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00:00 | this is lecture eight of neuroscience. today we will talk about the action |
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00:07 | . So the action potential three and propagation. We're going to review some |
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00:12 | the concepts that you learned over the couple of lectures onto this slide here |
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00:38 | potential. So now you know a about what's happening during the action |
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00:43 | Uh but we also reviewed some other is actually not the this is the |
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00:51 | that we reviewed last time. So to remember is that we still talked |
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00:57 | the membrane equivalent circuits which was basically of the properties of the biophysics of |
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01:03 | plasma membrane. And I've asked you know the symbols for resistor conductor or |
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01:11 | resistance conductor for battery as well as . We talked about these circuits that |
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01:19 | essentially membrane equivalent circuits that can be by these different parliaments, the batteries |
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01:32 | , capacitor, active pumps. Even that was one important concept that you |
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01:39 | get a question or two on. other important concept is the resistance and |
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01:47 | with properties of the cell. And fact that the resistance is inversely proportional |
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01:56 | to the size of the radius of cell and capacitance, the larger to |
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02:02 | , the larger the surface area, larger is the capacities. So that |
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02:07 | an important concept that contributed to us about the fact that when you look |
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02:13 | the cellular response as opposed to the that comes from instrumentation, the change |
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02:21 | current stepwise current. A cellular response gonna have this ramp up and then |
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02:30 | down and that's because of the resistance capacity, the properties of the |
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02:37 | Number three important concept that we discussed lecture was the I. V. |
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02:44 | . And we talked about the current plots and when we talked about current |
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02:51 | plots we discussed the following concepts. said that first of all you have |
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03:05 | nana empires, negative nana empires for . Then the voltage have milli |
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03:16 | And let's say this is -100 -50 plus 50 plus more. So we |
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03:31 | about the fact that some of that current voltage plots may be linear. |
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03:40 | means that for the same change in you will have an equivalent change in |
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03:50 | because we're talking about channels and flux ions through membrane channels that are dependent |
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03:59 | voltage. So we talked about how is gating the channels we're talking about |
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04:06 | for the action potential. Okay and drew a couple of other plots and |
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04:15 | said that this is a linear on chi v plot. But I indicated |
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04:22 | there are some responses from the south the channels that are nonlinear. That |
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04:31 | that the same change. And the actually generates a very different change in |
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04:42 | and that there is a preference for channel to conduct ions and the direction |
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04:48 | conductance is inward. So by definition negative nana Appiah deflections is an inward |
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04:57 | . Positive is an outward current. so now the other two plots that |
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05:10 | drew on here is I said I ask you in the exam for something |
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05:17 | this if I drew a plot and said um can you tell me if |
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05:25 | ivy plot refers to sodium or potassium ? And I've asked you to know |
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05:33 | uh nursed equation, global equation and potential values potassium and I said the |
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05:42 | equilibrium potential value is gonna be And so this is would be a |
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05:50 | of potassium because at -90 there's no between VM and the equilibrium potential and |
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05:59 | you recall the change in current is strides, the driving force, there's |
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06:05 | driving force here for potassium and then said I may draw another plot that |
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06:12 | like this and ask you, does represent potassium and sodium? And there |
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06:18 | be many ways that you can envision that potassium is going outwardly on this |
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06:24 | . This is positive 55. And said remember this is a sodium reversal |
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06:29 | . So this would be a representative the sodium current. Okay, and |
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06:41 | that when we talk about the membrane value which is calculated from some of |
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06:51 | sodium, even chloride ions from the is really important for mobility at rest |
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06:58 | the greatest potassium from the ability during rising phase of action potential is the |
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07:04 | sodium. So these things change and will hugely influence the overall membrane |
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07:12 | Okay, so now we're down to four from last lecture and that is |
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07:18 | voltage plan. So you don't need memorize the circuit but what you have |
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07:25 | is conceptually understand what this technology allows to do. And what this technology |
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07:32 | you to do is to control membrane to clamp membrane voltage. Or there's |
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07:40 | desired or what we call a holding command potential. So this technique is |
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07:49 | in order to tease out individual Is that underlie the action potentials? |
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07:57 | originally action potentials were recorded, you reporting voltage change in voltage. Now |
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08:08 | want to be the equals IR you the current to control the voltage. |
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08:13 | you want to be on the other of the equation. V control the |
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08:19 | to record the current. Okay. this technique was used by Hodgkin and |
