> 00:01:31,960 part of the body to another. 25 00:01:31,960 --> 00:01:36,430 And so neurons are highly polarized cells, 26 00:01:36,430 --> 00:01:38,110 which you can see here. 27 00:01:38,110 --> 00:01:43,090 On the left of this neuron, you see this arbor of protrusions, 28 00:01:43,090 --> 00:01:45,970 which are called dendrites. 29 00:01:45,970 --> 00:01:47,980 And then on this side of the cell body, 30 00:01:47,980 --> 00:01:50,530 you see a single extension, which 31 00:01:50,530 --> 00:01:55,150 is an axon, and then the terminus of the axon over here. 32 00:01:55,150 --> 00:01:58,660 And this nerve cell transmits information 33 00:01:58,660 --> 00:02:00,490 in a single direction. 34 00:02:00,490 --> 00:02:06,340 It will transmit information from this side to this side. 35 00:02:06,340 --> 00:02:10,180 And these neurons are able to communicate with each other. 36 00:02:10,180 --> 00:02:13,210 And they communicate at the ends of the neuron, which 37 00:02:13,210 --> 00:02:15,520 are known as synapses, which I'll come back to 38 00:02:15,520 --> 00:02:18,580 and talk about later on in the lecture. 39 00:02:18,580 --> 00:02:22,000 So neurons could be making synapses on this side 40 00:02:22,000 --> 00:02:24,805 and also making synapses on this side with other neurons. 41 00:02:28,840 --> 00:02:33,080 So to start to unpack the function of this neuron-- 42 00:02:33,080 --> 00:02:36,130 and I should highlight that this flow of information 43 00:02:36,130 --> 00:02:38,990 can occur over very long distances, right? 44 00:02:38,990 --> 00:02:42,670 Your sciatic nerve extends from the base of your spine 45 00:02:42,670 --> 00:02:44,980 all the way down into your foot, OK? 46 00:02:44,980 --> 00:02:49,130 So that axon is one meter in length. 47 00:02:49,130 --> 00:02:51,340 So that's an extremely long distance 48 00:02:51,340 --> 00:02:54,550 to transmit information along a single cell. 49 00:02:57,100 --> 00:03:00,550 And so we're going to go from thinking about how signals are 50 00:03:00,550 --> 00:03:03,070 transmitted in single cells, and this will 51 00:03:03,070 --> 00:03:05,500 evolve electrical signaling. 52 00:03:05,500 --> 00:03:09,310 Then we'll talk about synapses and how synapses function 53 00:03:09,310 --> 00:03:11,720 to communicate between neurons. 54 00:03:11,720 --> 00:03:15,040 And this is going to involve also 55 00:03:15,040 --> 00:03:18,190 sort of understanding how certain antidepressants, 56 00:03:18,190 --> 00:03:19,810 like Prozac, work. 57 00:03:19,810 --> 00:03:21,880 And then we'll end by talking about how 58 00:03:21,880 --> 00:03:26,430 researchers did this experiment to wake up the mouse. 59 00:03:26,430 --> 00:03:28,660 And it all starts with something that I told you 60 00:03:28,660 --> 00:03:31,930 about at the beginning of the semester, which 61 00:03:31,930 --> 00:03:35,710 is that the plasma membrane separates 62 00:03:35,710 --> 00:03:38,380 distinct compartments the outside of the cell 63 00:03:38,380 --> 00:03:39,910 from the cytoplasm. 64 00:03:39,910 --> 00:03:42,700 And there are distinct ion concentrations 65 00:03:42,700 --> 00:03:46,990 on either side of this boundary. 66 00:03:46,990 --> 00:03:51,115 So we're starting now talking about a single neuron cell. 67 00:03:55,690 --> 00:03:59,790 And we're going to talk about a type of signal 68 00:03:59,790 --> 00:04:03,012 known as an action potential. 69 00:04:03,012 --> 00:04:03,720 Oh, that's right. 70 00:04:08,460 --> 00:04:11,370 So we're going to talk about an action potential. 71 00:04:11,370 --> 00:04:13,500 And what an action potential is, is it's 72 00:04:13,500 --> 00:04:15,390 an electrical signal that travels 73 00:04:15,390 --> 00:04:17,680 the length of the neuron. 74 00:04:17,680 --> 00:04:22,710 So this action potential, I'll abbreviate this AP. 75 00:04:22,710 --> 00:04:25,260 So when I refer to AP, I'm not referring 76 00:04:25,260 --> 00:04:29,850 to advanced placement, but action potential, OK? 77 00:04:29,850 --> 00:04:37,020 So this is an electrical signal that 78 00:04:37,020 --> 00:04:40,920 travels the length of the axon and the neuron. 79 00:04:51,290 --> 00:04:54,630 And so in order to have an electrical signal propagate, 80 00:04:54,630 --> 00:04:57,000 we need some sort of electrical property 81 00:04:57,000 --> 00:05:01,180 that the cell has that enables this. 82 00:05:01,180 --> 00:05:05,070 And so I showed you or I told you earlier in the semester 83 00:05:05,070 --> 00:05:09,330 how sodium ions are concentrated on the outside of the cell 84 00:05:09,330 --> 00:05:13,540 and potassium ions are concentrated on the inside. 85 00:05:13,540 --> 00:05:15,900 You see here's the sodium gradient here, 86 00:05:15,900 --> 00:05:17,690 potassium gradient here. 87 00:05:17,690 --> 00:05:20,160 And now I'm going to tell you how it is that this happens, 88 00:05:20,160 --> 00:05:22,310 because this is thermodynamically not favored, 89 00:05:22,310 --> 00:05:22,810 right? 90 00:05:22,810 --> 00:05:26,190 These ions would prefer, by diffusion, 91 00:05:26,190 --> 00:05:30,090 to be equal concentrations on both sides of this plasma 92 00:05:30,090 --> 00:05:35,670 membrane, which means that the cell to shift this 93 00:05:35,670 --> 00:05:38,340 from equilibrium has to expend energy 94 00:05:38,340 --> 00:05:41,980 to set up this situation. 95 00:05:41,980 --> 00:05:46,600 And so in the plasma membrane of the cell, there is a protein. 96 00:05:46,600 --> 00:05:48,360 It's an integral membrane protein 97 00:05:48,360 --> 00:05:51,340 and sits inside the plasma membrane. 98 00:05:51,340 --> 00:05:55,080 So this here is the plasma membrane. 99 00:05:55,080 --> 00:05:57,210 And this integral membrane protein 100 00:05:57,210 --> 00:06:02,010 is called a sodium potassium ATPase. 101 00:06:02,010 --> 00:06:10,770 So it's going to have a subunit that hydrolyzes ATP to ADP. 102 00:06:10,770 --> 00:06:15,870 And the protein uses the energy of ATP hydrolysis 103 00:06:15,870 --> 00:06:20,650 to pump sodium ions up their concentration gradient. 104 00:06:20,650 --> 00:06:24,440 So the sodium ions are going out of the cell. 105 00:06:24,440 --> 00:06:26,790 And this is going against the flow 106 00:06:26,790 --> 00:06:28,900 that sodium would normally like to take, 107 00:06:28,900 --> 00:06:31,800 which would be going downstream. 108 00:06:31,800 --> 00:06:37,380 And it pumps potassium ions into the cytoplasm such 109 00:06:37,380 --> 00:06:40,350 that there's a higher concentration of potassium 110 00:06:40,350 --> 00:06:43,140 ions in the cytoplasm, OK? 111 00:06:43,140 --> 00:06:47,130 So these neurons expend a huge-- 112 00:06:47,130 --> 00:06:52,290 a quarter of their ATP is used by pumping ions like this, such 113 00:06:52,290 --> 00:06:56,595 that there is gradients of ions across the plasma membrane. 114 00:06:59,310 --> 00:07:03,030 Now, if one sodium ion was pumped out 115 00:07:03,030 --> 00:07:06,000 for every potassium ion pumped in, 116 00:07:06,000 --> 00:07:09,300 there'd be no charge difference between the exterior 117 00:07:09,300 --> 00:07:12,090 and the cytoplasm. 118 00:07:12,090 --> 00:07:16,260 But what happens in the plasma membrane 119 00:07:16,260 --> 00:07:20,010 is that in addition to the sodium potassium ATPase, 120 00:07:20,010 --> 00:07:23,340 there are other channels that are present. 121 00:07:23,340 --> 00:07:25,300 There are sodium channels. 122 00:07:25,300 --> 00:07:29,400 These are mostly closed, but there are some potassium 123 00:07:29,400 --> 00:07:31,230 channels that are leaky. 124 00:07:31,230 --> 00:07:34,860 And they're basically leaking potassium from the cytoplasm 125 00:07:34,860 --> 00:07:38,130 out into the exoplasm, OK? 126 00:07:38,130 --> 00:07:42,330 And if you have positive charges going out the cell, 127 00:07:42,330 --> 00:07:44,270 then the inside of the membrane is going 128 00:07:44,270 --> 00:07:47,413 to have a net negative charge. 