WEBVTT 00:00:16.540 --> 00:00:18.550 ADAM MARTIN: All right, let's get started. 00:00:18.550 --> 00:00:21.670 So I'm starting with this video here. 00:00:21.670 --> 00:00:24.710 What's happening here is there's this mouse, 00:00:24.710 --> 00:00:27.700 and you see there's like this fiber optic cable going 00:00:27.700 --> 00:00:29.580 into its brain. 00:00:29.580 --> 00:00:32.170 And the mouse is asleep right now. 00:00:32.170 --> 00:00:36.070 And now the researchers are shining light 00:00:36.070 --> 00:00:39.040 into its brain, a specific region of the brain, 00:00:39.040 --> 00:00:41.710 to activate specific neurons in order 00:00:41.710 --> 00:00:44.620 to test whether they function in arousal. 00:00:44.620 --> 00:00:48.237 And here, you see the mouse is going to wake up. 00:00:48.237 --> 00:00:48.820 There it goes. 00:00:48.820 --> 00:00:49.510 It's awake now. 00:00:52.570 --> 00:00:54.860 So for today's lecture, we're going 00:00:54.860 --> 00:01:00.010 to work towards understanding how this experiment works. 00:01:00.010 --> 00:01:03.040 And we're going to talk about how neurons function 00:01:03.040 --> 00:01:07.510 and how researchers are able to control that function in order 00:01:07.510 --> 00:01:09.670 to modify behavior-- 00:01:09.670 --> 00:01:12.400 in this case, the arousal of this mouse. 00:01:15.670 --> 00:01:19.570 OK, so this is going to involve a particular type of cell 00:01:19.570 --> 00:01:21.700 in our body, which is the neuron. 00:01:21.700 --> 00:01:25.060 And neurons are highly specialized cells 00:01:25.060 --> 00:01:28.510 that have a function to transmit information from one 00:01:28.510 --> 00:01:31.960 part of the body to another. 00:01:31.960 --> 00:01:36.430 And so neurons are highly polarized cells, 00:01:36.430 --> 00:01:38.110 which you can see here. 00:01:38.110 --> 00:01:43.090 On the left of this neuron, you see this arbor of protrusions, 00:01:43.090 --> 00:01:45.970 which are called dendrites. 00:01:45.970 --> 00:01:47.980 And then on this side of the cell body, 00:01:47.980 --> 00:01:50.530 you see a single extension, which 00:01:50.530 --> 00:01:55.150 is an axon, and then the terminus of the axon over here. 00:01:55.150 --> 00:01:58.660 And this nerve cell transmits information 00:01:58.660 --> 00:02:00.490 in a single direction. 00:02:00.490 --> 00:02:06.340 It will transmit information from this side to this side. 00:02:06.340 --> 00:02:10.180 And these neurons are able to communicate with each other. 00:02:10.180 --> 00:02:13.210 And they communicate at the ends of the neuron, which 00:02:13.210 --> 00:02:15.520 are known as synapses, which I'll come back to 00:02:15.520 --> 00:02:18.580 and talk about later on in the lecture. 00:02:18.580 --> 00:02:22.000 So neurons could be making synapses on this side 00:02:22.000 --> 00:02:24.805 and also making synapses on this side with other neurons. 00:02:28.840 --> 00:02:33.080 So to start to unpack the function of this neuron-- 00:02:33.080 --> 00:02:36.130 and I should highlight that this flow of information 00:02:36.130 --> 00:02:38.990 can occur over very long distances, right? 00:02:38.990 --> 00:02:42.670 Your sciatic nerve extends from the base of your spine 00:02:42.670 --> 00:02:44.980 all the way down into your foot, OK? 00:02:44.980 --> 00:02:49.130 So that axon is one meter in length. 00:02:49.130 --> 00:02:51.340 So that's an extremely long distance 00:02:51.340 --> 00:02:54.550 to transmit information along a single cell. 00:02:57.100 --> 00:03:00.550 And so we're going to go from thinking about how signals are 00:03:00.550 --> 00:03:03.070 transmitted in single cells, and this will 00:03:03.070 --> 00:03:05.500 evolve electrical signaling. 00:03:05.500 --> 00:03:09.310 Then we'll talk about synapses and how synapses function 00:03:09.310 --> 00:03:11.720 to communicate between neurons. 00:03:11.720 --> 00:03:15.040 And this is going to involve also 00:03:15.040 --> 00:03:18.190 sort of understanding how certain antidepressants, 00:03:18.190 --> 00:03:19.810 like Prozac, work. 00:03:19.810 --> 00:03:21.880 And then we'll end by talking about how 00:03:21.880 --> 00:03:26.430 researchers did this experiment to wake up the mouse. 00:03:26.430 --> 00:03:28.660 And it all starts with something that I told you 00:03:28.660 --> 00:03:31.930 about at the beginning of the semester, which 00:03:31.930 --> 00:03:35.710 is that the plasma membrane separates 00:03:35.710 --> 00:03:38.380 distinct compartments the outside of the cell 00:03:38.380 --> 00:03:39.910 from the cytoplasm. 00:03:39.910 --> 00:03:42.700 And there are distinct ion concentrations 00:03:42.700 --> 00:03:46.990 on either side of this boundary. 00:03:46.990 --> 00:03:51.115 So we're starting now talking about a single neuron cell. 00:03:55.690 --> 00:03:59.790 And we're going to talk about a type of signal 00:03:59.790 --> 00:04:03.012 known as an action potential. 00:04:03.012 --> 00:04:03.720 Oh, that's right. 00:04:08.460 --> 00:04:11.370 So we're going to talk about an action potential. 00:04:11.370 --> 00:04:13.500 And what an action potential is, is it's 00:04:13.500 --> 00:04:15.390 an electrical signal that travels 00:04:15.390 --> 00:04:17.680 the length of the neuron. 00:04:17.680 --> 00:04:22.710 So this action potential, I'll abbreviate this AP. 00:04:22.710 --> 00:04:25.260 So when I refer to AP, I'm not referring 00:04:25.260 --> 00:04:29.850 to advanced placement, but action potential, OK? 00:04:29.850 --> 00:04:37.020 So this is an electrical signal that 00:04:37.020 --> 00:04:40.920 travels the length of the axon and the neuron. 00:04:51.290 --> 00:04:54.630 And so in order to have an electrical signal propagate, 00:04:54.630 --> 00:04:57.000 we need some sort of electrical property 00:04:57.000 --> 00:05:01.180 that the cell has that enables this. 00:05:01.180 --> 00:05:05.070 And so I showed you or I told you earlier in the semester 00:05:05.070 --> 00:05:09.330 how sodium ions are concentrated on the outside of the cell 00:05:09.330 --> 00:05:13.540 and potassium ions are concentrated on the inside. 00:05:13.540 --> 00:05:15.900 You see here's the sodium gradient here, 00:05:15.900 --> 00:05:17.690 potassium gradient here. 00:05:17.690 --> 00:05:20.160 And now I'm going to tell you how it is that this happens, 00:05:20.160 --> 00:05:22.310 because this is thermodynamically not favored, 00:05:22.310 --> 00:05:22.810 right? 00:05:22.810 --> 00:05:26.190 These ions would prefer, by diffusion, 00:05:26.190 --> 00:05:30.090 to be equal concentrations on both sides of this plasma 00:05:30.090 --> 00:05:35.670 membrane, which means that the cell to shift this 00:05:35.670 --> 00:05:38.340 from equilibrium has to expend energy 00:05:38.340 --> 00:05:41.980 to set up this situation. 00:05:41.980 --> 00:05:46.600 And so in the plasma membrane of the cell, there is a protein. 00:05:46.600 --> 00:05:48.360 It's an integral membrane protein 00:05:48.360 --> 00:05:51.340 and sits inside the plasma membrane. 00:05:51.340 --> 00:05:55.080 So this here is the plasma membrane. 00:05:55.080 --> 00:05:57.210 And this integral membrane protein 00:05:57.210 --> 00:06:02.010 is called a sodium potassium ATPase. 00:06:02.010 --> 00:06:10.770 So it's going to have a subunit that hydrolyzes ATP to ADP. 00:06:10.770 --> 00:06:15.870 And the protein uses the energy of ATP hydrolysis 00:06:15.870 --> 00:06:20.650 to pump sodium ions up their concentration gradient. 00:06:20.650 --> 00:06:24.440 So the sodium ions are going out of the cell. 00:06:24.440 --> 00:06:26.790 And this is going against the flow 00:06:26.790 --> 00:06:28.900 that sodium would normally like to take, 00:06:28.900 --> 00:06:31.800 which would be going downstream. 