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00:02 | This is Lecture seven of neuroscience. we're first going to talk about membrane |
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00:08 | circuits. Uh If we if you we talked about how channels ion channels |
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00:16 | selected filters and ion channels in this , when you talk about action |
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00:22 | you're talking about voltage gated ion So those channels will open and close |
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00:28 | on the voltage, there's no ligand to these channels to open them or |
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00:32 | them. So it's really the And we know that these channels are |
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00:39 | they're closed, they have very high and if they're open they have low |
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00:45 | . And that means that a lot ions can be conducted through these |
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00:49 | And if you remember arms law E Ir also remember that conductance is the |
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00:56 | of the resistance. Mhm. And if you look at the top |
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01:02 | what you have is a representation of channel in the plasma membrane using membrane |
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01:09 | circuits. So those are the kind a circuit you'd see in electronics. |
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01:14 | Physics department. And this symbol stands resistor. Or if you're in another |
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01:27 | , it stands for conductor And conductance jeep. And quite often these channels |
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01:34 | variable resistance or conductors. And this indicated by an arrow going across the |
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01:41 | symbol, each one of the ions you know, has a separation of |
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01:46 | across plasma membrane and it has its charge. Therefore the separation of charge |
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01:54 | on the inside, positive on the serves as a battery and each of |
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02:00 | islands is going to react to that , depending on the charge, This |
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02:04 | electrical forces. Electoral chemical forces that in this case stands for the battery |
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02:13 | this is the symbol for battery. electrochemical forces. The battery and in |
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02:22 | case it's a battery for potassium. this is a symbol for a |
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02:27 | And obviously if you have plasma membrane will have more than one channel. |
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02:35 | lot of times neurons will have 10-20 voltage gated types of channels. You |
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02:42 | have four subtypes of sodium, five of potassium, some subtypes of |
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02:47 | calcium and so on. It depends the individual cells. Remember the channels |
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02:53 | they will express and the intracellular markers they express, which makes them unique |
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02:59 | their subtypes and their functions. So can see that each one, the |
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03:05 | , the potassium and the chloride will . The channel can be represented as |
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03:10 | resistor with a battery across plasma membrane the charges build up and notice that |
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03:17 | plates of the battery are different for than it is for potassium because like |
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03:22 | said, potassium is built up and charge on the outside of the south |
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03:28 | of the cell where there's negative charge sodium is built up on the outside |
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03:32 | the cell, there's positive charge. if you wanted to know for example |
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03:38 | is the overall potassium conductance, you want to know how much single potassium |
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03:45 | conducts. So if you rewrite ALMS into VM minus C. K, |
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03:52 | is the driving force and will continue about that concept today equals IR V |
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04:00 | IR But here is the difference. difference in voltage with the difference |
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04:05 | when the equilibrium potentials for the ion between the membrane potential, which is |
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04:10 | by several ionic species conductance here, or G is one over R. |
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04:18 | I, current is equal B over . Or current is equal conductance times |
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04:25 | driving force driving force right here. , if you have that for potassium |
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04:35 | conductance and its driving force for an channel, then you have to know |
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04:42 | many potassium channels you may have in piece of the membrane or in the |
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04:47 | . And the densities of channels may themselves. They have dense populations of |
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04:54 | and certain parts of plasma membrane and more sparsely distributed channels. If you |
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05:03 | a total number of channels which is of potassium channels and individual conductance, |
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05:09 | can know the overall conductance of potassium that cell and most of the electro |
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05:16 | recordings when they record activity from they can actually record either from single |
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05:24 | or single channel activity or the whole current activity. The whole self current |
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05:31 | will be the collection of all of channels in the membrane and what they're |
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05:35 | is it is reflected in Vietnam. you're recording single channel activity, you |
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05:41 | recording a single channel activity that will the rules that we know with equilibrium |
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05:47 | , that's own individual batteries. In to that, we also mentioned in |
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05:55 | past that whenever you use electronics and is an a. one on the |
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06:01 | and you stimulate with the current. you inject current into the south and |
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06:06 | will say, why do I have care about injecting current into the cell |
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06:10 | action potential firing properties Because this is the brain operates. You will understand |
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06:15 | in the course that the activity the the numb brain handles activity, the |