129 00:07:47,413 --> 00:07:49,080 And the outside of the membrane is going 130 00:07:49,080 --> 00:07:53,070 to have a net positive charge. 131 00:07:53,070 --> 00:07:55,740 And this charge across the membrane, 132 00:07:55,740 --> 00:07:58,690 where you have positive on the outside 133 00:07:58,690 --> 00:08:00,320 and minus on the inside-- 134 00:08:00,320 --> 00:08:06,390 I should label this exterior, and this is cytoplasm. 135 00:08:11,580 --> 00:08:16,650 This voltage difference is known as a membrane potential. 136 00:08:16,650 --> 00:08:18,250 So this is a membrane potential. 137 00:08:24,950 --> 00:08:28,520 And it's an electrical potential across the membrane. 138 00:08:28,520 --> 00:08:30,020 If you're an electrical engineer, 139 00:08:30,020 --> 00:08:33,740 you can think of the plasma membrane as a capacitor, OK? 140 00:08:33,740 --> 00:08:37,549 So this plasma membrane is holding this charge difference 141 00:08:37,549 --> 00:08:39,559 across it. 142 00:08:39,559 --> 00:08:42,169 And so there's a voltage across the membrane. 143 00:08:42,169 --> 00:08:51,020 And in a resting state, the cell's resting potential 144 00:08:51,020 --> 00:08:53,180 is negative 70 millivolts. 145 00:08:57,410 --> 00:09:00,950 So if the cell is not getting stimulated by something 146 00:09:00,950 --> 00:09:03,440 like a neurotransmitter, the resting potential 147 00:09:03,440 --> 00:09:07,310 is negative 70 millivolts, where the inside is negative 148 00:09:07,310 --> 00:09:10,370 and the outside is positive, OK? 149 00:09:10,370 --> 00:09:12,578 So now I just want to define some terms that 150 00:09:12,578 --> 00:09:14,120 are going to be useful for us when we 151 00:09:14,120 --> 00:09:17,160 talk about action potentials. 152 00:09:17,160 --> 00:09:24,455 So when there's this negative inside potential, 153 00:09:24,455 --> 00:09:28,760 a negative inside potential is referred to as polarized. 154 00:09:28,760 --> 00:09:34,400 So it's polarized because there's 155 00:09:34,400 --> 00:09:38,120 a polarity across this membrane, where one side is positive 156 00:09:38,120 --> 00:09:41,660 and the other side is negative, OK? 157 00:09:41,660 --> 00:09:43,940 So polarized refers to if there's 158 00:09:43,940 --> 00:09:45,830 a negative inside potential. 159 00:09:45,830 --> 00:09:49,150 So the resting state of the side is there's a polarized-- 160 00:09:49,150 --> 00:09:52,100 it's polarized. 161 00:09:52,100 --> 00:09:55,640 However, the cell can lose this polarity 162 00:09:55,640 --> 00:09:57,500 and not have a charge differential, 163 00:09:57,500 --> 00:10:00,950 or it can flip and be positive on the inside. 164 00:10:00,950 --> 00:10:05,750 And when that happens, if there's either zero or positive 165 00:10:05,750 --> 00:10:10,070 inside potential, this is referred to as depolarized. 166 00:10:17,330 --> 00:10:20,420 Anyone have an idea as to how the cell would 167 00:10:20,420 --> 00:10:22,580 flip the potential? 168 00:10:22,580 --> 00:10:25,280 What would have to happen in the plasma membrane 169 00:10:25,280 --> 00:10:28,310 to flip this potential and depolarize the cell? 170 00:10:28,310 --> 00:10:28,900 Yes, Stephen? 171 00:10:28,900 --> 00:10:30,710 AUDIENCE: You could open the ion channels. 172 00:10:30,710 --> 00:10:33,600 ADAM MARTIN: So Stephen suggested opening ion channels. 173 00:10:33,600 --> 00:10:36,431 Which ion channels would you open? 174 00:10:36,431 --> 00:10:38,120 AUDIENCE: The sodium channels. 175 00:10:38,120 --> 00:10:38,870 ADAM MARTIN: Yeah. 176 00:10:38,870 --> 00:10:42,260 So Stephen suggested if you open these, 177 00:10:42,260 --> 00:10:43,970 it's going to depolarize the cell. 178 00:10:43,970 --> 00:10:48,450 Because remember, sodium is high on the outside, out here. 179 00:10:48,450 --> 00:10:50,180 And so if you open these channels, 180 00:10:50,180 --> 00:10:52,730 positive ions are going to flow in. 181 00:10:52,730 --> 00:10:56,120 And that's going to make this less negative and this less 182 00:10:56,120 --> 00:10:58,800 positive, OK? 183 00:10:58,800 --> 00:11:02,870 So this is the situation here, where these sodium channels 184 00:11:02,870 --> 00:11:06,050 open, and the sodium channels-- or the sodium 185 00:11:06,050 --> 00:11:09,650 ions rushing in is going to create a depolarization, 186 00:11:09,650 --> 00:11:11,780 where you now flip the potential. 187 00:11:11,780 --> 00:11:14,120 And there's a greater positive charge 188 00:11:14,120 --> 00:11:18,620 on the inside of the plasma membrane. 189 00:11:18,620 --> 00:11:20,270 Everyone see how? 190 00:11:20,270 --> 00:11:23,360 Because the sodium ions are going to just go downstream. 191 00:11:23,360 --> 00:11:25,400 They're higher concentration out here. 192 00:11:25,400 --> 00:11:27,740 So just by opening these channels, 193 00:11:27,740 --> 00:11:30,410 the cell doesn't have to do any work to do this. 194 00:11:30,410 --> 00:11:32,600 Sodium is just going to flow down its gradient 195 00:11:32,600 --> 00:11:33,920 into the cytoplasm. 196 00:11:41,110 --> 00:11:43,750 So what an action potential is, is it's 197 00:11:43,750 --> 00:11:49,090 a transient depolarization of the nerve cell. 198 00:11:49,090 --> 00:12:02,180 So the Action Potential, or AP, is a transient depolarization 199 00:12:02,180 --> 00:12:07,160 of the neuron, which means it doesn't just 200 00:12:07,160 --> 00:12:12,020 depolarize and stay depolarized, but it depolarizes and then 201 00:12:12,020 --> 00:12:16,010 restores itself back to the resting polarity. 202 00:12:16,010 --> 00:12:19,310 And so what you see when you measure the voltage 203 00:12:19,310 --> 00:12:22,010 across the plasma membrane in a neuron, 204 00:12:22,010 --> 00:12:24,890 you see that it can spike and depolarize, 205 00:12:24,890 --> 00:12:28,880 but then it's rapidly restored to its resting state, OK? 206 00:12:28,880 --> 00:12:30,200 So it's a transient process. 207 00:12:33,080 --> 00:12:36,470 When we think about the neuron at higher resolution, what 208 00:12:36,470 --> 00:12:39,140 you're going to see is not only is it transient, 209 00:12:39,140 --> 00:12:42,500 but it's also a traveling wave that propagates along 210 00:12:42,500 --> 00:12:45,870 the entire length of the cell. 211 00:12:45,870 --> 00:12:47,870 So this is also a traveling wave. 212 00:12:56,830 --> 00:13:01,240 And one thing that you can notice about these neurons, 213 00:13:01,240 --> 00:13:05,510 or the action potentials here, is that they all 214 00:13:05,510 --> 00:13:08,000 depolarize to the same extent. 215 00:13:08,000 --> 00:13:12,380 So they all depolarize to this positive 50 millivolts. 216 00:13:12,380 --> 00:13:14,710 And so this illustrates a key property 217 00:13:14,710 --> 00:13:19,870 of neurons, in that the level of activity of a neuron 218 00:13:19,870 --> 00:13:25,480 is not determined by the size of this action potential. 219 00:13:25,480 --> 00:13:28,450 This action potential is an all-or-nothing event. 220 00:13:28,450 --> 00:13:30,140 It either happens or it doesn't. 221 00:13:30,140 --> 00:13:33,070 And when it happens, it depolarizes to the same level. 222 00:13:35,890 --> 00:13:38,470 So the action potential is all or nothing. 223 00:13:42,680 --> 00:13:45,490 You can think of it as a binary signal. 224 00:13:45,490 --> 00:13:47,530 And therefore, the way that neurons 225 00:13:47,530 --> 00:13:50,950 encode sort of the magnitude of activation 226 00:13:50,950 --> 00:13:54,040 is not through the level of depolarization 227 00:13:54,040 --> 00:13:56,920 of a single action potential, but it 228 00:13:56,920 --> 00:14:00,280 is able to distinguish between different frequencies of action 229 00:14:00,280 --> 00:14:03,220 potentials that are propagating along the neuron. 