00:06:31.800 --> 00:06:37.380 And it pumps potassium ions into the cytoplasm such 00:06:37.380 --> 00:06:40.350 that there's a higher concentration of potassium 00:06:40.350 --> 00:06:43.140 ions in the cytoplasm, OK? 00:06:43.140 --> 00:06:47.130 So these neurons expend a huge-- 00:06:47.130 --> 00:06:52.290 a quarter of their ATP is used by pumping ions like this, such 00:06:52.290 --> 00:06:56.595 that there is gradients of ions across the plasma membrane. 00:06:59.310 --> 00:07:03.030 Now, if one sodium ion was pumped out 00:07:03.030 --> 00:07:06.000 for every potassium ion pumped in, 00:07:06.000 --> 00:07:09.300 there'd be no charge difference between the exterior 00:07:09.300 --> 00:07:12.090 and the cytoplasm. 00:07:12.090 --> 00:07:16.260 But what happens in the plasma membrane 00:07:16.260 --> 00:07:20.010 is that in addition to the sodium potassium ATPase, 00:07:20.010 --> 00:07:23.340 there are other channels that are present. 00:07:23.340 --> 00:07:25.300 There are sodium channels. 00:07:25.300 --> 00:07:29.400 These are mostly closed, but there are some potassium 00:07:29.400 --> 00:07:31.230 channels that are leaky. 00:07:31.230 --> 00:07:34.860 And they're basically leaking potassium from the cytoplasm 00:07:34.860 --> 00:07:38.130 out into the exoplasm, OK? 00:07:38.130 --> 00:07:42.330 And if you have positive charges going out the cell, 00:07:42.330 --> 00:07:44.270 then the inside of the membrane is going 00:07:44.270 --> 00:07:47.413 to have a net negative charge. 00:07:47.413 --> 00:07:49.080 And the outside of the membrane is going 00:07:49.080 --> 00:07:53.070 to have a net positive charge. 00:07:53.070 --> 00:07:55.740 And this charge across the membrane, 00:07:55.740 --> 00:07:58.690 where you have positive on the outside 00:07:58.690 --> 00:08:00.320 and minus on the inside-- 00:08:00.320 --> 00:08:06.390 I should label this exterior, and this is cytoplasm. 00:08:11.580 --> 00:08:16.650 This voltage difference is known as a membrane potential. 00:08:16.650 --> 00:08:18.250 So this is a membrane potential. 00:08:24.950 --> 00:08:28.520 And it's an electrical potential across the membrane. 00:08:28.520 --> 00:08:30.020 If you're an electrical engineer, 00:08:30.020 --> 00:08:33.740 you can think of the plasma membrane as a capacitor, OK? 00:08:33.740 --> 00:08:37.549 So this plasma membrane is holding this charge difference 00:08:37.549 --> 00:08:39.559 across it. 00:08:39.559 --> 00:08:42.169 And so there's a voltage across the membrane. 00:08:42.169 --> 00:08:51.020 And in a resting state, the cell's resting potential 00:08:51.020 --> 00:08:53.180 is negative 70 millivolts. 00:08:57.410 --> 00:09:00.950 So if the cell is not getting stimulated by something 00:09:00.950 --> 00:09:03.440 like a neurotransmitter, the resting potential 00:09:03.440 --> 00:09:07.310 is negative 70 millivolts, where the inside is negative 00:09:07.310 --> 00:09:10.370 and the outside is positive, OK? 00:09:10.370 --> 00:09:12.578 So now I just want to define some terms that 00:09:12.578 --> 00:09:14.120 are going to be useful for us when we 00:09:14.120 --> 00:09:17.160 talk about action potentials. 00:09:17.160 --> 00:09:24.455 So when there's this negative inside potential, 00:09:24.455 --> 00:09:28.760 a negative inside potential is referred to as polarized. 00:09:28.760 --> 00:09:34.400 So it's polarized because there's 00:09:34.400 --> 00:09:38.120 a polarity across this membrane, where one side is positive 00:09:38.120 --> 00:09:41.660 and the other side is negative, OK? 00:09:41.660 --> 00:09:43.940 So polarized refers to if there's 00:09:43.940 --> 00:09:45.830 a negative inside potential. 00:09:45.830 --> 00:09:49.150 So the resting state of the side is there's a polarized-- 00:09:49.150 --> 00:09:52.100 it's polarized. 00:09:52.100 --> 00:09:55.640 However, the cell can lose this polarity 00:09:55.640 --> 00:09:57.500 and not have a charge differential, 00:09:57.500 --> 00:10:00.950 or it can flip and be positive on the inside. 00:10:00.950 --> 00:10:05.750 And when that happens, if there's either zero or positive 00:10:05.750 --> 00:10:10.070 inside potential, this is referred to as depolarized. 00:10:17.330 --> 00:10:20.420 Anyone have an idea as to how the cell would 00:10:20.420 --> 00:10:22.580 flip the potential? 00:10:22.580 --> 00:10:25.280 What would have to happen in the plasma membrane 00:10:25.280 --> 00:10:28.310 to flip this potential and depolarize the cell? 00:10:28.310 --> 00:10:28.900 Yes, Stephen? 00:10:28.900 --> 00:10:30.710 AUDIENCE: You could open the ion channels. 00:10:30.710 --> 00:10:33.600 ADAM MARTIN: So Stephen suggested opening ion channels. 00:10:33.600 --> 00:10:36.431 Which ion channels would you open? 00:10:36.431 --> 00:10:38.120 AUDIENCE: The sodium channels. 00:10:38.120 --> 00:10:38.870 ADAM MARTIN: Yeah. 00:10:38.870 --> 00:10:42.260 So Stephen suggested if you open these, 00:10:42.260 --> 00:10:43.970 it's going to depolarize the cell. 00:10:43.970 --> 00:10:48.450 Because remember, sodium is high on the outside, out here. 00:10:48.450 --> 00:10:50.180 And so if you open these channels, 00:10:50.180 --> 00:10:52.730 positive ions are going to flow in. 00:10:52.730 --> 00:10:56.120 And that's going to make this less negative and this less 00:10:56.120 --> 00:10:58.800 positive, OK? 00:10:58.800 --> 00:11:02.870 So this is the situation here, where these sodium channels 00:11:02.870 --> 00:11:06.050 open, and the sodium channels-- or the sodium 00:11:06.050 --> 00:11:09.650 ions rushing in is going to create a depolarization, 00:11:09.650 --> 00:11:11.780 where you now flip the potential. 00:11:11.780 --> 00:11:14.120 And there's a greater positive charge 00:11:14.120 --> 00:11:18.620 on the inside of the plasma membrane. 00:11:18.620 --> 00:11:20.270 Everyone see how? 00:11:20.270 --> 00:11:23.360 Because the sodium ions are going to just go downstream. 00:11:23.360 --> 00:11:25.400 They're higher concentration out here. 00:11:25.400 --> 00:11:27.740 So just by opening these channels, 00:11:27.740 --> 00:11:30.410 the cell doesn't have to do any work to do this. 00:11:30.410 --> 00:11:32.600 Sodium is just going to flow down its gradient 00:11:32.600 --> 00:11:33.920 into the cytoplasm. 00:11:41.110 --> 00:11:43.750 So what an action potential is, is it's 00:11:43.750 --> 00:11:49.090 a transient depolarization of the nerve cell. 00:11:49.090 --> 00:12:02.180 So the Action Potential, or AP, is a transient depolarization 00:12:02.180 --> 00:12:07.160 of the neuron, which means it doesn't just 00:12:07.160 --> 00:12:12.020 depolarize and stay depolarized, but it depolarizes and then 00:12:12.020 --> 00:12:16.010 restores itself back to the resting polarity. 00:12:16.010 --> 00:12:19.310 And so what you see when you measure the voltage 00:12:19.310 --> 00:12:22.010 across the plasma membrane in a neuron, 00:12:22.010 --> 00:12:24.890 you see that it can spike and depolarize, 00:12:24.890 --> 00:12:28.880 but then it's rapidly restored to its resting state, OK? 00:12:28.880 --> 00:12:30.200 So it's a transient process. 00:12:33.080 --> 00:12:36.470 When we think about the neuron at higher resolution, what 00:12:36.470 --> 00:12:39.140 you're going to see is not only is it transient, 00:12:39.140 --> 00:12:42.500 but it's also a traveling wave that propagates along 00:12:42.500 --> 00:12:45.870 the entire length of the cell. 00:12:45.870 --> 00:12:47.870 So this is also a traveling wave. 00:12:56.830 --> 00:13:01.240 And one thing that you can notice about these neurons, 00:13:01.240 --> 00:13:05.510 or the action potentials here, is that they all 00:13:05.510 --> 00:13:08.000 depolarize to the same extent. 