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08:29 | in isolating the individual conductance is for and potassium mines. So, what |
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08:37 | did in this experiment that reviewed is stepwise deep polarization, showed an inward |
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08:45 | that's transient, followed by an outward that sustained and persistent during the |
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08:52 | And that the inward current reverse of 52 which I call positive 55. |
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08:58 | this is a reversal of the sodium because in the other values which are |
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09:04 | more positive potentials holding potentials. This a voltage clamp holding potential positive |
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09:11 | It shows that now sodium is flowing the opposite direction. Okay, It's |
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09:19 | outward instead of inward and that there's sustained outward current. So, as |
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09:26 | discuss, the action potential. Rising is dominated by many sodium channels opening |
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09:34 | for a millisecond or so in reflected in an average of these civilian |
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09:41 | here to multiple channels and then potassium are delayed. But once they're open |
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09:49 | potassium channels, the currents are So we call them sustained as long |
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09:55 | there is a sustained deep polarizing Um the next thing that we talked |
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10:04 | is the structure of the voltage gated channel And we pointed out that it's |
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10:10 | four subunit structure that has six trans segments where S4 is a voltaic sense |
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10:19 | it has positively charged amino acid residues us five and a six. You |
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10:25 | the for loop that comes together from subunits to serve as a selectivity filter |
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10:30 | select for sodium. Uh the way the sodium channel gates open is through |
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10:38 | confirmation all change In this three dimensional structure. And the way that confirmation |
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10:45 | change comes about is that once you the membrane from negative 65 which is |
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10:52 | negative charge and attracting this positive charge stay here on the side of plasma |
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10:58 | of the membrane, you add positive here again, positive charge would be |
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11:03 | from synaptic inputs. And if it the membrane potential, the threshold you |
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11:08 | produce an action potential. So if reaches those close values, what happens |
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11:13 | now the inside of the number and becoming more positive. It's not completely |
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11:19 | but it's more positive than the build of that positive charge or less negative |
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11:24 | starts repelling. It's not as attractive this both incentive to stay on the |
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11:31 | of plasma side. So it shifts this protein structure and as it shifted |
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11:36 | conformational change which opens the gates for sodium channel. And we talked about |
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11:42 | types of gates, these arms that closed here, we call them activation |
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11:48 | and this ball and chain like structure called inactivation gates. And if you |
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11:56 | polarize plasma members of the south, sodium channels will open so activation the |
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12:02 | sensor will slide up the activation gates open. But that same confirmation all |
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12:07 | in the protein structure will encourage for ball and chain mechanism to basically plug |
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12:14 | the channel four. And at this the channel and number three is inactivated |
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12:21 | this channel will remain inactivated until you the D polarizing stimulus in the plasma |
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12:29 | Repola rises to a resting membrane And as it re polarizes to resting |
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12:36 | potential, that voltage sensor is gonna drawn to the negative car and downward |
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12:43 | causing this ball and chain to swing which is called Dean activation and subsequently |
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12:51 | closure of the activation gates. So have to go 1234, 1234. |
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12:58 | this is the reason why, as spoke that sodium, one of the |
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13:02 | why sodium doesn't reach the Librium potential sodium during the rising peak of the |
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13:07 | potential. This reason is the kinetics the closure of the sodium channels |
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13:13 | In other words. Okay, so is what a voltage clamp. Modern |
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13:21 | clamp would look like. Instead of circuit with two electrodes, you have |
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13:27 | electrode. And the reason why from electorates you can go down to one |
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13:33 | is once the circuit became super they can do both stimulate and sample |
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13:40 | they can do it at such fast rates 10 kHz, 16 kHz, |
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13:46 | kHz. Which means that 10,000 samples second. So we can capture a |
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13:52 | of information still on the data without information at such high sampling rates. |
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13:59 | this is a typical setup that I you earlier that I said it's underneath |
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14:05 | microscope, you guide the electors to south. And this illustrates that in |
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14:11 | instances instead of recording activity from the south, you may want to record |
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14:17 | just from a patch of the And what you're hoping for is that |
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14:21 | of the membrane will contain your voltage gated channels or receptor ligand gated |
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14:30 | that this piece of the member will that channel eventually. And this is |
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14:36 | like a reduced way of looking at cell even more so than recording activity |
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14:41 | the whole cell. But it's very because now you can test the flux |
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14:47 | ions. You can change the concentration the pipette, you can change the |
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14:52 | of this outside environment and you can testing how different substances such as in |
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14:59 | original days of roderick Mackinnon, how toxins were affecting the flux of ions |