230 00:14:05,770 --> 00:14:12,640 So signal strength, in this case, 231 00:14:12,640 --> 00:14:16,240 is related to the frequency of action potentials firing. 232 00:14:26,660 --> 00:14:28,340 So now we're going to unpack how it 233 00:14:28,340 --> 00:14:31,820 is a nerve cell fires an action potential 234 00:14:31,820 --> 00:14:34,940 and how it propagates along the entire cell length, right? 235 00:14:34,940 --> 00:14:36,740 In the case of the sciatic nerve, 236 00:14:36,740 --> 00:14:39,230 this has to happen across an entire meter, OK? 237 00:14:39,230 --> 00:14:41,840 That's a very long distance to propagate 238 00:14:41,840 --> 00:14:46,410 this change in electrical signal, at least for a cell. 239 00:14:46,410 --> 00:14:49,010 And so we're going to talk about the mechanism. 240 00:14:49,010 --> 00:14:52,070 And I'm going to start at the beginning, when this action 241 00:14:52,070 --> 00:14:55,340 potential initiates. 242 00:14:55,340 --> 00:14:59,510 So we'll start at the initiation of the action potential. 243 00:15:03,390 --> 00:15:07,140 So how is it that this nerve cell 244 00:15:07,140 --> 00:15:11,300 is told to start depolarizing at the dendrites? 245 00:15:11,300 --> 00:15:14,250 Because there's going to be another neuron here, 246 00:15:14,250 --> 00:15:17,820 which is going to communicate to this neuron over here 247 00:15:17,820 --> 00:15:21,160 to tell it to start depolarizing. 248 00:15:21,160 --> 00:15:24,720 It does this at the location known as the synapse, which 249 00:15:24,720 --> 00:15:28,080 is basically sort of the connection between the two 250 00:15:28,080 --> 00:15:30,870 neurons. 251 00:15:30,870 --> 00:15:32,970 And the way this process is initiated 252 00:15:32,970 --> 00:15:34,980 is similar to the type of signaling 253 00:15:34,980 --> 00:15:37,860 that you saw in the past few lectures, where you have 254 00:15:37,860 --> 00:15:41,430 a ligand and a receptor, OK? 255 00:15:41,430 --> 00:15:50,310 In this case, the ligand is going 256 00:15:50,310 --> 00:15:55,960 to be what's known as a neurotransmitter, which 257 00:15:55,960 --> 00:15:57,400 is a small molecule. 258 00:15:57,400 --> 00:16:01,210 And I'll show you some later on. 259 00:16:01,210 --> 00:16:05,590 And the receptor is going to be a receptor that 260 00:16:05,590 --> 00:16:07,660 binds to this ligand. 261 00:16:07,660 --> 00:16:09,820 But in this case, rather than being something 262 00:16:09,820 --> 00:16:13,510 like a G protein coupled receptor or a receptor tyrosine 263 00:16:13,510 --> 00:16:18,160 kinase, the receptor is going to be an ion channel, OK? 264 00:16:18,160 --> 00:16:20,560 So the receptor is going to be an ion channel. 265 00:16:25,150 --> 00:16:27,250 And so you see one example in the slide 266 00:16:27,250 --> 00:16:30,820 up here, where here's a receptor. 267 00:16:30,820 --> 00:16:35,410 And these receptors are what are known as ligand-gated ion 268 00:16:35,410 --> 00:16:35,950 channels. 269 00:16:35,950 --> 00:16:38,150 In this case, it's a sodium channel. 270 00:16:38,150 --> 00:16:40,030 So it's going to be-- 271 00:16:40,030 --> 00:16:44,000 whether or not it's open depends on the presence of the ligand. 272 00:16:44,000 --> 00:16:48,180 So if we take a neurotransmitter like serotonin, 273 00:16:48,180 --> 00:16:50,230 if it's not bound to the receptor, 274 00:16:50,230 --> 00:16:52,090 the receptor is closed. 275 00:16:52,090 --> 00:16:55,060 But if serotonin binds to the receptor, 276 00:16:55,060 --> 00:16:58,360 it opens up the channel, which can selectively 277 00:16:58,360 --> 00:17:00,070 let in a type of ion-- 278 00:17:00,070 --> 00:17:02,020 in this case, sodium. 279 00:17:02,020 --> 00:17:05,230 In this case, this is an activating channel, 280 00:17:05,230 --> 00:17:07,150 because letting in sodium is going 281 00:17:07,150 --> 00:17:11,740 to depolarize the cell, OK? 282 00:17:11,740 --> 00:17:16,470 So this ligand receptor binding uses a ligand-gated-- 283 00:17:19,060 --> 00:17:21,445 there's a ligand-gated sodium channel. 284 00:17:25,030 --> 00:17:29,680 And it's this ligand-gated sodium channel which 285 00:17:29,680 --> 00:17:31,390 starts the depolarization. 286 00:17:39,940 --> 00:17:45,400 So that's how you sort of knock over the first domino, right? 287 00:17:45,400 --> 00:17:47,800 But then there has to be some mechanism 288 00:17:47,800 --> 00:17:52,570 to propagate this along the length of a very long cell. 289 00:17:52,570 --> 00:17:58,390 And so I'll tell you this involves a different type 290 00:17:58,390 --> 00:18:01,690 of sort of signaling mechanism from what you're 291 00:18:01,690 --> 00:18:04,960 used to thinking about, because this involves a different type 292 00:18:04,960 --> 00:18:06,730 of an ion channel. 293 00:18:06,730 --> 00:18:08,860 And it's called a voltage gated. 294 00:18:12,440 --> 00:18:16,800 And I'll abbreviate voltage gated just VG. 295 00:18:16,800 --> 00:18:19,000 And in this case, it will be a sodium channel. 296 00:18:23,890 --> 00:18:27,290 So what's a voltage-gated sodium channel? 297 00:18:27,290 --> 00:18:29,950 This is a voltage-gated sodium channel here. 298 00:18:29,950 --> 00:18:32,930 And you can see, in the resting state of the cell, 299 00:18:32,930 --> 00:18:35,020 this channel is closed. 300 00:18:35,020 --> 00:18:38,470 And it's closed because of this red rod structure 301 00:18:38,470 --> 00:18:40,450 that's positively charged. 302 00:18:40,450 --> 00:18:43,240 That's a positively charged alpha helix 303 00:18:43,240 --> 00:18:45,430 that is a part of this protein and is 304 00:18:45,430 --> 00:18:48,520 embedded in the membrane. 305 00:18:48,520 --> 00:18:52,600 But this alpha helix is positioned down 306 00:18:52,600 --> 00:18:56,020 towards the cytoplasm, because it's positively charged. 307 00:18:56,020 --> 00:18:58,540 And the cytosolic face of the plasma membrane 308 00:18:58,540 --> 00:19:01,120 is negatively charged, OK? 309 00:19:01,120 --> 00:19:03,700 And the confirmation of this protein 310 00:19:03,700 --> 00:19:07,810 then depends on the charge across this membrane. 311 00:19:07,810 --> 00:19:10,720 Because when there is depolarization, 312 00:19:10,720 --> 00:19:15,070 that shifts the position of this alpha helix, such that now it 313 00:19:15,070 --> 00:19:19,160 shifts up towards the exterior face of the plasma membrane. 314 00:19:19,160 --> 00:19:23,040 And that opens the channel, which lets sodium ions rush in, 315 00:19:23,040 --> 00:19:24,750 OK? 316 00:19:24,750 --> 00:19:28,870 Again, sodium ions here, they're always rushing downstream. 317 00:19:28,870 --> 00:19:32,290 They're concentration gradient. 318 00:19:32,290 --> 00:19:36,190 So in this case, whether or not this channel is open or closed 319 00:19:36,190 --> 00:19:38,830 depends not on the presence of a ligand, 320 00:19:38,830 --> 00:19:43,330 but on the membrane potential across the plasma membrane. 321 00:19:43,330 --> 00:19:46,210 So these voltage-gated sodium channels, 322 00:19:46,210 --> 00:19:49,990 they're opened by depolarization. 323 00:20:01,310 --> 00:20:02,990 And then the question becomes, if you 324 00:20:02,990 --> 00:20:06,770 open these channels at the very end of the neuron, 325 00:20:06,770 --> 00:20:10,550 how do you get it such that this electrical signal moves 326 00:20:10,550 --> 00:20:13,940 unidirectionally along the neuron? 327 00:20:13,940 --> 00:20:17,510 So what leads to unidirectionality? 328 00:20:25,300 --> 00:20:29,160 Who's been to a sporting event lately? 329 00:20:29,160 --> 00:20:30,750 OK, good. 330 00:20:30,750 --> 00:20:33,690 You guys know the wave? 331 00:20:33,690 --> 00:20:35,752 So we're going to do the wave. 332 00:20:35,752 --> 00:20:37,710 Once you to stand up, you're going to be tired, 333 00:20:37,710 --> 00:20:40,440 and you're going to have to sit down for a while. 