00:13:08.000 --> 00:13:12.380 So they all depolarize to this positive 50 millivolts. 00:13:12.380 --> 00:13:14.710 And so this illustrates a key property 00:13:14.710 --> 00:13:19.870 of neurons, in that the level of activity of a neuron 00:13:19.870 --> 00:13:25.480 is not determined by the size of this action potential. 00:13:25.480 --> 00:13:28.450 This action potential is an all-or-nothing event. 00:13:28.450 --> 00:13:30.140 It either happens or it doesn't. 00:13:30.140 --> 00:13:33.070 And when it happens, it depolarizes to the same level. 00:13:35.890 --> 00:13:38.470 So the action potential is all or nothing. 00:13:42.680 --> 00:13:45.490 You can think of it as a binary signal. 00:13:45.490 --> 00:13:47.530 And therefore, the way that neurons 00:13:47.530 --> 00:13:50.950 encode sort of the magnitude of activation 00:13:50.950 --> 00:13:54.040 is not through the level of depolarization 00:13:54.040 --> 00:13:56.920 of a single action potential, but it 00:13:56.920 --> 00:14:00.280 is able to distinguish between different frequencies of action 00:14:00.280 --> 00:14:03.220 potentials that are propagating along the neuron. 00:14:05.770 --> 00:14:12.640 So signal strength, in this case, 00:14:12.640 --> 00:14:16.240 is related to the frequency of action potentials firing. 00:14:26.660 --> 00:14:28.340 So now we're going to unpack how it 00:14:28.340 --> 00:14:31.820 is a nerve cell fires an action potential 00:14:31.820 --> 00:14:34.940 and how it propagates along the entire cell length, right? 00:14:34.940 --> 00:14:36.740 In the case of the sciatic nerve, 00:14:36.740 --> 00:14:39.230 this has to happen across an entire meter, OK? 00:14:39.230 --> 00:14:41.840 That's a very long distance to propagate 00:14:41.840 --> 00:14:46.410 this change in electrical signal, at least for a cell. 00:14:46.410 --> 00:14:49.010 And so we're going to talk about the mechanism. 00:14:49.010 --> 00:14:52.070 And I'm going to start at the beginning, when this action 00:14:52.070 --> 00:14:55.340 potential initiates. 00:14:55.340 --> 00:14:59.510 So we'll start at the initiation of the action potential. 00:15:03.390 --> 00:15:07.140 So how is it that this nerve cell 00:15:07.140 --> 00:15:11.300 is told to start depolarizing at the dendrites? 00:15:11.300 --> 00:15:14.250 Because there's going to be another neuron here, 00:15:14.250 --> 00:15:17.820 which is going to communicate to this neuron over here 00:15:17.820 --> 00:15:21.160 to tell it to start depolarizing. 00:15:21.160 --> 00:15:24.720 It does this at the location known as the synapse, which 00:15:24.720 --> 00:15:28.080 is basically sort of the connection between the two 00:15:28.080 --> 00:15:30.870 neurons. 00:15:30.870 --> 00:15:32.970 And the way this process is initiated 00:15:32.970 --> 00:15:34.980 is similar to the type of signaling 00:15:34.980 --> 00:15:37.860 that you saw in the past few lectures, where you have 00:15:37.860 --> 00:15:41.430 a ligand and a receptor, OK? 00:15:41.430 --> 00:15:50.310 In this case, the ligand is going 00:15:50.310 --> 00:15:55.960 to be what's known as a neurotransmitter, which 00:15:55.960 --> 00:15:57.400 is a small molecule. 00:15:57.400 --> 00:16:01.210 And I'll show you some later on. 00:16:01.210 --> 00:16:05.590 And the receptor is going to be a receptor that 00:16:05.590 --> 00:16:07.660 binds to this ligand. 00:16:07.660 --> 00:16:09.820 But in this case, rather than being something 00:16:09.820 --> 00:16:13.510 like a G protein coupled receptor or a receptor tyrosine 00:16:13.510 --> 00:16:18.160 kinase, the receptor is going to be an ion channel, OK? 00:16:18.160 --> 00:16:20.560 So the receptor is going to be an ion channel. 00:16:25.150 --> 00:16:27.250 And so you see one example in the slide 00:16:27.250 --> 00:16:30.820 up here, where here's a receptor. 00:16:30.820 --> 00:16:35.410 And these receptors are what are known as ligand-gated ion 00:16:35.410 --> 00:16:35.950 channels. 00:16:35.950 --> 00:16:38.150 In this case, it's a sodium channel. 00:16:38.150 --> 00:16:40.030 So it's going to be-- 00:16:40.030 --> 00:16:44.000 whether or not it's open depends on the presence of the ligand. 00:16:44.000 --> 00:16:48.180 So if we take a neurotransmitter like serotonin, 00:16:48.180 --> 00:16:50.230 if it's not bound to the receptor, 00:16:50.230 --> 00:16:52.090 the receptor is closed. 00:16:52.090 --> 00:16:55.060 But if serotonin binds to the receptor, 00:16:55.060 --> 00:16:58.360 it opens up the channel, which can selectively 00:16:58.360 --> 00:17:00.070 let in a type of ion-- 00:17:00.070 --> 00:17:02.020 in this case, sodium. 00:17:02.020 --> 00:17:05.230 In this case, this is an activating channel, 00:17:05.230 --> 00:17:07.150 because letting in sodium is going 00:17:07.150 --> 00:17:11.740 to depolarize the cell, OK? 00:17:11.740 --> 00:17:16.470 So this ligand receptor binding uses a ligand-gated-- 00:17:19.060 --> 00:17:21.445 there's a ligand-gated sodium channel. 00:17:25.030 --> 00:17:29.680 And it's this ligand-gated sodium channel which 00:17:29.680 --> 00:17:31.390 starts the depolarization. 00:17:39.940 --> 00:17:45.400 So that's how you sort of knock over the first domino, right? 00:17:45.400 --> 00:17:47.800 But then there has to be some mechanism 00:17:47.800 --> 00:17:52.570 to propagate this along the length of a very long cell. 00:17:52.570 --> 00:17:58.390 And so I'll tell you this involves a different type 00:17:58.390 --> 00:18:01.690 of sort of signaling mechanism from what you're 00:18:01.690 --> 00:18:04.960 used to thinking about, because this involves a different type 00:18:04.960 --> 00:18:06.730 of an ion channel. 00:18:06.730 --> 00:18:08.860 And it's called a voltage gated. 00:18:12.440 --> 00:18:16.800 And I'll abbreviate voltage gated just VG. 00:18:16.800 --> 00:18:19.000 And in this case, it will be a sodium channel. 00:18:23.890 --> 00:18:27.290 So what's a voltage-gated sodium channel? 00:18:27.290 --> 00:18:29.950 This is a voltage-gated sodium channel here. 00:18:29.950 --> 00:18:32.930 And you can see, in the resting state of the cell, 00:18:32.930 --> 00:18:35.020 this channel is closed. 00:18:35.020 --> 00:18:38.470 And it's closed because of this red rod structure 00:18:38.470 --> 00:18:40.450 that's positively charged. 00:18:40.450 --> 00:18:43.240 That's a positively charged alpha helix 00:18:43.240 --> 00:18:45.430 that is a part of this protein and is 00:18:45.430 --> 00:18:48.520 embedded in the membrane. 00:18:48.520 --> 00:18:52.600 But this alpha helix is positioned down 00:18:52.600 --> 00:18:56.020 towards the cytoplasm, because it's positively charged. 00:18:56.020 --> 00:18:58.540 And the cytosolic face of the plasma membrane 00:18:58.540 --> 00:19:01.120 is negatively charged, OK? 00:19:01.120 --> 00:19:03.700 And the confirmation of this protein 00:19:03.700 --> 00:19:07.810 then depends on the charge across this membrane. 00:19:07.810 --> 00:19:10.720 Because when there is depolarization, 00:19:10.720 --> 00:19:15.070 that shifts the position of this alpha helix, such that now it 00:19:15.070 --> 00:19:19.160 shifts up towards the exterior face of the plasma membrane. 00:19:19.160 --> 00:19:23.040 And that opens the channel, which lets sodium ions rush in, 00:19:23.040 --> 00:19:24.750 OK? 00:19:24.750 --> 00:19:28.870 Again, sodium ions here, they're always rushing downstream. 00:19:28.870 --> 00:19:32.290 They're concentration gradient. 