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06:21 | the cells produce these different patterns of and later the structure in which it |
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06:27 | imposed in systems like visual system. that leads to varied levels of computation |
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06:36 | is communicated between networks as different frequency as waves or brain waves. So |
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06:44 | is really important. And this is of the basis behind how different membranes |
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06:50 | different channels can produce different responses. ? So this is the electronics. |
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06:57 | you were to inject current into the of the electrode, electrophysiology, readouts |
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07:03 | potentials and plasma numb brain read us you to understand the properties of the |
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07:10 | experimentally record them, manipulate them and predict of what might be happening in |
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07:18 | conditions, not just physiological conditions or of physiological conditions versus normal. |
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07:27 | the response of the cell is an . two and for all of the |
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07:32 | stimulus that is immediate, like a in the electronics on the cell doesn't |
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07:39 | with immediate maximal change in voltage. it takes a few milliseconds to change |
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07:48 | voltage because you have to open up channel. So there's a resistance that's |
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07:54 | the fluxus of currents to be immediately the plasma membrane. The second thing |
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08:00 | the South has capacitive properties. So is the symbol for capacitance. Plasma |
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08:17 | of neurons are very good capacities. future is a very good capacitor is |
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08:22 | it has large surface area because if has a large surface area it can |
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08:27 | a lot of charge. The two of the capacitor, the positive and |
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08:32 | negative plate of the capacitor should be close to each other. You have |
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08:38 | here by possible lipid bi layer of and negative charge and that this discharge |
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08:45 | charge of storage and then discharge and between the plates of positive and negative |
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08:51 | on the two plates of the capacitor fast and neurons are very good because |
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08:58 | of course is because of the resistance the capacitance. It takes time to |
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09:04 | the maximum amount of change in voltage you inject a certain amount of |
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09:09 | And also after you stop this it will take time for it to |
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09:14 | and re polarize also take a few , but it's a few milliseconds. |
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09:19 | it's fast, lots of surface Yes, because you have all of |
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09:24 | processes. Not just so much as not just around south. You have |
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09:27 | of these processes and riddick spines that the surface area and therefore the ability |
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09:32 | store charged across plasma number. Very . Very highly charged capacitors. |
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09:41 | And so you can also see that the injected amount of current these channels |
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09:47 | react with a certain amount of change the voltage. And so this current |
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09:54 | here outward current or inward current which simulating through recording electrode or through an |
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10:03 | physiological electrode. Those changes in current causes certain changes in voltage. I |
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10:12 | for current. V for voltage. shows a Vm numbering potential in millet |
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10:20 | and current in nano amperes by definition inward currents is negative values of of |
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10:31 | and bears. Mhm. And the current by definition has positive values of |
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10:40 | . In this case, nano amperes the value for the current. But |
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10:45 | shows for example that for certain channels relationship between current and voltage or ivy |
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10:55 | or I. V. Plot is . So in this case it's showing |
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11:00 | if you changed outward current. Well say half a banana and pear. |
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11:09 | get the change in membrane potential of mil levels. One nanogram pair, |
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11:16 | get a change in membrane potential in million bowls. And then if you |
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11:22 | the inward current for all. For of a nanogram peer you get five |
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11:26 | of old. Another direction. For you get 10 mil level change in |
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11:30 | other direction. And this is a or atomic as an arms law. |
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11:36 | . I'd plot in reality the cells contain channels that will have linear plots |
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11:47 | the channels that will have complex plots don't look linear. A lot of |
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11:53 | activity. A lot of flux of through the channels is nonlinear dynamics. |
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12:02 | again this is just speaks to how surface area of the historical neuron plays |
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12:09 | the resistance and capacitance of the So if you have Small sparkle neuron |
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12:18 | square is the radius of hysterical You have a small neuron then you |
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12:25 | high resistance of that neuron. The resistance is referred to are in which |
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12:34 | on the membrane resistance divided by four a squared small cells. High |
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12:47 | Okay small uh hose for the water high resistance. You're gonna take your |
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12:58 | pressure to put things through that. that water through the hose for |
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13:06 | The input capacitance is the opposite input is the member in capacity and stands |
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13:15 | pi squared which is the larger the , the larger the surface area, |
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13:21 | larger the capacity, it's just the because you're in verse. Well not |