334 00:20:40,440 --> 00:20:42,660 I'm going to be a ligand-- 335 00:20:42,660 --> 00:20:45,340 I'm a ligand-gated sodium channel, 336 00:20:45,340 --> 00:20:49,090 so I'm going to start things off, OK? 337 00:20:49,090 --> 00:20:51,510 You ready? 338 00:20:51,510 --> 00:20:52,480 All right, here we go. 339 00:20:57,550 --> 00:21:01,720 OK, that's basically an action potential. 340 00:21:01,720 --> 00:21:06,670 So the way that this was unidirectional 341 00:21:06,670 --> 00:21:11,920 is once you stood up and did the wave, you then sat down, 342 00:21:11,920 --> 00:21:15,520 and you stopped doing anything. 343 00:21:15,520 --> 00:21:19,060 And so these voltage-gated sodium channels 344 00:21:19,060 --> 00:21:20,080 have a similar property. 345 00:21:22,690 --> 00:21:25,480 If we look at the next step in this, 346 00:21:25,480 --> 00:21:29,160 the sodium channel is opened by depolarization. 347 00:21:29,160 --> 00:21:33,460 And you see there's this ball of chain segment of the protein. 348 00:21:33,460 --> 00:21:35,290 You see that yellow ball? 349 00:21:35,290 --> 00:21:39,160 Once the sodium channel opens, after about a millisecond, 350 00:21:39,160 --> 00:21:44,080 that ball sticks in the channel pore and blocks it, OK? 351 00:21:44,080 --> 00:21:48,220 So these sodium channels open to let in sodium ions, 352 00:21:48,220 --> 00:21:50,590 but then they're immediately inactivated 353 00:21:50,590 --> 00:21:54,790 after about a millisecond, OK? 354 00:21:54,790 --> 00:21:59,830 And so that enables unidirectionality. 355 00:21:59,830 --> 00:22:06,090 So this is what I'll call voltage-gated sodium channel 356 00:22:06,090 --> 00:22:07,000 inactivation. 357 00:22:14,260 --> 00:22:16,600 And how this promotes a traveling 358 00:22:16,600 --> 00:22:21,610 wave of depolarization is that if we consider an action 359 00:22:21,610 --> 00:22:25,670 potential moving along this axon from left to right 360 00:22:25,670 --> 00:22:28,390 and if the sodium channels in the green zone 361 00:22:28,390 --> 00:22:31,880 are currently open, it came from the left, 362 00:22:31,880 --> 00:22:33,940 which means that all the sodium channels 363 00:22:33,940 --> 00:22:39,340 to the left of this green zone are going to be inactivated. 364 00:22:39,340 --> 00:22:41,590 So because they're inactivated here, 365 00:22:41,590 --> 00:22:43,930 there won't be further depolarization 366 00:22:43,930 --> 00:22:46,570 going to the left, but depolarization 367 00:22:46,570 --> 00:22:48,640 will have to move to the right. 368 00:22:48,640 --> 00:22:51,340 And you basically get this traveling wave. 369 00:22:51,340 --> 00:22:53,950 And it goes one direction, because if it 370 00:22:53,950 --> 00:22:57,910 came from somewhere, which it always does, then where it just 371 00:22:57,910 --> 00:23:00,520 was coming from, all those sodium 372 00:23:00,520 --> 00:23:02,710 channels, the voltage-gated sodium channels 373 00:23:02,710 --> 00:23:04,720 are going to be closed. 374 00:23:04,720 --> 00:23:07,990 So this allows it to move in a single direction 375 00:23:07,990 --> 00:23:09,220 along the neuron. 376 00:23:09,220 --> 00:23:12,670 Also, once the action potential gets to the end of the neuron, 377 00:23:12,670 --> 00:23:15,560 it doesn't reflect back the other way in the neuron. 378 00:23:15,560 --> 00:23:18,730 This can only go one direction. 379 00:23:18,730 --> 00:23:21,820 So this provides unidirectionality. 380 00:23:21,820 --> 00:23:28,570 So it's this inactive or refractory period 381 00:23:28,570 --> 00:23:31,060 of the voltage-gated sodium channel 382 00:23:31,060 --> 00:23:34,180 which prevents the action potential 383 00:23:34,180 --> 00:23:35,380 from moving backwards. 384 00:23:39,200 --> 00:23:43,470 Now, if you look at these action potentials in the cell, 385 00:23:43,470 --> 00:23:47,540 you see that they happen, but you don't just 386 00:23:47,540 --> 00:23:50,150 depolarize and stay depolarized. 387 00:23:50,150 --> 00:23:54,830 The cell body depolarizes and then repolarizes very rapidly. 388 00:23:54,830 --> 00:23:57,140 So there's an oscillation. 389 00:23:57,140 --> 00:24:03,180 So there has to be some way to terminate the action potential. 390 00:24:03,180 --> 00:24:09,170 So there's a termination or repolarization of the cell. 391 00:24:14,670 --> 00:24:17,090 So there has to be a way for this nerve cell 392 00:24:17,090 --> 00:24:21,950 to rapidly restore membrane potential. 393 00:24:21,950 --> 00:24:24,530 And I want you to think for just a couple of seconds 394 00:24:24,530 --> 00:24:27,530 about what type of channel might you open 395 00:24:27,530 --> 00:24:29,390 to re-establish this polarity. 396 00:24:33,670 --> 00:24:37,390 What ion do you need to flow from where to where in order 397 00:24:37,390 --> 00:24:40,240 to get a net negative charge on the inside? 398 00:24:44,260 --> 00:24:45,127 Udo? 399 00:24:45,127 --> 00:24:46,955 AUDIENCE: You need to move the sodium ions 400 00:24:46,955 --> 00:24:49,240 from the inside to the outside. 401 00:24:49,240 --> 00:24:52,270 ADAM MARTIN: OK, you could pump the sodium ions out, 402 00:24:52,270 --> 00:24:54,460 and that's totally accurate. 403 00:24:54,460 --> 00:24:57,430 So that's going to require moving sodium ions 404 00:24:57,430 --> 00:25:01,270 up a concentration gradient, which is going to take energy 405 00:25:01,270 --> 00:25:02,950 and is going to be slow. 406 00:25:02,950 --> 00:25:05,890 So is there another option we could take advantage of here 407 00:25:05,890 --> 00:25:07,270 to repolarize? 408 00:25:07,270 --> 00:25:08,650 Rachel? 409 00:25:08,650 --> 00:25:10,840 AUDIENCE: Move the potassium ions. 410 00:25:10,840 --> 00:25:12,340 ADAM MARTIN: So Rachel has suggested 411 00:25:12,340 --> 00:25:17,200 to moving the potassium ions to the outside, which 412 00:25:17,200 --> 00:25:19,190 is how this is done. 413 00:25:19,190 --> 00:25:22,930 So remember, potassium is high in the cytoplasmic, 414 00:25:22,930 --> 00:25:25,180 low on the exoplasm. 415 00:25:25,180 --> 00:25:27,610 And therefore, if you have a voltage-gated potassium 416 00:25:27,610 --> 00:25:31,210 channel, that's going to cause a rush of positive ions out 417 00:25:31,210 --> 00:25:32,540 of the cell. 418 00:25:32,540 --> 00:25:36,340 And that will be able to restore the net negative potential 419 00:25:36,340 --> 00:25:39,670 on the inside of the cell. 420 00:25:39,670 --> 00:25:43,660 So this termination or repolarization 421 00:25:43,660 --> 00:25:49,390 is the result of the opening of voltage gated, in this case, 422 00:25:49,390 --> 00:25:54,110 not sodium channels, but potassium channels. 423 00:25:54,110 --> 00:25:56,110 When do you think these have to open relative 424 00:25:56,110 --> 00:25:57,220 to the sodium channel? 425 00:26:02,430 --> 00:26:05,340 Should they open right with the sodium channel? 426 00:26:05,340 --> 00:26:07,170 Carmen's shaking her head no. 427 00:26:07,170 --> 00:26:10,612 Do you want to explain your logic? 428 00:26:10,612 --> 00:26:13,002 AUDIENCE: Well, I mean, they both carry the same charge, 429 00:26:13,002 --> 00:26:16,830 so they wind up getting out at the same time [INAUDIBLE].. 430 00:26:16,830 --> 00:26:18,780 ADAM MARTIN: Exactly. 431 00:26:18,780 --> 00:26:22,080 So what Carmen said is if they open simultaneously, 432 00:26:22,080 --> 00:26:24,150 you have sodium flowing in. 433 00:26:24,150 --> 00:26:25,800 You have potassium flowing out. 434 00:26:25,800 --> 00:26:29,760 And that's not going to necessarily change the charge. 435 00:26:29,760 --> 00:26:33,510 So when would these have to open relative to sodium channels? 436 00:26:37,340 --> 00:26:38,000 Yeah, Carmen? 437 00:26:38,000 --> 00:26:41,100 AUDIENCE: When it reaches that potential [INAUDIBLE].. 