00:19:32.290 --> 00:19:36.190 So in this case, whether or not this channel is open or closed 00:19:36.190 --> 00:19:38.830 depends not on the presence of a ligand, 00:19:38.830 --> 00:19:43.330 but on the membrane potential across the plasma membrane. 00:19:43.330 --> 00:19:46.210 So these voltage-gated sodium channels, 00:19:46.210 --> 00:19:49.990 they're opened by depolarization. 00:20:01.310 --> 00:20:02.990 And then the question becomes, if you 00:20:02.990 --> 00:20:06.770 open these channels at the very end of the neuron, 00:20:06.770 --> 00:20:10.550 how do you get it such that this electrical signal moves 00:20:10.550 --> 00:20:13.940 unidirectionally along the neuron? 00:20:13.940 --> 00:20:17.510 So what leads to unidirectionality? 00:20:25.300 --> 00:20:29.160 Who's been to a sporting event lately? 00:20:29.160 --> 00:20:30.750 OK, good. 00:20:30.750 --> 00:20:33.690 You guys know the wave? 00:20:33.690 --> 00:20:35.752 So we're going to do the wave. 00:20:35.752 --> 00:20:37.710 Once you to stand up, you're going to be tired, 00:20:37.710 --> 00:20:40.440 and you're going to have to sit down for a while. 00:20:40.440 --> 00:20:42.660 I'm going to be a ligand-- 00:20:42.660 --> 00:20:45.340 I'm a ligand-gated sodium channel, 00:20:45.340 --> 00:20:49.090 so I'm going to start things off, OK? 00:20:49.090 --> 00:20:51.510 You ready? 00:20:51.510 --> 00:20:52.480 All right, here we go. 00:20:57.550 --> 00:21:01.720 OK, that's basically an action potential. 00:21:01.720 --> 00:21:06.670 So the way that this was unidirectional 00:21:06.670 --> 00:21:11.920 is once you stood up and did the wave, you then sat down, 00:21:11.920 --> 00:21:15.520 and you stopped doing anything. 00:21:15.520 --> 00:21:19.060 And so these voltage-gated sodium channels 00:21:19.060 --> 00:21:20.080 have a similar property. 00:21:22.690 --> 00:21:25.480 If we look at the next step in this, 00:21:25.480 --> 00:21:29.160 the sodium channel is opened by depolarization. 00:21:29.160 --> 00:21:33.460 And you see there's this ball of chain segment of the protein. 00:21:33.460 --> 00:21:35.290 You see that yellow ball? 00:21:35.290 --> 00:21:39.160 Once the sodium channel opens, after about a millisecond, 00:21:39.160 --> 00:21:44.080 that ball sticks in the channel pore and blocks it, OK? 00:21:44.080 --> 00:21:48.220 So these sodium channels open to let in sodium ions, 00:21:48.220 --> 00:21:50.590 but then they're immediately inactivated 00:21:50.590 --> 00:21:54.790 after about a millisecond, OK? 00:21:54.790 --> 00:21:59.830 And so that enables unidirectionality. 00:21:59.830 --> 00:22:06.090 So this is what I'll call voltage-gated sodium channel 00:22:06.090 --> 00:22:07.000 inactivation. 00:22:14.260 --> 00:22:16.600 And how this promotes a traveling 00:22:16.600 --> 00:22:21.610 wave of depolarization is that if we consider an action 00:22:21.610 --> 00:22:25.670 potential moving along this axon from left to right 00:22:25.670 --> 00:22:28.390 and if the sodium channels in the green zone 00:22:28.390 --> 00:22:31.880 are currently open, it came from the left, 00:22:31.880 --> 00:22:33.940 which means that all the sodium channels 00:22:33.940 --> 00:22:39.340 to the left of this green zone are going to be inactivated. 00:22:39.340 --> 00:22:41.590 So because they're inactivated here, 00:22:41.590 --> 00:22:43.930 there won't be further depolarization 00:22:43.930 --> 00:22:46.570 going to the left, but depolarization 00:22:46.570 --> 00:22:48.640 will have to move to the right. 00:22:48.640 --> 00:22:51.340 And you basically get this traveling wave. 00:22:51.340 --> 00:22:53.950 And it goes one direction, because if it 00:22:53.950 --> 00:22:57.910 came from somewhere, which it always does, then where it just 00:22:57.910 --> 00:23:00.520 was coming from, all those sodium 00:23:00.520 --> 00:23:02.710 channels, the voltage-gated sodium channels 00:23:02.710 --> 00:23:04.720 are going to be closed. 00:23:04.720 --> 00:23:07.990 So this allows it to move in a single direction 00:23:07.990 --> 00:23:09.220 along the neuron. 00:23:09.220 --> 00:23:12.670 Also, once the action potential gets to the end of the neuron, 00:23:12.670 --> 00:23:15.560 it doesn't reflect back the other way in the neuron. 00:23:15.560 --> 00:23:18.730 This can only go one direction. 00:23:18.730 --> 00:23:21.820 So this provides unidirectionality. 00:23:21.820 --> 00:23:28.570 So it's this inactive or refractory period 00:23:28.570 --> 00:23:31.060 of the voltage-gated sodium channel 00:23:31.060 --> 00:23:34.180 which prevents the action potential 00:23:34.180 --> 00:23:35.380 from moving backwards. 00:23:39.200 --> 00:23:43.470 Now, if you look at these action potentials in the cell, 00:23:43.470 --> 00:23:47.540 you see that they happen, but you don't just 00:23:47.540 --> 00:23:50.150 depolarize and stay depolarized. 00:23:50.150 --> 00:23:54.830 The cell body depolarizes and then repolarizes very rapidly. 00:23:54.830 --> 00:23:57.140 So there's an oscillation. 00:23:57.140 --> 00:24:03.180 So there has to be some way to terminate the action potential. 00:24:03.180 --> 00:24:09.170 So there's a termination or repolarization of the cell. 00:24:14.670 --> 00:24:17.090 So there has to be a way for this nerve cell 00:24:17.090 --> 00:24:21.950 to rapidly restore membrane potential. 00:24:21.950 --> 00:24:24.530 And I want you to think for just a couple of seconds 00:24:24.530 --> 00:24:27.530 about what type of channel might you open 00:24:27.530 --> 00:24:29.390 to re-establish this polarity. 00:24:33.670 --> 00:24:37.390 What ion do you need to flow from where to where in order 00:24:37.390 --> 00:24:40.240 to get a net negative charge on the inside? 00:24:44.260 --> 00:24:45.127 Udo? 00:24:45.127 --> 00:24:46.955 AUDIENCE: You need to move the sodium ions 00:24:46.955 --> 00:24:49.240 from the inside to the outside. 00:24:49.240 --> 00:24:52.270 ADAM MARTIN: OK, you could pump the sodium ions out, 00:24:52.270 --> 00:24:54.460 and that's totally accurate. 00:24:54.460 --> 00:24:57.430 So that's going to require moving sodium ions 00:24:57.430 --> 00:25:01.270 up a concentration gradient, which is going to take energy 00:25:01.270 --> 00:25:02.950 and is going to be slow. 00:25:02.950 --> 00:25:05.890 So is there another option we could take advantage of here 00:25:05.890 --> 00:25:07.270 to repolarize? 00:25:07.270 --> 00:25:08.650 Rachel? 00:25:08.650 --> 00:25:10.840 AUDIENCE: Move the potassium ions. 00:25:10.840 --> 00:25:12.340 ADAM MARTIN: So Rachel has suggested 00:25:12.340 --> 00:25:17.200 to moving the potassium ions to the outside, which 00:25:17.200 --> 00:25:19.190 is how this is done. 00:25:19.190 --> 00:25:22.930 So remember, potassium is high in the cytoplasmic, 00:25:22.930 --> 00:25:25.180 low on the exoplasm. 00:25:25.180 --> 00:25:27.610 And therefore, if you have a voltage-gated potassium 00:25:27.610 --> 00:25:31.210 channel, that's going to cause a rush of positive ions out 00:25:31.210 --> 00:25:32.540 of the cell. 00:25:32.540 --> 00:25:36.340 And that will be able to restore the net negative potential 00:25:36.340 --> 00:25:39.670 on the inside of the cell. 00:25:39.670 --> 00:25:43.660 So this termination or repolarization 00:25:43.660 --> 00:25:49.390 is the result of the opening of voltage gated, in this case, 00:25:49.390 --> 00:25:54.110 not sodium channels, but potassium channels. 00:25:54.110 --> 00:25:56.110 When do you think these have to open relative 00:25:56.110 --> 00:25:57.220 to the sodium channel? 00:26:02.430 --> 00:26:05.340 Should they open right with the sodium channel? 00:26:05.340 --> 00:26:07.170 Carmen's shaking her head no. 00:26:07.170 --> 00:26:10.612 Do you want to explain your logic? 