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15:04 | potassium channels. As he was deriving structure of those potassium channels. You |
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15:09 | see how different chemicals pharmacological agents affect of different channels such as sodium |
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15:18 | And these techniques they called voltage clamp or or patch clamp techniques. They |
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15:27 | several, they come in several so to speak. It's still that |
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15:32 | recording pipette. That pipette if you has to have a certain solution inside |
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15:40 | represents either the inside of the cellar of the cell, whatever experimental you |
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15:45 | it to be. And in some you can have an attached recording. |
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15:51 | this attached recording is basically the end that elector just attaches to the plasma |
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15:59 | . And then now you have access records from a small patch of the |
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16:05 | just through the channels that are open . So that's one way of doing |
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16:10 | . Very common way of doing these physiological recordings of neuronal activity. Is |
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16:18 | whole cell recording in that situation when guide that micro electorate to the |
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16:24 | it's not only attached to the amplifiers it's also attached to a little tube |
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16:30 | that little tube is attached to another tube? And that another little tube |
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16:34 | attached to syringe. And the experimenter a syringe so the experimenter can approach |
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16:41 | cell with the lecture and suction So it attaches to the neuronal membrane |
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16:49 | then produce even stronger fast suction through syringe to bust open that plasma membrane |
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16:56 | separate it to gain access to the cell and record all of the car |
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17:02 | . That would be flexing through the cell and the side of plaza in |
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17:07 | situation becomes continuous with the pipette So that means that whatever you have |
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17:12 | the pipe at what we call the pipette solution or inter cellular solution should |
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17:19 | what the cytoplasm of the neuron would in some other instances, instead of |
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17:28 | the membrane to gain wholesale access, electrode actually withdraws itself a little |
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17:37 | Well, you know, it takes skill to do that. It's a |
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17:41 | , not a robot that does that it breaks off a piece of the |
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17:47 | from the rest of the south. this is an interesting configuration because now |
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17:53 | inside of this channel say sodium the inside of this channel is exposed |
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18:01 | the outside. Okay, that's why called inside out recording. Now, |
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18:09 | you put certain substances for example that not cross the channel and do not |
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18:13 | the membrane, especially in pharmacology, may have a question, which part |
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18:19 | the channel does it bind, bind side of plas mix side of the |
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18:23 | . Does it bind the extra cellular of the channel? If it binds |
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18:28 | cytoplasmic side of the channel, you'd to do the inside out recordings because |
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18:33 | would expose the inside of the channel whatever would be binding to that channel |
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18:39 | you see what effect it has on current flux through the channel there. |
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18:45 | it's an inside out recording. Uh in some other instances you actually withdraw |
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18:54 | piece of the number rain and you it as you're retracting it. And |
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19:01 | happens is that if you're lucky, membrane will Rien il. But instead |
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19:07 | exposing the cytoplasmic side, it actually the extra cellular side of that |
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19:16 | So once again, if you have that do not cross through the channels |
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19:20 | not cross through the membranes or not soluble and you're interested to know how |
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19:26 | given substance with the fact that flux sodium channels through potassium channels. |
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19:32 | you have a lot of tools at , you can use chemicals for pharmacological |
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19:38 | , you can clamp the voltage. you can just look at sodium current |
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19:44 | of these patches of membranes will contain potassium and calcium channels. And so |
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19:50 | can isolate them based on their equilibrium and based on their kinetic properties of |
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19:57 | and closing to identify different currents and different substances would affect. Either the |
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20:04 | inside out or outside, which is out recordings or outside out activity. |
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20:11 | would be exerted on these channels by substances. So there is this uh |
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20:22 | interesting story and I'm gonna maybe pause recording for a second. Yeah |
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20:32 | Fan tastic. Beautiful language isn't God's . Don't eat another bite. Couldn't |
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20:52 | mr Simpson, I shall be We have reason to believe you have |
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20:57 | poison poison. What should I What should I do? Tell me |
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21:02 | . No need to panic. There's map to the hospital on the back |
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21:05 | the menu. Try something new What will it hurt you homer? |
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21:12 | never heard of a poison pork Your wife agreed that I should break |
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21:16 | to you know need I can read like a book. Oh it's good |
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21:23 | isn't it? No. Mr If in fact you've consumed the venom |
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21:28 | the blowfish and from what the chef told me it's quite probable you have |
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21:33 | hours to live 24 hours. Well I'm sorry I kept you waiting so |
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21:39 | . Oh Mark, I'm gonna I'm gonna die. Well if there's |
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21:44 | consolation is that you will feel no at all until sometime tomorrow evening when |