438 00:26:41,100 --> 00:26:44,150 ADAM MARTIN: So after it's depolarized, yeah. 439 00:26:44,150 --> 00:26:46,820 So this has to be delayed relative to the sodium 440 00:26:46,820 --> 00:26:48,470 channels, OK? 441 00:26:48,470 --> 00:26:53,090 So this has to be delayed relative 442 00:26:53,090 --> 00:26:56,540 to the voltage-gated sodium channels. 443 00:27:02,030 --> 00:27:04,070 Because if you're thinking about this traveling 444 00:27:04,070 --> 00:27:08,180 wave of depolarization, the depolarization 445 00:27:08,180 --> 00:27:10,850 is going to be high where the sodium channels are only 446 00:27:10,850 --> 00:27:11,870 entering. 447 00:27:11,870 --> 00:27:13,700 And then following that, you would 448 00:27:13,700 --> 00:27:16,010 have potassium ions getting pumped out 449 00:27:16,010 --> 00:27:19,280 and basically repolarizing the cell. 450 00:27:19,280 --> 00:27:23,120 Everyone see how you sort of get depolarization 451 00:27:23,120 --> 00:27:25,760 with sodium rushing in, and then after that, you 452 00:27:25,760 --> 00:27:30,290 repolarize with the potassium getting pumped out, right? 453 00:27:30,290 --> 00:27:33,650 So here, you have a spike, and you complete the cycle. 454 00:27:33,650 --> 00:27:36,410 It can even get hyperpolarized, where it gets even more 455 00:27:36,410 --> 00:27:38,730 negative than it normally does. 456 00:27:38,730 --> 00:27:42,170 And then it eventually gets back to this resting potential 457 00:27:42,170 --> 00:27:45,080 of around negative 60 or negative 70 millivolts. 458 00:27:52,350 --> 00:27:54,970 OK, so this has to happen fast. 459 00:27:54,970 --> 00:27:59,500 And I want to tell you about one process or property of neurons 460 00:27:59,500 --> 00:28:02,110 and another helpful cell that enables 461 00:28:02,110 --> 00:28:05,680 this to go extremely fast. 462 00:28:05,680 --> 00:28:09,940 And that is that there are these glial cells in your body 463 00:28:09,940 --> 00:28:13,000 and your brain that wrap around the axons 464 00:28:13,000 --> 00:28:16,720 of the neurons and basically function like electrical tape 465 00:28:16,720 --> 00:28:18,820 for neurons, OK? 466 00:28:18,820 --> 00:28:21,540 So they are these-- 467 00:28:21,540 --> 00:28:32,320 there's electrical insulation around the axons 468 00:28:32,320 --> 00:28:34,760 of these neurons. 469 00:28:34,760 --> 00:28:37,360 And this is provided by another specialized cell 470 00:28:37,360 --> 00:28:39,830 type called a glial cell. 471 00:28:39,830 --> 00:28:41,260 So this is by a glial cell. 472 00:28:47,630 --> 00:28:50,960 And here are two examples of glial cells. 473 00:28:50,960 --> 00:28:52,940 There are oligodendrocytes-- and you 474 00:28:52,940 --> 00:28:56,360 can see how the cell is extending processes 475 00:28:56,360 --> 00:29:00,530 that wrap around the axons of these two neurons. 476 00:29:00,530 --> 00:29:02,990 Here's a Schwann cell over here, which 477 00:29:02,990 --> 00:29:05,300 again, wraps around the axon. 478 00:29:05,300 --> 00:29:12,420 And these cells basically form what's called a myelin sheath. 479 00:29:12,420 --> 00:29:16,810 So they form a myelin sheath around the axons. 480 00:29:16,810 --> 00:29:21,590 And that insulates the plasma membrane of the axon 481 00:29:21,590 --> 00:29:22,370 such that-- 482 00:29:25,170 --> 00:29:27,800 so here is an axon. 483 00:29:27,800 --> 00:29:31,290 You have glial cells that are wrapped around, 484 00:29:31,290 --> 00:29:34,170 and it sort of forms like beads on a string. 485 00:29:34,170 --> 00:29:38,330 And so there are these gaps between the myelin sheath 486 00:29:38,330 --> 00:29:42,950 that are known as the nodes of Ranvier. 487 00:29:42,950 --> 00:29:51,470 So there are these nodes of Ranvier, which 488 00:29:51,470 --> 00:29:54,740 are gaps in the myelin sheath. 489 00:29:59,540 --> 00:30:02,000 And these nodes perform an important function 490 00:30:02,000 --> 00:30:05,720 for the neuron, because where the axon is wrapped, 491 00:30:05,720 --> 00:30:09,200 the membrane is electrically insulated. 492 00:30:09,200 --> 00:30:11,930 And so the sodium ions-- 493 00:30:11,930 --> 00:30:14,240 or the sodium channels and potassium channels, 494 00:30:14,240 --> 00:30:18,170 the voltage gated ones, localize to these nodes. 495 00:30:18,170 --> 00:30:22,190 And when the action potential is traveling along the axon, 496 00:30:22,190 --> 00:30:26,120 because these regions where the myelin sheath is 497 00:30:26,120 --> 00:30:29,600 are electrically insulated, the axon potential 498 00:30:29,600 --> 00:30:32,870 doesn't just move continuously, but jumps from node 499 00:30:32,870 --> 00:30:36,050 to node, such that you are just opening the sodium 500 00:30:36,050 --> 00:30:37,700 channels at these nodes. 501 00:30:37,700 --> 00:30:39,710 And that allows the action potential 502 00:30:39,710 --> 00:30:43,820 to travel about 100-fold faster along the axon. 503 00:30:43,820 --> 00:30:45,470 And that's what allows your neurons 504 00:30:45,470 --> 00:30:47,420 to transmit these electrical signals 505 00:30:47,420 --> 00:30:49,820 from the base of your spine to your foot so rapidly. 506 00:30:53,320 --> 00:30:59,570 So you get an increase in speed because the action potential 507 00:30:59,570 --> 00:31:01,250 is jumping from node to node. 508 00:31:04,700 --> 00:31:07,610 And one important reason to bring this up 509 00:31:07,610 --> 00:31:11,930 is because there is an important human disease that 510 00:31:11,930 --> 00:31:15,260 affects the electrical insulation in the myelin sheath 511 00:31:15,260 --> 00:31:18,140 here, and that's multiple sclerosis. 512 00:31:24,120 --> 00:31:26,780 So we're going to unpack multiple sclerosis in a couple 513 00:31:26,780 --> 00:31:27,690 lectures. 514 00:31:27,690 --> 00:31:29,873 This is an autoimmune disorder. 515 00:31:29,873 --> 00:31:32,540 And so we're going to talk about immunity later in the semester, 516 00:31:32,540 --> 00:31:35,220 and we'll talk about how that happens. 517 00:31:35,220 --> 00:31:36,890 But for now, I just want to point out 518 00:31:36,890 --> 00:31:40,610 that multiple sclerosis happens when the immune system attacks 519 00:31:40,610 --> 00:31:41,870 this myelin sheath. 520 00:31:45,360 --> 00:31:48,530 So in multiple sclerosis, the myelin sheath is damaged. 521 00:31:51,800 --> 00:31:55,130 And if you damage this electrical insulation, 522 00:31:55,130 --> 00:31:58,730 you greatly slow down these action potentials, 523 00:31:58,730 --> 00:32:00,980 and that has a significant impact 524 00:32:00,980 --> 00:32:06,020 on nerve impulses in the brain and throughout the entire body. 525 00:32:06,020 --> 00:32:07,760 And that's why multiple sclerosis 526 00:32:07,760 --> 00:32:09,110 is such a devastating disease. 527 00:32:13,340 --> 00:32:15,350 All right, I'm going to start moving now 528 00:32:15,350 --> 00:32:17,840 to consider more than one neuron. 529 00:32:17,840 --> 00:32:19,730 So until now, we've just talked about how 530 00:32:19,730 --> 00:32:23,740 an electrical signal is sent along the length of one cell. 531 00:32:23,740 --> 00:32:26,240 And now we're going to start thinking about multiple neurons 532 00:32:26,240 --> 00:32:29,780 and how they connect and how neurons integrate information 533 00:32:29,780 --> 00:32:32,750 from multiple other neurons to decide whether or not 534 00:32:32,750 --> 00:32:36,480 to send an action potential. 535 00:32:36,480 --> 00:32:39,440 And so if we consider this connection right here, 536 00:32:39,440 --> 00:32:41,420 there's a synapse right here. 537 00:32:41,420 --> 00:32:44,720 Here's a cell that's sending information 538 00:32:44,720 --> 00:32:50,690 and a cell that is receiving that information. 539 00:32:50,690 --> 00:32:53,120 When we're considering a synapse-- 540 00:32:53,120 --> 00:32:57,350 so if we consider a synapse, there's 541 00:32:57,350 --> 00:33:00,410 a cell that is sending the signal, which 542 00:33:00,410 --> 00:33:02,020 is called the presynapse. 