00:26:10.612 --> 00:26:13.002 AUDIENCE: Well, I mean, they both carry the same charge, 00:26:13.002 --> 00:26:16.830 so they wind up getting out at the same time [INAUDIBLE].. 00:26:16.830 --> 00:26:18.780 ADAM MARTIN: Exactly. 00:26:18.780 --> 00:26:22.080 So what Carmen said is if they open simultaneously, 00:26:22.080 --> 00:26:24.150 you have sodium flowing in. 00:26:24.150 --> 00:26:25.800 You have potassium flowing out. 00:26:25.800 --> 00:26:29.760 And that's not going to necessarily change the charge. 00:26:29.760 --> 00:26:33.510 So when would these have to open relative to sodium channels? 00:26:37.340 --> 00:26:38.000 Yeah, Carmen? 00:26:38.000 --> 00:26:41.100 AUDIENCE: When it reaches that potential [INAUDIBLE].. 00:26:41.100 --> 00:26:44.150 ADAM MARTIN: So after it's depolarized, yeah. 00:26:44.150 --> 00:26:46.820 So this has to be delayed relative to the sodium 00:26:46.820 --> 00:26:48.470 channels, OK? 00:26:48.470 --> 00:26:53.090 So this has to be delayed relative 00:26:53.090 --> 00:26:56.540 to the voltage-gated sodium channels. 00:27:02.030 --> 00:27:04.070 Because if you're thinking about this traveling 00:27:04.070 --> 00:27:08.180 wave of depolarization, the depolarization 00:27:08.180 --> 00:27:10.850 is going to be high where the sodium channels are only 00:27:10.850 --> 00:27:11.870 entering. 00:27:11.870 --> 00:27:13.700 And then following that, you would 00:27:13.700 --> 00:27:16.010 have potassium ions getting pumped out 00:27:16.010 --> 00:27:19.280 and basically repolarizing the cell. 00:27:19.280 --> 00:27:23.120 Everyone see how you sort of get depolarization 00:27:23.120 --> 00:27:25.760 with sodium rushing in, and then after that, you 00:27:25.760 --> 00:27:30.290 repolarize with the potassium getting pumped out, right? 00:27:30.290 --> 00:27:33.650 So here, you have a spike, and you complete the cycle. 00:27:33.650 --> 00:27:36.410 It can even get hyperpolarized, where it gets even more 00:27:36.410 --> 00:27:38.730 negative than it normally does. 00:27:38.730 --> 00:27:42.170 And then it eventually gets back to this resting potential 00:27:42.170 --> 00:27:45.080 of around negative 60 or negative 70 millivolts. 00:27:52.350 --> 00:27:54.970 OK, so this has to happen fast. 00:27:54.970 --> 00:27:59.500 And I want to tell you about one process or property of neurons 00:27:59.500 --> 00:28:02.110 and another helpful cell that enables 00:28:02.110 --> 00:28:05.680 this to go extremely fast. 00:28:05.680 --> 00:28:09.940 And that is that there are these glial cells in your body 00:28:09.940 --> 00:28:13.000 and your brain that wrap around the axons 00:28:13.000 --> 00:28:16.720 of the neurons and basically function like electrical tape 00:28:16.720 --> 00:28:18.820 for neurons, OK? 00:28:18.820 --> 00:28:21.540 So they are these-- 00:28:21.540 --> 00:28:32.320 there's electrical insulation around the axons 00:28:32.320 --> 00:28:34.760 of these neurons. 00:28:34.760 --> 00:28:37.360 And this is provided by another specialized cell 00:28:37.360 --> 00:28:39.830 type called a glial cell. 00:28:39.830 --> 00:28:41.260 So this is by a glial cell. 00:28:47.630 --> 00:28:50.960 And here are two examples of glial cells. 00:28:50.960 --> 00:28:52.940 There are oligodendrocytes-- and you 00:28:52.940 --> 00:28:56.360 can see how the cell is extending processes 00:28:56.360 --> 00:29:00.530 that wrap around the axons of these two neurons. 00:29:00.530 --> 00:29:02.990 Here's a Schwann cell over here, which 00:29:02.990 --> 00:29:05.300 again, wraps around the axon. 00:29:05.300 --> 00:29:12.420 And these cells basically form what's called a myelin sheath. 00:29:12.420 --> 00:29:16.810 So they form a myelin sheath around the axons. 00:29:16.810 --> 00:29:21.590 And that insulates the plasma membrane of the axon 00:29:21.590 --> 00:29:22.370 such that-- 00:29:25.170 --> 00:29:27.800 so here is an axon. 00:29:27.800 --> 00:29:31.290 You have glial cells that are wrapped around, 00:29:31.290 --> 00:29:34.170 and it sort of forms like beads on a string. 00:29:34.170 --> 00:29:38.330 And so there are these gaps between the myelin sheath 00:29:38.330 --> 00:29:42.950 that are known as the nodes of Ranvier. 00:29:42.950 --> 00:29:51.470 So there are these nodes of Ranvier, which 00:29:51.470 --> 00:29:54.740 are gaps in the myelin sheath. 00:29:59.540 --> 00:30:02.000 And these nodes perform an important function 00:30:02.000 --> 00:30:05.720 for the neuron, because where the axon is wrapped, 00:30:05.720 --> 00:30:09.200 the membrane is electrically insulated. 00:30:09.200 --> 00:30:11.930 And so the sodium ions-- 00:30:11.930 --> 00:30:14.240 or the sodium channels and potassium channels, 00:30:14.240 --> 00:30:18.170 the voltage gated ones, localize to these nodes. 00:30:18.170 --> 00:30:22.190 And when the action potential is traveling along the axon, 00:30:22.190 --> 00:30:26.120 because these regions where the myelin sheath is 00:30:26.120 --> 00:30:29.600 are electrically insulated, the axon potential 00:30:29.600 --> 00:30:32.870 doesn't just move continuously, but jumps from node 00:30:32.870 --> 00:30:36.050 to node, such that you are just opening the sodium 00:30:36.050 --> 00:30:37.700 channels at these nodes. 00:30:37.700 --> 00:30:39.710 And that allows the action potential 00:30:39.710 --> 00:30:43.820 to travel about 100-fold faster along the axon. 00:30:43.820 --> 00:30:45.470 And that's what allows your neurons 00:30:45.470 --> 00:30:47.420 to transmit these electrical signals 00:30:47.420 --> 00:30:49.820 from the base of your spine to your foot so rapidly. 00:30:53.320 --> 00:30:59.570 So you get an increase in speed because the action potential 00:30:59.570 --> 00:31:01.250 is jumping from node to node. 00:31:04.700 --> 00:31:07.610 And one important reason to bring this up 00:31:07.610 --> 00:31:11.930 is because there is an important human disease that 00:31:11.930 --> 00:31:15.260 affects the electrical insulation in the myelin sheath 00:31:15.260 --> 00:31:18.140 here, and that's multiple sclerosis. 00:31:24.120 --> 00:31:26.780 So we're going to unpack multiple sclerosis in a couple 00:31:26.780 --> 00:31:27.690 lectures. 00:31:27.690 --> 00:31:29.873 This is an autoimmune disorder. 00:31:29.873 --> 00:31:32.540 And so we're going to talk about immunity later in the semester, 00:31:32.540 --> 00:31:35.220 and we'll talk about how that happens. 00:31:35.220 --> 00:31:36.890 But for now, I just want to point out 00:31:36.890 --> 00:31:40.610 that multiple sclerosis happens when the immune system attacks 00:31:40.610 --> 00:31:41.870 this myelin sheath. 00:31:45.360 --> 00:31:48.530 So in multiple sclerosis, the myelin sheath is damaged. 00:31:51.800 --> 00:31:55.130 And if you damage this electrical insulation, 00:31:55.130 --> 00:31:58.730 you greatly slow down these action potentials, 00:31:58.730 --> 00:32:00.980 and that has a significant impact 00:32:00.980 --> 00:32:06.020 on nerve impulses in the brain and throughout the entire body. 00:32:06.020 --> 00:32:07.760 And that's why multiple sclerosis 00:32:07.760 --> 00:32:09.110 is such a devastating disease. 00:32:13.340 --> 00:32:15.350 All right, I'm going to start moving now 00:32:15.350 --> 00:32:17.840 to consider more than one neuron. 00:32:17.840 --> 00:32:19.730 So until now, we've just talked about how 00:32:19.730 --> 00:32:23.740 an electrical signal is sent along the length of one cell. 00:32:23.740 --> 00:32:26.240 And now we're going to start thinking about multiple neurons 00:32:26.240 --> 00:32:29.780 and how they connect and how neurons integrate information 00:32:29.780 --> 00:32:32.750 from multiple other neurons to decide whether or not 00:32:32.750 --> 00:32:36.480 to send an action potential. 