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21:49 | heart suddenly explodes Now. A little anxiety is normal. You can expect |
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21:54 | go through five stages. The first denial. No way because I'm not |
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21:58 | . Second is anger you. Little that comes fear, Fear what's |
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22:04 | Fear bargaining doc. You gotta get out of this. I'll make it |
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22:07 | your while. Finally, acceptance. , we all gotta go sometime. |
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22:11 | Simpson your progress Astounds me. I leave you two alone. Perhaps this |
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22:16 | will be helpful. So you're going die. Mm. Faith tenses on |
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23:13 | success battle has been great. I supposed to be the last lecture. |
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23:24 | . That's truly not at his best . Let's see, I was trying |
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23:39 | find the Fish, which there are 100 species worldwide. You need a |
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23:48 | to sell puffer fish in japan, as a buyer you need one too |
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23:58 | Okamoto has a fuego restaurant and of a license. He's not here to |
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24:04 | the increasingly popular nontoxic farmed food which be recognized by its shorter fins. |
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24:10 | is he interested in the small species in the wild from japanese waters. |
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24:16 | true connoisseur is only looking for one toxic wild as fresh as possible and |
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24:23 | means tora fugu tiger puffer fish. Kobe beef of fugu cuisine. |
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24:43 | A single specimen of this species which only found in the sea of japan |
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24:48 | well cost €100 one of Tokyo's historic is located around Asakusa temple. Most |
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25:04 | fugu restaurants are to be found There are about 3000 restaurants specializing in |
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25:10 | in Tokyo today From the outside, usually easy to recognize and they're always |
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25:16 | specialized. One of them is Ricky's restaurant where sometimes even Prime Ministers drop |
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25:28 | war says its name, the pure place. You also need a license |
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25:34 | prepare fuku. The poison in Fugu tetrodotoxin. It's 1000 times more potent |
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25:41 | cyanide and there is no antidote. poison paralyzes its victims but leaves them |
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25:48 | conscious. Proper preparation is critical. skin and entrails of the fish are |
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25:55 | and they must not contaminate the non meat on the muscles. High concentrations |
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26:10 | highly poisonous tetrodotoxin are found in the , especially the liver and ovaries. |
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26:17 | disposal is necessary. So I want pause it for a second. So |
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26:22 | gonna talk about tetrodotoxin ttx and I'll you what it does. But I |
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26:28 | want to tell you that tetrodotoxin is the fish in these organs but it's |
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26:35 | not synthesized by this fish. It there because of the bacteria in the |
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26:44 | and in certain organs. And so is sort of gonna be a little |
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26:48 | of a theme to is we're gonna at some toxins that are produced by |
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26:54 | by clamps by shellfish and it's again not that the animal is synthesizing this |
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27:03 | but it's coming from bacteria that are in these animals. And so these |
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27:11 | of meat are obviously very highly prized they're prepared. They're definitely I guess |
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27:20 | the poison of the fish triggers numbness the mouth and is intoxicating. So |
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27:27 | has certain intoxicating value. The reason people pay a lot of money and |
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27:33 | have to have a seven year license the chef to prepare your food. |
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27:37 | people pay a lot of money because the tingling sensation and maybe some other |
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27:45 | or whatever sensations that people may feel the reason why you have to have |
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27:51 | license is because if you don't separate organs and you don't cut the fish |
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27:59 | you can basically cause the sushi and sashimi pieces to be poisoned. And |
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28:10 | there used to be quite a few from consuming raw fugu and it's become |
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28:19 | better now obviously just maybe one or or two or a few but there's |
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28:25 | whole ritual behind it the way it's , the way it's served and it's |
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28:31 | obviously for special occasions and people enjoy this. So this is a popular |
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28:40 | to do in Tokyo and I would to go to that restaurant to try |
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28:46 | food and fish some someday. Now that didn't work out as well for |
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28:55 | Simpson because the chef was busy but what we're talking about is what I |
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29:05 | mouthwatering tales of toxins because it looks delicious to try you know that sushi |
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29:14 | but it's it can be containing So Tetrodotoxin. Tetrodotoxin not not not |
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29:23 | miss accidentally is a is a traditional to consume. And so it's it's |
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29:32 | in Japan and the scientists that plays key role in demonstrating the cellular mechanisms |
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29:41 | action for mechanisms of action channel mechanisms action of tetrodotoxin is Toshio Narahashi. |
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29:50 | a very interesting story that he basically about late fifties, early sixties in |
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29:57 | story. That's one of the other of discoveries that are encouraged to to |
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30:02 | at just like we talked about roderick and the structure of potassium channels. |
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30:08 | this is his story, so he a toxin and he's very interested in |
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30:13 | channels and so he goes to biochemistry and there's even a description if I'm |
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30:19 | mistaken here or someplace else that after biochemists like after the big talk and |
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30:25 | meeting, he starts talking about these and people are like what are you |
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30:30 | about? What channels? So that late fifties sixties people were just catching |