543 00:33:05,600 --> 00:33:06,950 This is the sender cell. 544 00:33:10,440 --> 00:33:12,080 And there's a postsynaptic cell. 545 00:33:19,010 --> 00:33:21,320 But you can have more than one neuron 546 00:33:21,320 --> 00:33:26,240 sending a signal to a neuron at a given time, right? 547 00:33:26,240 --> 00:33:28,420 So here, you have one neuron that's 548 00:33:28,420 --> 00:33:31,220 sending a signal at this synapse, 549 00:33:31,220 --> 00:33:34,160 but you might have another neuron sending a signal 550 00:33:34,160 --> 00:33:36,620 to a synapse on this part of the cell. 551 00:33:36,620 --> 00:33:39,920 And you could have another signal coming in here. 552 00:33:39,920 --> 00:33:41,960 And so this neuron will then have 553 00:33:41,960 --> 00:33:44,390 to decide whether or not to fire an action 554 00:33:44,390 --> 00:33:48,740 potential down its axon. 555 00:33:48,740 --> 00:33:52,100 And the way that the neuron decides this 556 00:33:52,100 --> 00:33:54,950 is to integrate the signals. 557 00:33:54,950 --> 00:33:56,910 So there's a signal integration process. 558 00:34:01,210 --> 00:34:05,010 And what's important for signal integration in a neuron is 559 00:34:05,010 --> 00:34:07,680 whether or not the cell body-- 560 00:34:07,680 --> 00:34:11,010 whether the voltage increases above a certain threshold 561 00:34:11,010 --> 00:34:12,270 potential. 562 00:34:12,270 --> 00:34:14,880 So if the cell body doesn't increase-- 563 00:34:14,880 --> 00:34:18,159 if the voltage doesn't increase above this potential, 564 00:34:18,159 --> 00:34:20,889 there will be no action potential fired. 565 00:34:20,889 --> 00:34:25,739 But if the voltage increases above the threshold potential, 566 00:34:25,739 --> 00:34:27,840 then it fires the action potential 567 00:34:27,840 --> 00:34:30,120 and signals to a downstream neuron 568 00:34:30,120 --> 00:34:34,590 or muscle or another cell. 569 00:34:34,590 --> 00:34:49,020 So here, it is the threshold potential in the cell body 570 00:34:49,020 --> 00:34:51,750 that determines whether or not an action potential is 571 00:34:51,750 --> 00:34:52,650 sent down the axon. 572 00:34:55,590 --> 00:34:58,260 And there are different types of signals 573 00:34:58,260 --> 00:35:01,948 that nerve cells can send. 574 00:35:01,948 --> 00:35:03,615 So there are different types of signals. 575 00:35:08,220 --> 00:35:11,640 Signals can be excitatory, meaning it will 576 00:35:11,640 --> 00:35:14,940 tend to depolarize the neuron. 577 00:35:14,940 --> 00:35:25,110 So there are excitatory signals, which result in depolarization. 578 00:35:27,720 --> 00:35:31,770 For example, with serotonin, that 579 00:35:31,770 --> 00:35:35,310 opens the sodium channel, and that results in depolarization, 580 00:35:35,310 --> 00:35:37,890 so that's an excitatory signal. 581 00:35:37,890 --> 00:35:40,590 But there are other types of signals 582 00:35:40,590 --> 00:35:44,460 that bind to different types of receptors that are inhibitory. 583 00:35:47,610 --> 00:35:49,290 What might be a type of receptor that 584 00:35:49,290 --> 00:35:53,220 would inhibit this process of sending an action potential? 585 00:35:58,620 --> 00:36:00,930 What might an inhibitory receptor 586 00:36:00,930 --> 00:36:06,870 be to lower the chance that this action potential will be fired? 587 00:36:09,750 --> 00:36:12,960 What if I told you it's an ion channel? 588 00:36:12,960 --> 00:36:17,334 What ion would you expect it might pass? 589 00:36:17,334 --> 00:36:18,830 Udo? 590 00:36:18,830 --> 00:36:20,082 AUDIENCE: Potassium. 591 00:36:20,082 --> 00:36:21,040 ADAM MARTIN: Potassium. 592 00:36:21,040 --> 00:36:23,460 Udo is exactly right, right? 593 00:36:23,460 --> 00:36:25,650 If it passes potassium, then it's 594 00:36:25,650 --> 00:36:29,080 going to make the inside more negative. 595 00:36:29,080 --> 00:36:32,250 And that's what's known as hyperpolarization. 596 00:36:32,250 --> 00:36:36,060 So receptors that result in hyperpolarization 597 00:36:36,060 --> 00:36:38,475 would have an inhibitory effect on this process. 598 00:36:45,300 --> 00:36:48,330 And remember, if you're hyperpolarizing, 599 00:36:48,330 --> 00:36:51,630 then you could cause this to actually go down and get 600 00:36:51,630 --> 00:36:54,610 even farther away from this threshold potential, right? 601 00:36:54,610 --> 00:36:56,550 And if you have an activating signal 602 00:36:56,550 --> 00:36:58,860 and an inhibitory signal, they might cancel out, 603 00:36:58,860 --> 00:37:02,910 because one will depolarize and the other will hyperpolarize. 604 00:37:02,910 --> 00:37:08,100 So it's in this way a neuron is able to integrate signals 605 00:37:08,100 --> 00:37:09,720 coming from different neurons. 606 00:37:09,720 --> 00:37:11,820 And that influences whether or not 607 00:37:11,820 --> 00:37:17,550 it will send the signal to a downstream cell. 608 00:37:17,550 --> 00:37:20,010 OK, so now we're focusing on what 609 00:37:20,010 --> 00:37:23,790 is the communication between one neuron and another. 610 00:37:23,790 --> 00:37:27,585 And this revolves around this thing 611 00:37:27,585 --> 00:37:29,460 that's called the synapse, which is basically 612 00:37:29,460 --> 00:37:33,600 the gap between the axon terminal of one neuron 613 00:37:33,600 --> 00:37:36,355 and the dendrites of a postsynaptic neuron. 614 00:37:40,230 --> 00:37:43,590 And so the way that multiple neurons communicate 615 00:37:43,590 --> 00:37:46,230 with each other are through a type of signal 616 00:37:46,230 --> 00:37:51,090 known as a neurotransmitter. 617 00:37:51,090 --> 00:37:54,220 And this is what initiates the signal. 618 00:37:54,220 --> 00:37:58,770 So there's a signal initiation process at the synapse. 619 00:37:58,770 --> 00:38:01,430 Initiation. 620 00:38:01,430 --> 00:38:04,860 And this involves the presynaptic neuron 621 00:38:04,860 --> 00:38:08,170 secreting a neurotransmitter. 622 00:38:08,170 --> 00:38:11,280 So the signal, in this case, signals between neurons 623 00:38:11,280 --> 00:38:14,980 are called neurotransmitters. 624 00:38:14,980 --> 00:38:18,090 And as you see on the slide, these 625 00:38:18,090 --> 00:38:20,080 are examples of neurotransmitters. 626 00:38:20,080 --> 00:38:22,140 They're often derived from amino acids, 627 00:38:22,140 --> 00:38:23,940 and so they're small molecules. 628 00:38:23,940 --> 00:38:26,280 They're not the proteins that you often 629 00:38:26,280 --> 00:38:29,460 see with receptor tyrosine kinase ligands. 630 00:38:29,460 --> 00:38:32,490 This is a different class of signal. 631 00:38:32,490 --> 00:38:34,320 So one example is serotonin. 632 00:38:38,080 --> 00:38:43,200 And if you look up at those, we'll find serotonin here. 633 00:38:43,200 --> 00:38:43,710 There it is. 634 00:38:43,710 --> 00:38:47,190 Here, you can see it's a derivative of tryptophan. 635 00:38:47,190 --> 00:38:49,530 So it's a small molecule, and it's 636 00:38:49,530 --> 00:38:54,070 able to bind to a receptor on the postsynaptic cell 637 00:38:54,070 --> 00:38:55,650 and induce depolarization. 638 00:38:58,830 --> 00:39:02,770 And so neurons are-- the way that they communicate 639 00:39:02,770 --> 00:39:06,480 is-- neurons are a case of where luck favors the prepared. 640 00:39:06,480 --> 00:39:11,340 Neurons are totally prepared to send signals to each other. 641 00:39:11,340 --> 00:39:14,460 They have everything ready to go when they get word 642 00:39:14,460 --> 00:39:18,150 from upstream, and they're ready to send signals 643 00:39:18,150 --> 00:39:20,250 to the next cell. 644 00:39:20,250 --> 00:39:23,640 And that's because if we look at the synapse 645 00:39:23,640 --> 00:39:28,320 prior to an action potential, everything is ready to go. 646 00:39:28,320 --> 00:39:31,200 The cell has neurotransmitter, and it's 647 00:39:31,200 --> 00:39:35,340 packaged in these vesicles, and it's tethered to the plasma 648 00:39:35,340 --> 00:39:38,970 membrane, ready to be released. 