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13:28 | but they depend inversely on the radius the neuron. So this is numb |
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13:37 | equivalent circuits. And I would say maybe you should draw these. These |
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13:42 | gonna be exam questions for recognizing the and also you may encounter them and |
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13:51 | the subject matter that you may study you'll remember that wow you know what |
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13:59 | neurons can actually be represented as So now this is a circuit for |
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14:06 | potassium and chloride with their own distinct . Extra cellular side the side of |
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14:11 | mix side below you're seeing that you passive, you have chloride that is |
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14:19 | , there's no arrows so there's no of current going on here. But |
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14:23 | and potassium conductance is our active. that would be something representing of the |
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14:28 | potential. You also have active A. K pump and you can |
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14:33 | that this will always work against the gradient actively actively in this case it's |
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14:41 | transport. No not it's active transport a teepee of potassium into the south |
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14:48 | sodium out of the south against the gradient. And finally you have in |
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14:52 | circuit the positive and negatively charged capacitance which is overall capacities of the plasma |
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15:02 | . So you can use these circuits and plug them in and you can |
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15:09 | conductance, is to do these circuits you can make them really complex and |
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15:13 | can scale them up and you can introducing all of the different I. |
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15:22 | . Components, linear, nonlinear and start modeling essentially the selectivity and that |
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15:32 | be done computational and ultimately we're trying build machines like computers that will be |
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15:41 | good computing and processing things as we . They're already much better at computing |
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15:50 | processing things much faster fashion. But kind of walk on their own. |
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15:59 | no plasticity but artificial intelligence people will the opposite uh that there is learning |
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16:12 | , There is plasticity you can observe some model some behavior and it will |
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16:20 | from that behavior and it will self itself. And then you would want |
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16:26 | copy some of the rules that you in the south with ivy plots with |
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16:30 | synaptic transmission to make the computers and as close as possible to, you |
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16:40 | , to humans. So who's buying verse stock yet? It's tanking joking |
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16:51 | course. But you know, that's a lot of, a lot of |
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16:55 | are concerned. It's a lot of that can be modeled and calculated by |
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17:03 | circuits. Comes from understanding some of basic physiology of the plasma membrane and |
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17:09 | of the neuron, no individual neuronal then neuronal circuit conscience. Because these |
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17:15 | very complicated circuits that that are in machines that we're building, recreating a |
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17:21 | with Now during the action potential. that when we calculated the resting membrane |
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17:32 | , we said that the most dominant address it has leaked channel. So |
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17:40 | has the highest permeability. And this permeability for potassium sodium and chloride and |
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17:48 | resting membrane potential and during the action during the action potential, especially during |
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17:56 | rising phase of the action potential. conductance and the premier ability is 20 |
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18:02 | higher for sodium than it is to . But as you can see, |
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18:08 | is not flexing much either addressing member potential or during the action potential. |
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18:14 | when we talk about the dynamics of action potential here during the rising overshoot |
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18:21 | phase were mostly talking about um we're talking about these kind of ions like |
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18:36 | and potassium. Obviously sodium influx ng the rising phase and potassium e flux |
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18:42 | during the following phase. Let's go to this diagram here, remind ourselves |
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18:52 | that we've learned in the last lecture a half or two E que e |
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19:00 | and a calcium Standford equilibrium potentials for ions. We calculate using nurse equation |
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19:09 | . M. Stands for the overall of potential. So this blue trace |
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19:14 | the action potential is the overall number potential. Remember which is a combination |
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19:19 | sodium and potassium flux is happening at same time. Okay, so DM |
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19:28 | calculated using Goldman operation. The resting in potential is about minus 65. |
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19:35 | if the cell receives excitatory glutamate it d polarizes, it receives inhibitory |
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19:42 | Inputs that hyper polarizes. If it the threshold value for the action potential |
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19:47 | -45 it generates an all or non it goes through this deep polarization, |
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19:55 | deep polarization, sodium deep polarization sodium positive feedback loop And sodium because it's |
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20:03 | permeable now, more permeable to potassium is trying to drive the overall number |
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20:09 | potential value to the equilibrium potential for . It fails to reach the equilibrium |
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20:16 | for sodium for a couple of Because the more it d polarizes at |
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20:21 | beginning here, this is the green that you can say is a driving |
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20:26 | , which is the difference between equilibrium for sodium here and the number in |