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30:35 | that there are channels that they're conducting . And biochemists were not as interested |
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30:41 | that until they became really interested in , you know, so he has |
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30:46 | 10th or the toxin but he doesn't what it does exactly, He has |
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30:52 | to record action potentials and he sees there's a paralysis, there's a blockade |
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30:57 | action potentials. So he can test and the models where he can record |
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31:03 | but to definitively prove what it he needs to get to voltage |
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31:08 | So in the early 60s he has to travel the United States from Japan |
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31:14 | a year worth of research and And during that year he carries a |
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31:19 | of TTX in his jacket pocket. then he within that year he has |
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31:25 | opportunity to go and work with the clamp set up. They were rare |
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31:29 | that age still and what he does he demonstrates that when he applies |
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31:39 | So this is our stimulation here and have this very strong inward current followed |
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31:44 | an outward current. Just like we about with Hodgkin and Huxley and this |
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31:50 | in the presence of tetrodotoxin. So you add that to the toxin, |
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31:55 | selectively blocks sodium. Both educated sodium without affecting the outward potassium conductance |
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32:04 | And so now he understood definitively by voltage clamp that T. T. |
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32:10 | . And he postulated in blocks voltage sodium channels because he already knew that |
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32:16 | potential from the literature from Hodgkin and in the forties and fifties that action |
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32:22 | had sodium and potassium but he has seen this experimental so it took like |
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32:29 | years with some toxin to travel the States to some set up to actually |
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32:34 | show experimentally what it does. It affect outward potassium card. But there |
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32:40 | other blockers. Some of these are in nature derived toxins. But some |
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32:46 | them are just chemicals to that are blockers or they can even open channels |
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32:53 | their blockers they called antagonists that needs close or block the channel if it's |
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32:59 | that opens the channel or encourages downstream from that channel, it's called an |
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33:05 | . Okay, so you have a biological and chemical antagonists or blockers of |
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33:12 | channels. TtX for sodium potassium is little ammonium, abbreviated as T. |
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33:21 | . And these toxins are around So saxony toxin would be present and |
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33:27 | , mussels and during red tide and temperature when there's certain algae and blooms |
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33:34 | the water, you're suggested to stay from certain foods. We don't have |
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33:40 | much of the clams and mussels here texas and I guess the south coast |
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33:48 | the United States, but in the like north east where there is a |
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33:55 | of culture for muscles, your advice to eat, not to consume |
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34:00 | And especially not to consume them raw those certain periods of time in nature |
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34:06 | in texas. You know the same for uh crawfish that you're supposed to |
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34:15 | crawfish only. This is what I taught when I went to school in |
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34:20 | . You're only supposed to consume crawfish the months that have are in |
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34:25 | It's easy to remember. So june August don't have ours in all 11 |
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34:34 | have the letter R. So this when you know that you can eat |
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34:39 | is because the hottest months, it's recommended to eat crawfish. So for |
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34:48 | a number of reasons but we have regulations and there's another bad tract code |
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34:54 | and Colombian frog. Now when you like what what does it affect? |
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34:59 | does it block the channel? Remember talked about it has activation gate, |
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35:03 | has an activation gate. So these toxins will affect different parts of the |
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35:08 | . They may have specific and unique on this three dimensional channel structure where |
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35:14 | bind and if they bind here the is blocked and it cannot open. |
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35:20 | they bind here, the channel can but then it gets inactivated much |
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35:27 | Or maybe the opposite if it bounds , the channel is open and it |
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35:31 | inactivate for a long time since sodium keeps coming in also could be a |
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35:37 | condition. And these different binding sites different molecules help us reduce three dimensional |
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35:46 | structure. That's what helped roderick Mackinnon that structure in three dimensions in the |
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35:52 | . It allows you to study effects channel blockade. So you can see |
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35:58 | it affects if it's a membrane and molecule, you can use the techniques |
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36:05 | inside out recordings outside out recordings to where it binds on the channel different |
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36:13 | , how it affects flux through sodium potassium, you can isolate sodium and |
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36:19 | currents using voltage plan. Now, of these tools, basically the chemistry |
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36:27 | , electrophysiology and the voltage clamp. these advanced IQ meets with wholesale recordings |
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36:34 | do a lot of experimental discovery with tools. Nature is potent. It's |
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36:41 | message to there's some very potent spider that can kill us. Um If |
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36:47 | consume too much cetera the toxin it actually kill you by suffocating you. |
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36:52 | it will bind to sodium channels. talking about action potentials in the brain |