00:32:36.480 --> 00:32:39.440 And so if we consider this connection right here, 00:32:39.440 --> 00:32:41.420 there's a synapse right here. 00:32:41.420 --> 00:32:44.720 Here's a cell that's sending information 00:32:44.720 --> 00:32:50.690 and a cell that is receiving that information. 00:32:50.690 --> 00:32:53.120 When we're considering a synapse-- 00:32:53.120 --> 00:32:57.350 so if we consider a synapse, there's 00:32:57.350 --> 00:33:00.410 a cell that is sending the signal, which 00:33:00.410 --> 00:33:02.020 is called the presynapse. 00:33:05.600 --> 00:33:06.950 This is the sender cell. 00:33:10.440 --> 00:33:12.080 And there's a postsynaptic cell. 00:33:19.010 --> 00:33:21.320 But you can have more than one neuron 00:33:21.320 --> 00:33:26.240 sending a signal to a neuron at a given time, right? 00:33:26.240 --> 00:33:28.420 So here, you have one neuron that's 00:33:28.420 --> 00:33:31.220 sending a signal at this synapse, 00:33:31.220 --> 00:33:34.160 but you might have another neuron sending a signal 00:33:34.160 --> 00:33:36.620 to a synapse on this part of the cell. 00:33:36.620 --> 00:33:39.920 And you could have another signal coming in here. 00:33:39.920 --> 00:33:41.960 And so this neuron will then have 00:33:41.960 --> 00:33:44.390 to decide whether or not to fire an action 00:33:44.390 --> 00:33:48.740 potential down its axon. 00:33:48.740 --> 00:33:52.100 And the way that the neuron decides this 00:33:52.100 --> 00:33:54.950 is to integrate the signals. 00:33:54.950 --> 00:33:56.910 So there's a signal integration process. 00:34:01.210 --> 00:34:05.010 And what's important for signal integration in a neuron is 00:34:05.010 --> 00:34:07.680 whether or not the cell body-- 00:34:07.680 --> 00:34:11.010 whether the voltage increases above a certain threshold 00:34:11.010 --> 00:34:12.270 potential. 00:34:12.270 --> 00:34:14.880 So if the cell body doesn't increase-- 00:34:14.880 --> 00:34:18.159 if the voltage doesn't increase above this potential, 00:34:18.159 --> 00:34:20.889 there will be no action potential fired. 00:34:20.889 --> 00:34:25.739 But if the voltage increases above the threshold potential, 00:34:25.739 --> 00:34:27.840 then it fires the action potential 00:34:27.840 --> 00:34:30.120 and signals to a downstream neuron 00:34:30.120 --> 00:34:34.590 or muscle or another cell. 00:34:34.590 --> 00:34:49.020 So here, it is the threshold potential in the cell body 00:34:49.020 --> 00:34:51.750 that determines whether or not an action potential is 00:34:51.750 --> 00:34:52.650 sent down the axon. 00:34:55.590 --> 00:34:58.260 And there are different types of signals 00:34:58.260 --> 00:35:01.948 that nerve cells can send. 00:35:01.948 --> 00:35:03.615 So there are different types of signals. 00:35:08.220 --> 00:35:11.640 Signals can be excitatory, meaning it will 00:35:11.640 --> 00:35:14.940 tend to depolarize the neuron. 00:35:14.940 --> 00:35:25.110 So there are excitatory signals, which result in depolarization. 00:35:27.720 --> 00:35:31.770 For example, with serotonin, that 00:35:31.770 --> 00:35:35.310 opens the sodium channel, and that results in depolarization, 00:35:35.310 --> 00:35:37.890 so that's an excitatory signal. 00:35:37.890 --> 00:35:40.590 But there are other types of signals 00:35:40.590 --> 00:35:44.460 that bind to different types of receptors that are inhibitory. 00:35:47.610 --> 00:35:49.290 What might be a type of receptor that 00:35:49.290 --> 00:35:53.220 would inhibit this process of sending an action potential? 00:35:58.620 --> 00:36:00.930 What might an inhibitory receptor 00:36:00.930 --> 00:36:06.870 be to lower the chance that this action potential will be fired? 00:36:09.750 --> 00:36:12.960 What if I told you it's an ion channel? 00:36:12.960 --> 00:36:17.334 What ion would you expect it might pass? 00:36:17.334 --> 00:36:18.830 Udo? 00:36:18.830 --> 00:36:20.082 AUDIENCE: Potassium. 00:36:20.082 --> 00:36:21.040 ADAM MARTIN: Potassium. 00:36:21.040 --> 00:36:23.460 Udo is exactly right, right? 00:36:23.460 --> 00:36:25.650 If it passes potassium, then it's 00:36:25.650 --> 00:36:29.080 going to make the inside more negative. 00:36:29.080 --> 00:36:32.250 And that's what's known as hyperpolarization. 00:36:32.250 --> 00:36:36.060 So receptors that result in hyperpolarization 00:36:36.060 --> 00:36:38.475 would have an inhibitory effect on this process. 00:36:45.300 --> 00:36:48.330 And remember, if you're hyperpolarizing, 00:36:48.330 --> 00:36:51.630 then you could cause this to actually go down and get 00:36:51.630 --> 00:36:54.610 even farther away from this threshold potential, right? 00:36:54.610 --> 00:36:56.550 And if you have an activating signal 00:36:56.550 --> 00:36:58.860 and an inhibitory signal, they might cancel out, 00:36:58.860 --> 00:37:02.910 because one will depolarize and the other will hyperpolarize. 00:37:02.910 --> 00:37:08.100 So it's in this way a neuron is able to integrate signals 00:37:08.100 --> 00:37:09.720 coming from different neurons. 00:37:09.720 --> 00:37:11.820 And that influences whether or not 00:37:11.820 --> 00:37:17.550 it will send the signal to a downstream cell. 00:37:17.550 --> 00:37:20.010 OK, so now we're focusing on what 00:37:20.010 --> 00:37:23.790 is the communication between one neuron and another. 00:37:23.790 --> 00:37:27.585 And this revolves around this thing 00:37:27.585 --> 00:37:29.460 that's called the synapse, which is basically 00:37:29.460 --> 00:37:33.600 the gap between the axon terminal of one neuron 00:37:33.600 --> 00:37:36.355 and the dendrites of a postsynaptic neuron. 00:37:40.230 --> 00:37:43.590 And so the way that multiple neurons communicate 00:37:43.590 --> 00:37:46.230 with each other are through a type of signal 00:37:46.230 --> 00:37:51.090 known as a neurotransmitter. 00:37:51.090 --> 00:37:54.220 And this is what initiates the signal. 00:37:54.220 --> 00:37:58.770 So there's a signal initiation process at the synapse. 00:37:58.770 --> 00:38:01.430 Initiation. 00:38:01.430 --> 00:38:04.860 And this involves the presynaptic neuron 00:38:04.860 --> 00:38:08.170 secreting a neurotransmitter. 00:38:08.170 --> 00:38:11.280 So the signal, in this case, signals between neurons 00:38:11.280 --> 00:38:14.980 are called neurotransmitters. 00:38:14.980 --> 00:38:18.090 And as you see on the slide, these 00:38:18.090 --> 00:38:20.080 are examples of neurotransmitters. 00:38:20.080 --> 00:38:22.140 They're often derived from amino acids, 00:38:22.140 --> 00:38:23.940 and so they're small molecules. 00:38:23.940 --> 00:38:26.280 They're not the proteins that you often 00:38:26.280 --> 00:38:29.460 see with receptor tyrosine kinase ligands. 00:38:29.460 --> 00:38:32.490 This is a different class of signal. 00:38:32.490 --> 00:38:34.320 So one example is serotonin. 00:38:38.080 --> 00:38:43.200 And if you look up at those, we'll find serotonin here. 00:38:43.200 --> 00:38:43.710 There it is. 00:38:43.710 --> 00:38:47.190 Here, you can see it's a derivative of tryptophan. 00:38:47.190 --> 00:38:49.530 So it's a small molecule, and it's 00:38:49.530 --> 00:38:54.070 able to bind to a receptor on the postsynaptic cell 00:38:54.070 --> 00:38:55.650 and induce depolarization. 00:38:58.830 --> 00:39:02.770 And so neurons are-- the way that they communicate 00:39:02.770 --> 00:39:06.480 is-- neurons are a case of where luck favors the prepared. 00:39:06.480 --> 00:39:11.340 Neurons are totally prepared to send signals to each other. 