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20:33 | . And when the membrane is hyper , this green line, it's very |
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20:39 | , there's a very large driving force sodium. But when the number of |
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20:45 | is here at the peak of the potential, the difference between the member |
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20:49 | potential and the equilibrium potential for sodium minute. However, now at this |
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20:58 | the difference between the member and potential blue and the reversal or equilibrium potential |
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21:04 | potassium is huge. So that's one why sodium fails to drive the number |
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21:11 | potential to equilibrium value. The second is the actual kinetics and dynamics of |
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21:17 | channels. So, we'll start looking the sodium channel and how it opens |
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21:21 | closes and so it happens that sodium open very quickly, utilization more sodium |
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21:27 | they also closed very quickly. And in order for them to reopen |
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21:34 | , the membrane potential has to re or hyper polarized back to some resting |
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21:41 | potential level Once during the falling phase e flux takes over again as the |
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21:49 | dominant formidable ion. It tries to the number of potential value to equilibrium |
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21:56 | for catastrophe. But they're they're driving for potassium is minute. Of course |
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22:05 | are leaks channels. So the membrane still most permeable to potassium at these |
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22:11 | . But you also have N. . K. Active pumps kick in |
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22:16 | A. T. P. Rebuilding potential by transporting sodium and potassium against |
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22:22 | concentration here against. So if you in this phase here, which is |
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22:29 | absolute refractory phase of the action that means you cannot produce another action |
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22:35 | . If you were to stimulate the and give it the maximum stimulus you |
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22:39 | and help, oh, there's going be even more deep polarization I can |
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22:42 | Instead of 80,140 and another action It's not going to happen because you |
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22:49 | exhaust the sodium channels and they're all now. So even if you |
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22:53 | the south sodium channels are closed and not going to open again during the |
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22:59 | polarization. Then when it crosses this value with the action potential, it |
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23:06 | enters into the relative refractory period. if you were to produce a strong |
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23:10 | of shock onto the cell during the refractory period, it will be able |
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23:15 | produce in that action potential. And on the dynamics and properties of the |
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23:20 | and the channels that are in the membrane. The frequency of these action |
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23:25 | can be slow, it could be and that's why you get different firing |
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23:31 | of these different subtypes of cells that were discussing earlier in the course, |
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23:36 | this is driving force again. And action potential within the concept of the |
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23:44 | force. Oh and so again. is the depiction of what is happening |
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24:09 | the conductance is where you have potassium , G. K. Dominating and |
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24:15 | stronger than sodium at rest. You the sodium conductance that takes over. |
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24:22 | that mean that there's no at all conductance in in this area here in |
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24:29 | rising phase. Is it zero for conductance? No, It's just that |
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24:37 | is so so much greater. It's zero. You saw that there's still |
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24:41 | for both ions. It's not zero it's much much greater for sodium number |
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24:47 | potential here, it's showing this deep . But we now that we have |
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24:52 | sodium coming in and there's some potassium to come out and the more default |
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24:59 | , the bigger is the drive for the driving force falling phase, you |
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25:05 | see now potassium is all dominating and . You have leak channels that are |
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25:14 | here. That so now we are off these two major concepts for the |
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25:22 | remembering equivalent circuits. Okay and the force and I think that I hope |
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25:31 | this makes sense. And if you these action potentials a little bit in |
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25:38 | different light when you actually start understanding from the driving force perspective, and |
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25:45 | just from nerds equation or your involvement . Okay, voltage clamp. And |
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25:55 | do you have to start to understand technique? And it's because as I |
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26:02 | that this black line is the membrane , it's VM. And within that |
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26:09 | shows that it doesn't show that K. Is equal zero. So |
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26:15 | this box, within this rising phase the action potential, what is really |
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26:19 | on is mostly sodium is going in is dominated by a lot but there's |
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26:24 | little bit of potassium leaving at the time. But we can't see it |
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26:31 | we just look at the member of country. So we have to isolate |
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26:38 | sodium individual potassium cards. If we those currents we can then determine the |
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26:47 | of flux is of islands through these these channels and through these individual currents |
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26:52 | how they may be affected and how transpired during different phases of the action |
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26:59 | . So, we employ the technique called the voltage clamp technique. And |
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27:05 | the older days, voltage clamp technique performed by using two electrodes, as |