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36:56 | there's sodium channels in the periphery. need deep polarization through sodium channels for |
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37:02 | muscles to start contracting. And so levels of TTX can start impacting the |
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37:08 | trying muscles and basically causing you to to lose breath and suffocate. That's |
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37:15 | of the known uh effects that causes stoppage of the horrid tomb tetrodotoxin. |
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37:23 | when we talk about these toxins, puffer fish, newts, frogs, |
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37:28 | don't produce them. They don't synthesize animals don't synthesize these toxins. They |
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37:34 | them bacteria. You know that you microbiome in your guts and you have |
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37:41 | more and way more complex genetic composition this bacterial enclaves than in your own |
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37:51 | . So what you carry in your is actually really really complex in |
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37:56 | And even the facts of how you things and how you can synthesize even |
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38:02 | internally. But obviously this is coming these bacteria that we're talking about. |
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38:11 | Now these are the deep plots and review of the linear D. |
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38:17 | So this is the I. Plot. And this is the demonstration |
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38:22 | the reversal of the current and the of the current and the opposite direction |
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38:26 | zero millibars. Just like you're seeing . This is the simple oneK |
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38:32 | And this is actually a D. for something that will be discussing quite |
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38:38 | bit in the next section as acetylcholine channels. And we'll talk about that |
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38:45 | they have a linear plot. So this is examples of rectification. So |
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38:54 | told you I was gonna take But I think between this image here |
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38:59 | the board uh and the recording and description here in the slides I think |
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39:08 | should be able to sufficiently answer the from the exam that I may have |
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39:13 | to this material. Local anesthesia. It's actually light agonist for sodium and |
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39:25 | the periphery is cocaine but most importantly what I would like for you to |
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39:32 | is lidocaine because lidocaine is a local which means what already may have mentioned |
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39:39 | When you go to get your teeth the doctor may ask you do you |
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39:49 | local anesthesia? You probably say Um Sometimes uh dental offices is nitrous |
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39:59 | . So it's more of a kind a falling asleep feeling something you're inhaling |
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40:03 | lidocaine will bind to the nerve endings should be proceeding the pain and the |
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40:11 | when you're having a small surgery on teeth because you don't feel that. |
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40:17 | then quite often when lidocaine wears off it won't stay bound to that receptor |
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40:24 | . So some substances bind to receptors quickly and they get unbound. Some |
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40:30 | them bind and stay there for a exerting their effect. Some of the |
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40:35 | will have that substance locally concentrated sort keeps binding even if the other molecules |
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40:40 | that keeps binding. But then what after you come home and you had |
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40:46 | tooth done three or 4 hours Oh pain again. Right. And |
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40:54 | you leave the dentist's office, if had local anesthesia, then you would |
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41:00 | when you go home, you know it starts wearing off and the numbness |
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41:03 | coming off, you should take some , you know some Advil or Tylenol |
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41:07 | whatever works for you. So that's to control the pain uh in a |
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41:14 | binding site for this molecule. And this this structure can have so many |
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41:22 | uh nooks and crannies and three dimensions these different molecules to come in and |
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41:29 | up to them and regulate their Now, quite often when we talk |
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41:38 | these channels, You know, you often wonder well, okay, so |
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41:43 | channels are just so small, it's molecule, like it's a channel. |
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41:48 | do you isolate activity from one How do you really know when you |
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41:52 | out that patch of the membrane with that has sodium potassium calcium? How |
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41:58 | you really tease out? What if two, both educated sodium channels? |
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42:03 | if there's three? And they all kind of a similar kinetics and you're |
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42:07 | average over over three different subtypes of educated sodium channels. So to get |
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42:16 | specific than you can use other tools other systems. So frog do sides |
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42:23 | huge eggs and you can over you can isolate something so you can |
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42:28 | the voltage gated sodium channel of interest you can over express it in these |
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42:34 | Exoo sides. You can have very lectures recording activity and because it probably |
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42:41 | the dominant thing that that the egg expressing, you'll be able to record |
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42:45 | strong cars. So this shows an potassium channel that has been over expressed |
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42:52 | these very large cells. And then can record very strong currents and you'll |
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42:59 | why do you want to do Because if you can amplify something and |
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43:04 | plasma membrane and that patch, you have 10 of those multi educated sodium |
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43:10 | and 10 of that is and 10 that is and you really cannot tease |
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43:13 | apart using the techniques that we talked electrophysiology and and uh and even |
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43:20 | So, but you can still tease apart based on their on their |
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43:27 | And so once you take something small or two channels and you amplify through |