00:39:11.340 --> 00:39:14.460 They have everything ready to go when they get word 00:39:14.460 --> 00:39:18.150 from upstream, and they're ready to send signals 00:39:18.150 --> 00:39:20.250 to the next cell. 00:39:20.250 --> 00:39:23.640 And that's because if we look at the synapse 00:39:23.640 --> 00:39:28.320 prior to an action potential, everything is ready to go. 00:39:28.320 --> 00:39:31.200 The cell has neurotransmitter, and it's 00:39:31.200 --> 00:39:35.340 packaged in these vesicles, and it's tethered to the plasma 00:39:35.340 --> 00:39:38.970 membrane, ready to be released. 00:39:38.970 --> 00:39:41.000 So prior to the action potential, 00:39:41.000 --> 00:39:44.400 there are vesicles filled with neurotransmitter that are 00:39:44.400 --> 00:39:46.110 docked at the plasma membrane. 00:39:50.490 --> 00:39:53.340 I abbreviate plasma membrane PM, just so I 00:39:53.340 --> 00:39:55.440 don't have to write it out, OK? 00:39:55.440 --> 00:39:58.590 So these contain neurotransmitter, right? 00:39:58.590 --> 00:40:00.690 But you see in this docked vesicle, 00:40:00.690 --> 00:40:03.180 the neurotransmitter is in red, and it 00:40:03.180 --> 00:40:05.340 can't get out if that vesicle does not 00:40:05.340 --> 00:40:06.810 fuse with the plasma membrane. 00:40:10.830 --> 00:40:13.199 So these contain neurotransmitter. 00:40:22.490 --> 00:40:26.120 But at this point, the vesicles haven't fused. 00:40:26.120 --> 00:40:28.670 But the vesicle's not fused. 00:40:38.258 --> 00:40:39.175 When should they fuse? 00:40:41.890 --> 00:40:44.190 In this system of neuron signaling to each other, 00:40:44.190 --> 00:40:50.730 when should the vesicle fuse with the plasma membrane? 00:40:50.730 --> 00:40:54.210 What should trigger the fusion process? 00:40:54.210 --> 00:40:55.466 Yes, Miles? 00:40:55.466 --> 00:41:03.158 AUDIENCE: So after [INAUDIBLE] axon 00:41:03.158 --> 00:41:08.526 when it's time for the [INAUDIBLE] 00:41:08.526 --> 00:41:10.965 that's when the vesicles fuse. 00:41:10.965 --> 00:41:12.840 ADAM MARTIN: Yeah, so Miles is exactly right. 00:41:12.840 --> 00:41:17.070 If we consider my diagram here, there's 00:41:17.070 --> 00:41:20.460 an action potential traveling along this axon. 00:41:20.460 --> 00:41:22.950 When it gets to the axon terminus, 00:41:22.950 --> 00:41:26.010 that should be the signal for these vesicles 00:41:26.010 --> 00:41:28.530 to fuse to the plasma membrane and to release 00:41:28.530 --> 00:41:30.990 neurotransmitter. 00:41:30.990 --> 00:41:33.960 So it's the arrival of the action potential, right? 00:41:33.960 --> 00:41:36.750 So remember, in this case, serotonin 00:41:36.750 --> 00:41:38.650 is going to be in blue. 00:41:38.650 --> 00:41:41.810 If serotonin is inside my vesicle here, 00:41:41.810 --> 00:41:43.890 it's going to need to exocytose. 00:41:43.890 --> 00:41:48.510 And now the serotonin is going to be outside the cell, 00:41:48.510 --> 00:41:50.220 ready to bind to the receptor. 00:41:53.790 --> 00:41:56.740 All right, so as Miles pointed out, 00:41:56.740 --> 00:41:58.470 you have an action potential. 00:41:58.470 --> 00:42:01.410 The fusion should be triggered by the action potential. 00:42:01.410 --> 00:42:03.150 In order to fuse, there needs to be 00:42:03.150 --> 00:42:07.890 some signal inside the cytoplasm to tell the vesicles to fuse. 00:42:07.890 --> 00:42:12.710 That signal is increased calcium ion concentration. 00:42:12.710 --> 00:42:14.940 And then when calcium concentration 00:42:14.940 --> 00:42:17.700 increases in the cytoplasm, that triggers 00:42:17.700 --> 00:42:18.930 the fusion of these vesicles. 00:42:22.170 --> 00:42:25.200 And when you get fusion, that's exocytosis, 00:42:25.200 --> 00:42:28.380 and the serotonin is now on the outside of the cell, 00:42:28.380 --> 00:42:31.920 where it can travel across the synaptic cleft and bind 00:42:31.920 --> 00:42:35.340 to a receptor on the postsynaptic neuron. 00:42:35.340 --> 00:42:38.535 So this fusion is when neurotransmitter is released. 00:42:43.590 --> 00:42:45.750 Neurotransmitter is released here. 00:42:52.240 --> 00:42:56.230 And the way that this increasing calcium has to happen, 00:42:56.230 --> 00:43:00.770 when the action potential arrives at the axon terminus. 00:43:00.770 --> 00:43:03.070 So when it arrives in the axon terminus, 00:43:03.070 --> 00:43:07.390 there's depolarization of that part of the cell. 00:43:07.390 --> 00:43:09.820 And so there's a special type of protein 00:43:09.820 --> 00:43:14.680 called a voltage-gated calcium channel. 00:43:14.680 --> 00:43:17.870 All these channels are very selective for different ions. 00:43:17.870 --> 00:43:20.470 So a voltage-gated sodium channel 00:43:20.470 --> 00:43:24.610 isn't letting in all of the ions outside the cell. 00:43:24.610 --> 00:43:26.410 It's selective to sodium. 00:43:26.410 --> 00:43:29.230 And this case, this voltage-gated calcium channel 00:43:29.230 --> 00:43:31.540 is just going to let in calcium. 00:43:31.540 --> 00:43:34.510 And then there's a mechanism that links calcium entry 00:43:34.510 --> 00:43:36.700 to vesicle fusion. 00:43:36.700 --> 00:43:38.630 And that's going to be shown here. 00:43:38.630 --> 00:43:41.380 What you see on this docked synaptic vesicle 00:43:41.380 --> 00:43:45.310 is this calcium-binding protein called synaptotagmin 00:43:45.310 --> 00:43:47.380 that's present on the vesicle. 00:43:47.380 --> 00:43:50.710 And so when calcium goes into the cytoplasm, 00:43:50.710 --> 00:43:55.060 that protein binds to calcium, and it activates the fusion 00:43:55.060 --> 00:43:59.350 machinery such that the plasma membrane of the vesicle fuses-- 00:43:59.350 --> 00:44:02.650 or the membrane of the vesicle fuses with the plasma membrane 00:44:02.650 --> 00:44:05.680 of the cell, thus releasing the neurotransmitter 00:44:05.680 --> 00:44:06.970 into the synaptic cleft. 00:44:12.260 --> 00:44:14.960 So this is what starts the signal. 00:44:14.960 --> 00:44:19.430 Now, you probably know that these neurons are not active 00:44:19.430 --> 00:44:20.830 or on all the time. 00:44:20.830 --> 00:44:24.020 So something has to terminate the signal, usually 00:44:24.020 --> 00:44:25.280 quite rapidly. 00:44:25.280 --> 00:44:26.780 So now I want to talk about that. 00:44:29.660 --> 00:44:32.870 So like all signaling pathways, signaling 00:44:32.870 --> 00:44:35.000 is useless if you can just turn it on. 00:44:35.000 --> 00:44:38.180 You have to be able to toggle it on and off in order 00:44:38.180 --> 00:44:41.240 for biological systems to function properly, right? 00:44:41.240 --> 00:44:42.890 And that's the case with neurons. 00:44:42.890 --> 00:44:44.990 If you just turn on a neuron and you 00:44:44.990 --> 00:44:46.790 don't have a way to turn it back off again, 00:44:46.790 --> 00:44:47.915 then that's pretty useless. 00:44:50.480 --> 00:44:54.140 And so we have to have a way to turn off the signal. 00:44:54.140 --> 00:44:56.330 And if we consider the synapse, this 00:44:56.330 --> 00:44:59.090 is the presynaptic neuron here. 00:44:59.090 --> 00:45:02.000 I'm going to draw a postsynaptic neuron here. 00:45:05.540 --> 00:45:10.390 And neurotransmitter is released by the presynaptic neuron 00:45:10.390 --> 00:45:13.810 to the postsynaptic neuron here. 00:45:13.810 --> 00:45:19.670 Neurotransmitter is released into the synaptic cleft. 00:45:19.670 --> 00:45:23.690 So the sort of extracellular region 00:45:23.690 --> 00:45:27.275 between these two neurons is called the synaptic cleft. 00:45:33.720 --> 00:45:36.770 So now the cell just dumped a whole boatload 00:45:36.770 --> 00:45:39.650 of neurotransmitter into the synaptic cleft, right? 00:45:39.650 --> 00:45:41.650 How is it going to turn this off? 00:45:41.650 --> 00:45:42.650 What does it have to do? 00:45:48.610 --> 00:45:49.538 Yeah, Stephen? 