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27:11 | shown here, the green electrode which the recording electrode and the orange electorate |
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27:17 | is a stimulating electrode in modern day electrophysiology. The sampling rates or the |
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27:25 | of which the electorate's can inject. also a sample a record current is |
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27:31 | fast that you perform these experiments with electorate. However, looking at it |
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27:38 | way the technique right? Looking at this way you have the reference electrode |
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27:56 | you have this axon here this is giant squid axon squid axon. The |
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28:06 | is not like giant. It doesn't ships it's about this size but the |
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28:14 | on It's giant in that spirit about . So when they're older days and |
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28:21 | and will actually look at that's that's cool. What were you able to |
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28:27 | ? You were able to put this on on the dish and would stay |
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28:32 | separated from from the selma but stay for a couple of hours. So |
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28:37 | had a living nerve sitting in the . Now you can do a lot |
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28:40 | things. You can manipulate the extra environment, right? Which would be |
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28:46 | it's being bathed in in the Uh huh. You can inject |
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28:51 | You can report current. You can a lot of things with it. |
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28:55 | you have a reference electorate because if recall the outside of the cell as |
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29:00 | as the inside of the cellar. neutral. The charge and accumulation and |
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29:07 | is across plasma member. So the electorate will be zero saying the outside |
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29:12 | zero. This is the recording electorate you have one internal electorate that managers |
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29:19 | And it's connected to the voltage clamp . It's measuring the VM. And |
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29:25 | connected to a voltage clamp amplifier which member and potential to the desired command |
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29:31 | . And it says here command I said what is command voltage In |
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29:35 | case? Command voltage. It's what decided to be. Find the saving |
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29:43 | 40 zero plus 40. You command voltage. You are you are wanting |
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30:04 | voltage at a given member into potential because if you just do cellular recordings |
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30:14 | you put an electorate inside the south you record activity. Okay you're recording |
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30:19 | activity. It will look like this will produce some action potential protests with |
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30:24 | recording membrane voltage. The E. Ir. You can record voltage or |
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30:39 | can record current from current. You calculate voltage and so on. You |
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30:45 | be on either part of this It's a voltage clamp on the command |
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30:50 | . Instead of just recording this Instead of just recording this video, |
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30:57 | actually tells the membrane. I'm not gonna sit here and listen to you |
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31:02 | a radio, you're gonna play me song and I'm gonna listen to |
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31:05 | I can inject the current and still how you respond. I'm actually going |
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31:10 | tune that radio and dial it into different frequency which is your number. |
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31:17 | I'm frequency. But this is just analogy. It's a different station -80 |
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31:22 | his 40s at different stations. zero 40 is a different station. Different |
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31:28 | range for the membrane potential. So set this command voltage and you have |
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31:33 | voltage clamp amplifier when the member in Is different from the command voltage. |
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31:40 | let's say you said the command voltage -80. And all of a sudden |
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31:46 | see a deflection 2 -85. What clamp amplifier is going to do? |
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31:59 | going to inject current into an axon the 2nd orange electrode. This is |
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32:05 | feedback arrangement that will cause member in to become the same as command |
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32:11 | So every time you're going to have shift from I know Sadie's gonna clamp |
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32:15 | back 2 -80 and I have a shift to -75. I just don't |
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32:21 | the best and everything that you record that is different from your plan |
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32:27 | Are the currents that are flexing that are now picking up with this feedback |
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32:35 | . The current flowing back into the and thus across its membrane can be |
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32:40 | here. And so you would be these currents that are flowing in and |
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32:45 | currents that will be equal and opposite the ionic currents that are flexing through |
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32:50 | plasma membrane. So now you have wonderful feedback circuit. You want to |
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32:54 | at -80 and see what currency you at -80 and stimulate the cell or |
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33:01 | from it either way. But you clapped now different holding potentials. And |
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33:08 | you look during this deep polarization actually is shown is that you have concurrently |
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33:16 | inward sodium car. And you can that sodium current peaks very early and |
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33:23 | very fast. But at the same during the action potential, you also |
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33:30 | potassium current going outwardly and you can that there's a significant delay with potassium |
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33:40 | . So potassium current really starts engaging sodium currents starts reaching its maximum. |
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33:46 | when the potassium current goes almost through exponential conductance says, okay and now |