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43:32 | system into thousands and tens of thousands channels. Now you can see something |
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43:39 | much larger scale. Now you can back into more complex systems, back |
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43:43 | the mammalian systems back into neurons and for the equivalence of these types of |
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43:50 | in these types of kinetics. So type of amplification allows you to really |
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43:58 | things better. Now the purpose of action potential, the main purpose of |
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44:05 | action potential is something that we're going talk about a lot and the next |
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44:13 | and that is to cause the release the neurotransmitter. So what we've covered |
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44:19 | this section because we've covered the fact the action potential gets produced here. |
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44:29 | why does it get produced here in axon initial segment? Because this accident |
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44:34 | segment will be loaded with voltage gated and voltage gated potassium channels, neurons |
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44:43 | their strategy where they're going to place different subtypes of channels and receptor channels |
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44:50 | voltage gated channels that they express. like a little city. Okay. |
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44:56 | gonna decide what I'm gonna do by here. And you will find a |
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45:02 | large expression, very high number of and potassium channels expressed in the axon |
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45:10 | segment here, which makes us a place to produce the action potential. |
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45:18 | on the den rights, not on selma, but in the axon initial |
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45:23 | . Why? Because it is loaded both educated civilian and educated potassium channels |
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45:31 | play into the dynamics of action potential we talked about the cell, if |
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45:37 | recall this neuron is going to be excitatory input. So if it's receiving |
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45:43 | inputs that will be polarized. If is receiving inhibitory inputs from someplace else |
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45:49 | will hyper polarized. These are great synaptic potentials and this is gonna be |
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45:55 | transmission and neuronal networks that will start in the next section. But if |
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46:02 | shell is excited enough, this particular needs a little bit of current and |
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46:09 | will produce an action potential. Once action potential is produced it will get |
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46:17 | that each note of ranveer and each of ranveer will have the same shape |
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46:23 | amplitude as it did at the accident segment. And the reason for it |
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46:30 | those of Ron beers are unde. ated areas on the axon and are |
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46:38 | with voltage gated sodium and voltage gated challenge. So this charge breaks through |
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46:46 | , this action potential and then it through the axon. And in this |
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46:54 | of ranveer it breaks through again and itself and then travels again through the |
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47:02 | part of the wire until it reaches terminal where again produces the same size |
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47:10 | potential as it did the facts on set. So there's a theory or |
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47:17 | of dynamic polarization that was initiated by to how. And according to him |
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47:24 | you remember his diagrams, he said there's arrows flying flowing into dendrites and |
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47:30 | . So he says there's a problem antennas receiving the inputs and then he |
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47:35 | arrows from axons flowing in one So he says that there's one direction |
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47:41 | which these neurons communicate. But he right for the most part of the |
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47:45 | synaptic transmission and this action potential that here at the axon initial segment and |
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47:53 | down the axon and reproduces itself with axon terminal. It's a forward propagating |
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48:03 | potential. So it is moving in polar direction. But with Monica, |
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48:07 | they didn't know because there was no potential recordings in the late 19th |
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48:14 | beginning of 20th century. He didn't that there is gonna be a small |
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48:19 | that gets generated here that is actually to propagate. This is propagating, |
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48:26 | is regenerating and this small cars is to propagate back into the soma into |
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48:33 | dendrite is called the back propagating action back propagating spike. So in your |
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48:50 | documents you have in your supporting documents out in the folder by accident. |
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49:06 | . Uh you have the supporting Let me this is gonna be the |
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49:14 | slide that we go over actually in whole section. And the last concept |
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49:20 | will go over. So it's something you guys to review for the |
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49:25 | I may ask you a question or on this, but I may also |
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49:30 | back and ask you another question or on the subsequent midterm exam because there's |
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49:35 | be more information that we're adding onto . So remember I told you that |
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49:41 | may have multiple multi educated channel. I also said that one cell can |
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49:47 | multiple multi gated sodium channel sometimes just particular sodium island channel sometimes. So |
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49:55 | turns out that the channels that are close to the selma in this region |
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50:04 | . R. N. A. . 1.2. And this subtype of |
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50:09 | channels called high threshold sodium channels. high threshold which means it requires high |
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50:16 | of current, a lot of current order to open the vault educated |
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50:20 | That's high threshold a little bit further from the soma. In this |
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50:26 | In the axon direction you have maybe and M 81.6 are low threshold voltage |
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50:36 | channels. That means that they require little bit of positive current. Low |
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50:42 | for opening of the civilian general. this is an explanation of how can |