649 00:39:38,970 --> 00:39:41,000 So prior to the action potential, 650 00:39:41,000 --> 00:39:44,400 there are vesicles filled with neurotransmitter that are 651 00:39:44,400 --> 00:39:46,110 docked at the plasma membrane. 652 00:39:50,490 --> 00:39:53,340 I abbreviate plasma membrane PM, just so I 653 00:39:53,340 --> 00:39:55,440 don't have to write it out, OK? 654 00:39:55,440 --> 00:39:58,590 So these contain neurotransmitter, right? 655 00:39:58,590 --> 00:40:00,690 But you see in this docked vesicle, 656 00:40:00,690 --> 00:40:03,180 the neurotransmitter is in red, and it 657 00:40:03,180 --> 00:40:05,340 can't get out if that vesicle does not 658 00:40:05,340 --> 00:40:06,810 fuse with the plasma membrane. 659 00:40:10,830 --> 00:40:13,199 So these contain neurotransmitter. 660 00:40:22,490 --> 00:40:26,120 But at this point, the vesicles haven't fused. 661 00:40:26,120 --> 00:40:28,670 But the vesicle's not fused. 662 00:40:38,258 --> 00:40:39,175 When should they fuse? 663 00:40:41,890 --> 00:40:44,190 In this system of neuron signaling to each other, 664 00:40:44,190 --> 00:40:50,730 when should the vesicle fuse with the plasma membrane? 665 00:40:50,730 --> 00:40:54,210 What should trigger the fusion process? 666 00:40:54,210 --> 00:40:55,466 Yes, Miles? 667 00:40:55,466 --> 00:41:03,158 AUDIENCE: So after [INAUDIBLE] axon 668 00:41:03,158 --> 00:41:08,526 when it's time for the [INAUDIBLE] 669 00:41:08,526 --> 00:41:10,965 that's when the vesicles fuse. 670 00:41:10,965 --> 00:41:12,840 ADAM MARTIN: Yeah, so Miles is exactly right. 671 00:41:12,840 --> 00:41:17,070 If we consider my diagram here, there's 672 00:41:17,070 --> 00:41:20,460 an action potential traveling along this axon. 673 00:41:20,460 --> 00:41:22,950 When it gets to the axon terminus, 674 00:41:22,950 --> 00:41:26,010 that should be the signal for these vesicles 675 00:41:26,010 --> 00:41:28,530 to fuse to the plasma membrane and to release 676 00:41:28,530 --> 00:41:30,990 neurotransmitter. 677 00:41:30,990 --> 00:41:33,960 So it's the arrival of the action potential, right? 678 00:41:33,960 --> 00:41:36,750 So remember, in this case, serotonin 679 00:41:36,750 --> 00:41:38,650 is going to be in blue. 680 00:41:38,650 --> 00:41:41,810 If serotonin is inside my vesicle here, 681 00:41:41,810 --> 00:41:43,890 it's going to need to exocytose. 682 00:41:43,890 --> 00:41:48,510 And now the serotonin is going to be outside the cell, 683 00:41:48,510 --> 00:41:50,220 ready to bind to the receptor. 684 00:41:53,790 --> 00:41:56,740 All right, so as Miles pointed out, 685 00:41:56,740 --> 00:41:58,470 you have an action potential. 686 00:41:58,470 --> 00:42:01,410 The fusion should be triggered by the action potential. 687 00:42:01,410 --> 00:42:03,150 In order to fuse, there needs to be 688 00:42:03,150 --> 00:42:07,890 some signal inside the cytoplasm to tell the vesicles to fuse. 689 00:42:07,890 --> 00:42:12,710 That signal is increased calcium ion concentration. 690 00:42:12,710 --> 00:42:14,940 And then when calcium concentration 691 00:42:14,940 --> 00:42:17,700 increases in the cytoplasm, that triggers 692 00:42:17,700 --> 00:42:18,930 the fusion of these vesicles. 693 00:42:22,170 --> 00:42:25,200 And when you get fusion, that's exocytosis, 694 00:42:25,200 --> 00:42:28,380 and the serotonin is now on the outside of the cell, 695 00:42:28,380 --> 00:42:31,920 where it can travel across the synaptic cleft and bind 696 00:42:31,920 --> 00:42:35,340 to a receptor on the postsynaptic neuron. 697 00:42:35,340 --> 00:42:38,535 So this fusion is when neurotransmitter is released. 698 00:42:43,590 --> 00:42:45,750 Neurotransmitter is released here. 699 00:42:52,240 --> 00:42:56,230 And the way that this increasing calcium has to happen, 700 00:42:56,230 --> 00:43:00,770 when the action potential arrives at the axon terminus. 701 00:43:00,770 --> 00:43:03,070 So when it arrives in the axon terminus, 702 00:43:03,070 --> 00:43:07,390 there's depolarization of that part of the cell. 703 00:43:07,390 --> 00:43:09,820 And so there's a special type of protein 704 00:43:09,820 --> 00:43:14,680 called a voltage-gated calcium channel. 705 00:43:14,680 --> 00:43:17,870 All these channels are very selective for different ions. 706 00:43:17,870 --> 00:43:20,470 So a voltage-gated sodium channel 707 00:43:20,470 --> 00:43:24,610 isn't letting in all of the ions outside the cell. 708 00:43:24,610 --> 00:43:26,410 It's selective to sodium. 709 00:43:26,410 --> 00:43:29,230 And this case, this voltage-gated calcium channel 710 00:43:29,230 --> 00:43:31,540 is just going to let in calcium. 711 00:43:31,540 --> 00:43:34,510 And then there's a mechanism that links calcium entry 712 00:43:34,510 --> 00:43:36,700 to vesicle fusion. 713 00:43:36,700 --> 00:43:38,630 And that's going to be shown here. 714 00:43:38,630 --> 00:43:41,380 What you see on this docked synaptic vesicle 715 00:43:41,380 --> 00:43:45,310 is this calcium-binding protein called synaptotagmin 716 00:43:45,310 --> 00:43:47,380 that's present on the vesicle. 717 00:43:47,380 --> 00:43:50,710 And so when calcium goes into the cytoplasm, 718 00:43:50,710 --> 00:43:55,060 that protein binds to calcium, and it activates the fusion 719 00:43:55,060 --> 00:43:59,350 machinery such that the plasma membrane of the vesicle fuses-- 720 00:43:59,350 --> 00:44:02,650 or the membrane of the vesicle fuses with the plasma membrane 721 00:44:02,650 --> 00:44:05,680 of the cell, thus releasing the neurotransmitter 722 00:44:05,680 --> 00:44:06,970 into the synaptic cleft. 723 00:44:12,260 --> 00:44:14,960 So this is what starts the signal. 724 00:44:14,960 --> 00:44:19,430 Now, you probably know that these neurons are not active 725 00:44:19,430 --> 00:44:20,830 or on all the time. 726 00:44:20,830 --> 00:44:24,020 So something has to terminate the signal, usually 727 00:44:24,020 --> 00:44:25,280 quite rapidly. 728 00:44:25,280 --> 00:44:26,780 So now I want to talk about that. 729 00:44:29,660 --> 00:44:32,870 So like all signaling pathways, signaling 730 00:44:32,870 --> 00:44:35,000 is useless if you can just turn it on. 731 00:44:35,000 --> 00:44:38,180 You have to be able to toggle it on and off in order 732 00:44:38,180 --> 00:44:41,240 for biological systems to function properly, right? 733 00:44:41,240 --> 00:44:42,890 And that's the case with neurons. 734 00:44:42,890 --> 00:44:44,990 If you just turn on a neuron and you 735 00:44:44,990 --> 00:44:46,790 don't have a way to turn it back off again, 736 00:44:46,790 --> 00:44:47,915 then that's pretty useless. 737 00:44:50,480 --> 00:44:54,140 And so we have to have a way to turn off the signal. 738 00:44:54,140 --> 00:44:56,330 And if we consider the synapse, this 739 00:44:56,330 --> 00:44:59,090 is the presynaptic neuron here. 740 00:44:59,090 --> 00:45:02,000 I'm going to draw a postsynaptic neuron here. 741 00:45:05,540 --> 00:45:10,390 And neurotransmitter is released by the presynaptic neuron 742 00:45:10,390 --> 00:45:13,810 to the postsynaptic neuron here. 743 00:45:13,810 --> 00:45:19,670 Neurotransmitter is released into the synaptic cleft. 744 00:45:19,670 --> 00:45:23,690 So the sort of extracellular region 745 00:45:23,690 --> 00:45:27,275 between these two neurons is called the synaptic cleft. 746 00:45:33,720 --> 00:45:36,770 So now the cell just dumped a whole boatload 747 00:45:36,770 --> 00:45:39,650 of neurotransmitter into the synaptic cleft, right? 748 00:45:39,650 --> 00:45:41,650 How is it going to turn this off? 749 00:45:41,650 --> 00:45:42,650 What does it have to do? 750 00:45:48,610 --> 00:45:49,538 Yeah, Stephen? 751 00:45:49,538 --> 00:45:51,250 AUDIENCE: It could absorb the-- 752 00:45:51,250 --> 00:45:55,208 take back in the [INAUDIBLE]. 