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33:56 | you're starting to understand is that the potential represents an overlap of currents vo |
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34:11 | an action potential. And when you currents you will see that there is |
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34:20 | the word sodium current with our potassium . Yeah. And this is happening |
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34:33 | the same time. So if you're recording voltage, you cannot pick up |
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34:39 | currents. You're recording a some off the currents of ionic currents. But |
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34:45 | fact of the matter is the two happening at the same time. And |
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34:49 | when the voltage clamp was invented, and Huxley used this voltage clamp technique |
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34:57 | study the inward and the outward And so you can see that They |
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35:03 | the voltage clamp and they held the , they clamped it at -26. |
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35:10 | as they climbed it in -26 they this short transient inward current. This |
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35:17 | deflection followed by somewhat weak, late persistent, prolonged outward current. He |
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35:29 | the potential at zero. And they that inward current got stronger, but |
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35:33 | did the outward current positive 26. of a sudden they saw a decrease |
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35:40 | inward current, but they saw an in outward That's positive 52, inward |
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35:48 | disappeared. And this is why I you that reversal potential values Are different |
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35:54 | different textbooks. Can be positive 55 56, positive 62 in this experiment |
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36:01 | the Hodgkin and Huxley. The inward , which is the equilibrium potential value |
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36:07 | the inward conductance. It reversed. actually disappeared at positive 52 million |
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36:15 | There's no net inward flocks of sodium it's reached its equilibrium potential value, |
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36:21 | you have huge tremendous drive for And then if you surpass if you |
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36:29 | to even more positive clamping or holding in the membrane beyond the equilibrium potential |
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36:38 | for sodium. You see this little here, maybe not, mm |
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36:52 | You see this little blip here on right, this is sodium currents. |
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36:59 | it's reversed. It's flowing in the direction because you surpassed. They're delivering |
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37:06 | value and that's what equilibrium potential values also known as reversal potential values. |
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37:12 | currents will literally reverse in the opposite . Okay, The number is electro |
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37:19 | force is dependent On not just the gradient with the membrane potential. And |
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37:26 | course these d polarized potentials, you have a tremendous outward driving force. |
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37:33 | , in 1963 Hodgkin and Huxley received prize in physiology and medicine for their |
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37:40 | on the action potential. The experimental , but also the modeling work. |
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37:45 | there's a model, huh, chicken hustling model for the action potentials with |
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37:50 | . And that is I don't know it's part of it. I think |
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37:57 | publicly available, but this is a that allows you to play with different |
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38:01 | , is to recreate action potential. now you can see from that model |
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38:05 | from the number in equivalent circuits. you can build more complex models ah |
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38:11 | recreating different patterns. Not just one potential. But imagine if you had |
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38:17 | model to recreate this in the circuit then you had something like this that |
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38:21 | have to be creative. It's a more complex and it will take a |
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38:26 | more computation and preparation and and maybe a circuit of interconnected self, not |
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38:33 | one neuron doing it on its So before we go into the sodium |
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38:45 | structure which will be about the last to talk about today. Did I |
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38:51 | you the video of the of the the squid recording? No, I |
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38:57 | think I did. It's a really video here. That's why you sometimes |
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39:01 | to browse over into the support and lecture material where you find migrating neuronal |
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39:09 | and micro glial cell dynamics, I'm stop the shared and re shared and |
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39:16 | sure that I share the sound also some way and there might be some |
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39:27 | strange commercial. No, thanks very . The careful airpods, body plans |
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39:36 | habits are so very different from those humans that there might almost be aliens |
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39:41 | another world. So perhaps it's not that it took a long time for |
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39:47 | to discover that there are fundamental similarities the nervous systems of cephalopods and |
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39:57 | Yet it was the recognition of a difference in their nervous system, which |
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40:01 | scientists to undertake research that has led a growing understanding of the mechanisms controlling |
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40:07 | own nervous system. The breakthrough concerned nerves that control the contraction of the |
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40:13 | muscles used in jet propulsion. As archive film shows by simultaneously contracting it's |
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40:22 | muscles. Even a moderately sized squid inject a huge amount of water with |
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40:27 | force. In the mid 19 the british zoologist Professor James Young was |
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40:38 | in a study of the squid's Young observed an array of large tubular |
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40:45 | , each as much as a millimeter diameter, in the squid's mantle as |
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40:50 | structures were never filled with blood. could not have been blood vessels from |