00:45:49.538 --> 00:45:51.250 AUDIENCE: It could absorb the-- 00:45:51.250 --> 00:45:55.208 take back in the [INAUDIBLE]. 00:45:55.208 --> 00:45:56.750 ADAM MARTIN: Stephen's exactly right. 00:45:56.750 --> 00:45:58.460 What Stephen suggested is, is there 00:45:58.460 --> 00:46:02.360 a way for the presynaptic neuron to reabsorb 00:46:02.360 --> 00:46:04.670 this neurotransmitter and, thus, recycle it? 00:46:10.430 --> 00:46:12.560 So it could either reabsorb it or degrade 00:46:12.560 --> 00:46:14.870 the neurotransmitter. 00:46:14.870 --> 00:46:17.510 Different process for different neurotransmitters. 00:46:17.510 --> 00:46:20.810 For serotonin, there are channels 00:46:20.810 --> 00:46:23.990 that are present in the plasma membrane, 00:46:23.990 --> 00:46:29.450 and these mediate reuptake of the serotonin. 00:46:29.450 --> 00:46:31.520 So you have channels that are basically-- 00:46:31.520 --> 00:46:33.860 after the neurotransmitter is released, 00:46:33.860 --> 00:46:37.670 it sucks the neurotransmitter back into the presynaptic cell 00:46:37.670 --> 00:46:41.510 such that it can then reuse the neurotransmitter later on. 00:46:44.660 --> 00:46:53.570 And so this process of reuptake highlights a very important 00:46:53.570 --> 00:46:56.690 process that's been utilized by drug companies 00:46:56.690 --> 00:47:00.200 to create antidepressants. 00:47:00.200 --> 00:47:04.250 So antidepressants like Prozac and Zoloft 00:47:04.250 --> 00:47:06.620 affect this reuptake process. 00:47:06.620 --> 00:47:09.920 And what that does is it keeps the neurotransmitter 00:47:09.920 --> 00:47:12.700 in the synaptic cleft for longer, such 00:47:12.700 --> 00:47:14.990 that it enhances the signaling. 00:47:14.990 --> 00:47:17.420 And so the idea behind these drugs 00:47:17.420 --> 00:47:19.940 is that if you are suffering depression 00:47:19.940 --> 00:47:22.790 from a lack of serotonin, then you 00:47:22.790 --> 00:47:27.830 can rescue that by preventing the rapid reuptake 00:47:27.830 --> 00:47:30.320 of the neurotransmitter into the cell 00:47:30.320 --> 00:47:34.170 after the synapse is stimulated and the neurotransmitter 00:47:34.170 --> 00:47:34.670 is released. 00:47:39.010 --> 00:47:46.240 And so Prozac, Zoloft, these are a class 00:47:46.240 --> 00:47:53.500 of drugs that are known as selective serotonin reuptake 00:47:53.500 --> 00:47:54.220 inhibitors. 00:48:00.600 --> 00:48:01.600 It's kind of a mouthful. 00:48:04.360 --> 00:48:05.860 This is abbreviated SSRIs. 00:48:08.870 --> 00:48:12.220 But the way they function is to leave the neurotransmitter 00:48:12.220 --> 00:48:14.140 in the synaptic cleft for longer so 00:48:14.140 --> 00:48:16.420 that you enhance signaling, even if you 00:48:16.420 --> 00:48:19.750 have low levels of the neurotransmitter to begin with. 00:48:29.000 --> 00:48:32.710 I also want to point out that if we look at this diagram here, 00:48:32.710 --> 00:48:36.070 the synaptic vesicle fuses, and then this 00:48:36.070 --> 00:48:37.870 releases the neurotransmitter. 00:48:37.870 --> 00:48:40.090 But all the machinery on this vesicle 00:48:40.090 --> 00:48:44.470 is recycled by endocytosis such that it can be reused again, 00:48:44.470 --> 00:48:45.220 OK? 00:48:45.220 --> 00:48:47.890 So cells are really good at recycling stuff. 00:48:47.890 --> 00:48:51.850 If this is sort of the membrane, you endocytose and then 00:48:51.850 --> 00:48:56.760 you can use it again later on, OK? 00:48:56.760 --> 00:49:00.460 And so there's recycling not only of the neurotransmitter, 00:49:00.460 --> 00:49:04.090 but also all of the machinery on the synaptic vesicles 00:49:04.090 --> 00:49:08.320 that are responsible for the fusion event. 00:49:08.320 --> 00:49:10.660 All right, now I want to end by just telling you 00:49:10.660 --> 00:49:14.230 how this experiment works, where we're 00:49:14.230 --> 00:49:17.860 able to activate specific neurons in a brain 00:49:17.860 --> 00:49:23.680 and that leads to the animal sort of waking up. 00:49:23.680 --> 00:49:25.480 So in a normal neuron-- 00:49:25.480 --> 00:49:28.750 so this is the last part, optogenetics. 00:49:28.750 --> 00:49:32.110 And I'm going to go through this very fast. 00:49:32.110 --> 00:49:34.510 But normally, you need a neurotransmitter 00:49:34.510 --> 00:49:36.850 to induce depolarization. 00:49:36.850 --> 00:49:39.610 But what optogenetics is, is an approach 00:49:39.610 --> 00:49:44.140 to control the activity of a cell with light, OK? 00:49:44.140 --> 00:49:46.300 So in this case, we're going to have 00:49:46.300 --> 00:49:48.880 light inducing depolarization. 00:49:52.840 --> 00:49:55.510 And the way this is done is there's a protein discovered 00:49:55.510 --> 00:50:00.800 from photosynthetic algae that's responsive to light, 00:50:00.800 --> 00:50:03.580 and it is a sodium channel. 00:50:03.580 --> 00:50:12.400 And this protein is called channelrhodopsin, specifically 00:50:12.400 --> 00:50:14.590 ChR2. 00:50:14.590 --> 00:50:18.550 And this is a light-sensitive protein where light 00:50:18.550 --> 00:50:20.800 induces sodium channel opening. 00:50:24.670 --> 00:50:26.515 So that's going to depolarize the cell. 00:50:29.800 --> 00:50:33.490 And what you can do is if you have a gene that you know 00:50:33.490 --> 00:50:37.060 is specifically expressed in a certain type of neuron, 00:50:37.060 --> 00:50:40.870 you can take the promoter and enhancer region of that gene 00:50:40.870 --> 00:50:44.920 and hook it up to this single component, channelrhodopsin, 00:50:44.920 --> 00:50:49.970 that open reading frame, using recombinant DNA technology. 00:50:49.970 --> 00:50:52.450 And if that's expressed specifically in the neurons 00:50:52.450 --> 00:50:54.340 that you're trying to test, you can then 00:50:54.340 --> 00:50:58.090 shine a light into the brain of the organism and activate, 00:50:58.090 --> 00:51:00.550 specifically, this type of neuron. 00:51:00.550 --> 00:51:04.060 And that allows you to test the function of the neuron 00:51:04.060 --> 00:51:06.320 in the behavior of an organism. 00:51:06.320 --> 00:51:08.710 So, in this case, this mouse, the light 00:51:08.710 --> 00:51:10.660 is shined into its brain, and they're 00:51:10.660 --> 00:51:13.540 testing a specific type of neuron 00:51:13.540 --> 00:51:18.220 that is involved in arousal of the mouse, and it wakes up. 00:51:18.220 --> 00:51:20.330 Oh, it's not playing. 00:51:20.330 --> 00:51:26.020 So here, this is the brain activity on the top, 00:51:26.020 --> 00:51:28.970 and the muscle activity on the bottom. 00:51:28.970 --> 00:51:30.340 So you're going to see light. 00:51:30.340 --> 00:51:31.090 There's the light. 00:51:31.090 --> 00:51:31.590 You see it? 00:51:31.590 --> 00:51:34.880 Light going into the brain. 00:51:34.880 --> 00:51:38.930 They induce light at that frequency for a while. 00:51:38.930 --> 00:51:41.890 And then they're going to wait and see 00:51:41.890 --> 00:51:43.150 when the mouse wakes up. 00:51:43.150 --> 00:51:46.107 And it's going to wake up right now. 00:51:46.107 --> 00:51:46.690 There it goes. 00:51:46.690 --> 00:51:47.200 It woke up. 00:51:47.200 --> 00:51:50.230 You see now its muscle activity is going, OK? 00:51:50.230 --> 00:51:53.080 So you can test the function of specific nerve cells 00:51:53.080 --> 00:51:55.480 using this approach, and it's because you 00:51:55.480 --> 00:51:57.830 have a light-sensitive sodium channel. 00:51:57.830 --> 00:51:58.880 So I'm done for today. 00:51:58.880 --> 00:51:59.990 Have a great weekend. 00:51:59.990 --> 00:52:02.160 I will see you on Monday.