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50:49 | cell produce a forward propagating spy in back propagating. And we talked about |
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50:59 | it can produce the forward propagating It activates the inputs d polarizing |
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51:05 | If they overcome the inhibitory inputs, membrane potential value can reach the threshold |
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51:12 | action potential and the sodium and potassium in here. Boom will set off |
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51:18 | action potential. But then I said going to be forward propagating and back |
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51:24 | forward propagated. The one that's be cloud comes in and you see this |
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51:29 | arrow in wong actually this current although is positive current and quite a bit |
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51:35 | it. It bypasses this area that inhabited by N. A. D |
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51:43 | And it's not strong enough to open 81.2. But then when it reaches |
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51:49 | area that has low threshold require low and maybe 1.6 it sets off the |
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51:57 | which is the action potential, the phase of the action and this action |
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52:04 | three will be forward propagating, it go regenerated note of run there and |
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52:10 | the release of the neurotransmitter as you this explosion and deep polarization nearby. |
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52:19 | A V 1.2 which require high threshold . Now feeling this polarizing input and |
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52:28 | explosion from this it's some positive charge leaks into the area and the combination |
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52:35 | the two is now strong enough to N A V 1.2 and when N |
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52:41 | D 1.2 opens the sodium starts flexing and here you have a very large |
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52:48 | potential already a lot of positive charge you don't have as much of positive |
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52:55 | coming in with the deep polarization. these channels say the only way my |
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53:00 | can go is back into the south produces a small number five back propagating |
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53:08 | potential that travels into the cell, into the south and back into the |
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53:16 | drives. So we have the forward action potential and 81.6 low threshold And |
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53:27 | 81.2 high threshold which now sends some this positive input and this positive input |
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53:33 | generate back propagating spike spike. Let is really a fraction system on the |
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53:41 | of a few million volts. So main forward propagating action potential in the |
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53:46 | of 100 million volts. The small propagating action potentials in the order of |
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|
53:50 | funeral vaults. Yeah. Does this propagation has? Yeah. That's a |
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53:57 | question that propagation has. What is propagating spike. And why should I |
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54:04 | about it? So uh it's uh gonna actually tell me about it briefly |
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54:16 | I said it's gonna be a last and I wanted to uh talk about |
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54:22 | maybe under your review, just kind put some of the things together. |
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54:27 | this very fast communication. And this of union spike is very important for |
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54:34 | plasticity that informs the cell and informs Den writes that this cell has been |
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54:41 | by the influence the cell has a ability to learn and it has a |
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54:48 | ability to strengthen the inputs that caused to fire action potential. So in |
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54:54 | way it's reporting back of what happened saying, yeah, all these inputs |
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54:59 | the spike. It's paid off and just letting you know, we're good |
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55:03 | if you don't produce a spike and don't have the back propagating action |
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55:09 | This network the synapses doesn't tune as as in florida as well. So |
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55:16 | important for plasticity. There's a concept spike timing dependent plasticity and that is |
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55:24 | if this cell fires and you have back propagating spike in in very short |
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55:32 | period from Neutrogena, then they know the signal is relevant, incoming signal |
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55:37 | relevant because otherwise it's fires, fires and we sell a silent, |
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55:42 | , there's no back propagating spike back spike comes to this network a second |
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55:49 | , which is forever and neurons and irrelevant. So there's something about the |
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55:55 | and timing that's very important. You can think of, you have this |
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56:01 | summation that's coming in. Now, you d polarize the cell back up |
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56:07 | again and the den rides, then inputs have a greater chance of having |
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56:12 | sell reach the threshold begin for action . So it's really tuning the pre |
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56:17 | inputs of post synaptic inputs through this propagation. And tuning the plasticity of |
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56:23 | learning rules and the networks. I a question there challenge of the |
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56:31 | but I believe I'm gonna leave that for the for the next uh |
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56:38 | Let me just check. Well, boy, I didn't record the last |
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56:46 | portion here. I talked about different channels. I'm not going to rerecord |
|
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56:51 | , but maybe I'll re mention this Uh in the review. So also |
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56:59 | you have any other questions about the , I expect to spend about 45 |
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57:06 | maybe on the review myself. I a lot of the material and action |
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57:11 | is pretty fresh. Uh and I'll over some of the other concepts in |
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57:17 | fairly fast manner, so maybe seven per lecture, so or less 5-7 |
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57:24 | . Uh for each lecture is about lectures that we had. So come |
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57:30 | , bring your questions. All of materials are available to you, and |
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57:34 | see you all on |
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