753 00:45:55,208 --> 00:45:56,750 ADAM MARTIN: Stephen's exactly right. 754 00:45:56,750 --> 00:45:58,460 What Stephen suggested is, is there 755 00:45:58,460 --> 00:46:02,360 a way for the presynaptic neuron to reabsorb 756 00:46:02,360 --> 00:46:04,670 this neurotransmitter and, thus, recycle it? 757 00:46:10,430 --> 00:46:12,560 So it could either reabsorb it or degrade 758 00:46:12,560 --> 00:46:14,870 the neurotransmitter. 759 00:46:14,870 --> 00:46:17,510 Different process for different neurotransmitters. 760 00:46:17,510 --> 00:46:20,810 For serotonin, there are channels 761 00:46:20,810 --> 00:46:23,990 that are present in the plasma membrane, 762 00:46:23,990 --> 00:46:29,450 and these mediate reuptake of the serotonin. 763 00:46:29,450 --> 00:46:31,520 So you have channels that are basically-- 764 00:46:31,520 --> 00:46:33,860 after the neurotransmitter is released, 765 00:46:33,860 --> 00:46:37,670 it sucks the neurotransmitter back into the presynaptic cell 766 00:46:37,670 --> 00:46:41,510 such that it can then reuse the neurotransmitter later on. 767 00:46:44,660 --> 00:46:53,570 And so this process of reuptake highlights a very important 768 00:46:53,570 --> 00:46:56,690 process that's been utilized by drug companies 769 00:46:56,690 --> 00:47:00,200 to create antidepressants. 770 00:47:00,200 --> 00:47:04,250 So antidepressants like Prozac and Zoloft 771 00:47:04,250 --> 00:47:06,620 affect this reuptake process. 772 00:47:06,620 --> 00:47:09,920 And what that does is it keeps the neurotransmitter 773 00:47:09,920 --> 00:47:12,700 in the synaptic cleft for longer, such 774 00:47:12,700 --> 00:47:14,990 that it enhances the signaling. 775 00:47:14,990 --> 00:47:17,420 And so the idea behind these drugs 776 00:47:17,420 --> 00:47:19,940 is that if you are suffering depression 777 00:47:19,940 --> 00:47:22,790 from a lack of serotonin, then you 778 00:47:22,790 --> 00:47:27,830 can rescue that by preventing the rapid reuptake 779 00:47:27,830 --> 00:47:30,320 of the neurotransmitter into the cell 780 00:47:30,320 --> 00:47:34,170 after the synapse is stimulated and the neurotransmitter 781 00:47:34,170 --> 00:47:34,670 is released. 782 00:47:39,010 --> 00:47:46,240 And so Prozac, Zoloft, these are a class 783 00:47:46,240 --> 00:47:53,500 of drugs that are known as selective serotonin reuptake 784 00:47:53,500 --> 00:47:54,220 inhibitors. 785 00:48:00,600 --> 00:48:01,600 It's kind of a mouthful. 786 00:48:04,360 --> 00:48:05,860 This is abbreviated SSRIs. 787 00:48:08,870 --> 00:48:12,220 But the way they function is to leave the neurotransmitter 788 00:48:12,220 --> 00:48:14,140 in the synaptic cleft for longer so 789 00:48:14,140 --> 00:48:16,420 that you enhance signaling, even if you 790 00:48:16,420 --> 00:48:19,750 have low levels of the neurotransmitter to begin with. 791 00:48:29,000 --> 00:48:32,710 I also want to point out that if we look at this diagram here, 792 00:48:32,710 --> 00:48:36,070 the synaptic vesicle fuses, and then this 793 00:48:36,070 --> 00:48:37,870 releases the neurotransmitter. 794 00:48:37,870 --> 00:48:40,090 But all the machinery on this vesicle 795 00:48:40,090 --> 00:48:44,470 is recycled by endocytosis such that it can be reused again, 796 00:48:44,470 --> 00:48:45,220 OK? 797 00:48:45,220 --> 00:48:47,890 So cells are really good at recycling stuff. 798 00:48:47,890 --> 00:48:51,850 If this is sort of the membrane, you endocytose and then 799 00:48:51,850 --> 00:48:56,760 you can use it again later on, OK? 800 00:48:56,760 --> 00:49:00,460 And so there's recycling not only of the neurotransmitter, 801 00:49:00,460 --> 00:49:04,090 but also all of the machinery on the synaptic vesicles 802 00:49:04,090 --> 00:49:08,320 that are responsible for the fusion event. 803 00:49:08,320 --> 00:49:10,660 All right, now I want to end by just telling you 804 00:49:10,660 --> 00:49:14,230 how this experiment works, where we're 805 00:49:14,230 --> 00:49:17,860 able to activate specific neurons in a brain 806 00:49:17,860 --> 00:49:23,680 and that leads to the animal sort of waking up. 807 00:49:23,680 --> 00:49:25,480 So in a normal neuron-- 808 00:49:25,480 --> 00:49:28,750 so this is the last part, optogenetics. 809 00:49:28,750 --> 00:49:32,110 And I'm going to go through this very fast. 810 00:49:32,110 --> 00:49:34,510 But normally, you need a neurotransmitter 811 00:49:34,510 --> 00:49:36,850 to induce depolarization. 812 00:49:36,850 --> 00:49:39,610 But what optogenetics is, is an approach 813 00:49:39,610 --> 00:49:44,140 to control the activity of a cell with light, OK? 814 00:49:44,140 --> 00:49:46,300 So in this case, we're going to have 815 00:49:46,300 --> 00:49:48,880 light inducing depolarization. 816 00:49:52,840 --> 00:49:55,510 And the way this is done is there's a protein discovered 817 00:49:55,510 --> 00:50:00,800 from photosynthetic algae that's responsive to light, 818 00:50:00,800 --> 00:50:03,580 and it is a sodium channel. 819 00:50:03,580 --> 00:50:12,400 And this protein is called channelrhodopsin, specifically 820 00:50:12,400 --> 00:50:14,590 ChR2. 821 00:50:14,590 --> 00:50:18,550 And this is a light-sensitive protein where light 822 00:50:18,550 --> 00:50:20,800 induces sodium channel opening. 823 00:50:24,670 --> 00:50:26,515 So that's going to depolarize the cell. 824 00:50:29,800 --> 00:50:33,490 And what you can do is if you have a gene that you know 825 00:50:33,490 --> 00:50:37,060 is specifically expressed in a certain type of neuron, 826 00:50:37,060 --> 00:50:40,870 you can take the promoter and enhancer region of that gene 827 00:50:40,870 --> 00:50:44,920 and hook it up to this single component, channelrhodopsin, 828 00:50:44,920 --> 00:50:49,970 that open reading frame, using recombinant DNA technology. 829 00:50:49,970 --> 00:50:52,450 And if that's expressed specifically in the neurons 830 00:50:52,450 --> 00:50:54,340 that you're trying to test, you can then 831 00:50:54,340 --> 00:50:58,090 shine a light into the brain of the organism and activate, 832 00:50:58,090 --> 00:51:00,550 specifically, this type of neuron. 833 00:51:00,550 --> 00:51:04,060 And that allows you to test the function of the neuron 834 00:51:04,060 --> 00:51:06,320 in the behavior of an organism. 835 00:51:06,320 --> 00:51:08,710 So, in this case, this mouse, the light 836 00:51:08,710 --> 00:51:10,660 is shined into its brain, and they're 837 00:51:10,660 --> 00:51:13,540 testing a specific type of neuron 838 00:51:13,540 --> 00:51:18,220 that is involved in arousal of the mouse, and it wakes up. 839 00:51:18,220 --> 00:51:20,330 Oh, it's not playing. 840 00:51:20,330 --> 00:51:26,020 So here, this is the brain activity on the top, 841 00:51:26,020 --> 00:51:28,970 and the muscle activity on the bottom. 842 00:51:28,970 --> 00:51:30,340 So you're going to see light. 843 00:51:30,340 --> 00:51:31,090 There's the light. 844 00:51:31,090 --> 00:51:31,590 You see it? 845 00:51:31,590 --> 00:51:34,880 Light going into the brain. 846 00:51:34,880 --> 00:51:38,930 They induce light at that frequency for a while. 847 00:51:38,930 --> 00:51:41,890 And then they're going to wait and see 848 00:51:41,890 --> 00:51:43,150 when the mouse wakes up. 849 00:51:43,150 --> 00:51:46,107 And it's going to wake up right now. 850 00:51:46,107 --> 00:51:46,690 There it goes. 851 00:51:46,690 --> 00:51:47,200 It woke up. 852 00:51:47,200 --> 00:51:50,230 You see now its muscle activity is going, OK? 853 00:51:50,230 --> 00:51:53,080 So you can test the function of specific nerve cells 854 00:51:53,080 --> 00:51:55,480 using this approach, and it's because you 855 00:51:55,480 --> 00:51:57,830 have a light-sensitive sodium channel. 856 00:51:57,830 --> 00:51:58,880 So I'm done for today. 857 00:51:58,880 --> 00:51:59,990 Have a great weekend. 858 00:51:59,990 --> 00:52:02,160 I will see you on Monday.