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40:55 | similarity to surrounding nerve fibers. Young they must be single neurons. Giant |
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41:01 | , they're transmitted nerve impulses from the of nervous tissue called the cingulate ganglion |
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41:07 | the mantle muscles using electrodes. He the surrounding nerve fibers and found that |
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41:18 | could only produce large muscle contractions in mantle when the large tubular structures remained |
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41:29 | . So these were indeed giant Scientists quickly appreciated the significance of young's |
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41:40 | for here at last was an large and robust enough to investigate with |
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41:44 | techniques available at the time and one survived for several hours when isolated from |
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41:49 | nucleus, the intracellular contents of the axon could be removed and analyzed, |
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42:00 | to the that's exactly how you would the concentration of ions and talked about |
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42:06 | you would use for non situation concentration islands on the outside versus the inside |
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42:13 | outside is, you know, the spinal fluid and the inside of the |
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42:20 | . I mean the the outside is interstitial fluids around the cell and the |
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42:26 | is the side. Applause. And in the squid, the outside |
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42:32 | is the ocean, which is very high salinity. It's a lot |
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42:38 | salty here and our brain fluids. nonetheless, this is how you would |
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42:45 | . Different ions would literally squeeze it . Discovery that sodium ions were more |
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42:50 | outside the nerve cell and potassium ions concentrated inside by refilling the empty axons |
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42:59 | solutions of precisely known chemical composition. were able to unravel the mechanisms of |
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43:05 | transport across the membrane. The giant are large enough and robust enough for |
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43:16 | electrodes to be inserted through the cell and into the axa plasm. In |
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43:27 | early techniques. A fine glass tube first inserted into the axon and secured |
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43:32 | thread. That's it. Then the was used to introduce a fine wire |
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43:58 | from which the voltage between the inside the outside could be measured. But |
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44:04 | formation of the Nerve Impulse was far rapid for detailed study with any of |
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44:09 | electrical measuring devices of the late It wasn't until the 1950s following the |
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44:16 | improvement of electronic equipment such as the ray Oscilloscope, that major progress was |
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44:25 | . Scientists found that the nerve impulse transmitted as a characteristic wave of electrical |
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44:32 | and that this all or nothing action was generated mainly by transient movements of |
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44:37 | and potassium ions across the nerve Research on the squid giant axon unravel |
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44:46 | mechanisms of the formation and propagation of nerve action potentials. This understanding led |
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44:53 | to the development of drugs that block potential formation and so act as local |
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44:59 | now used routinely as painkillers in dentistry minor surgery. There's also your answer |
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45:07 | you want to know these things, and the changes because a lot of |
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45:15 | channels that we're talking about are also for therapies, various therapies for different |
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45:25 | substances. So we are still on action potential. And we are now |
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45:33 | to understand the second reason that I you earlier why sodium doesn't reach its |
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45:38 | delivering potential value. And that's because the structure and how that structure functions |
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45:46 | the sodium channels. So sodium channels four sub units 1234. Each one |
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45:54 | six trans membrane segments as one through six as for trans membrane segments is |
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46:04 | charged as high polarity. And it dubbed as a voltage sensor. This |
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46:10 | the voltage sensor that will influence the and the closing of this channel. |
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46:15 | within the structure of the three dimensional of the channel itself. Within this |
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46:23 | acid sequences that are positively charged between five and the six. We have |
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46:29 | selectivity for the roderick mackinnon when he potassium channels showed that selectivity four and |
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46:38 | is between five and 6. So subunit will contribute this poor loop and |
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46:45 | poor loop coming together will be selecting the islands to pass through the |
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46:51 | In this case for sodium channel also out that sodium channels both educated sodium |
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47:01 | , they have two gates. Let's . I cannot feel it draw from |
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47:17 | , but I can explain it in following way, resting membrane potential. |
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47:25 | have this voltage sensor positively charged pulpits that is sitting on near side of |
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47:32 | mix side of the membrane that is charged. So this positively charged amino |
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47:39 | residues within sodium channel are attracted to negatively charged inside of the plasma |
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47:47 | keeping the gates closed. So the polarized potentials that hyper polarized voltage. |
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47:54 | sodium channels are closed. What is to open the gates of the sodium |
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48:00 | ? It's the voltage that's going to the gates is nothing binding sodium minds |
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48:05 | bind two channels to go through What is going to happen when there |
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48:10 | a deep polarization from -65 to about 40 Myla balls is you have accumulation |
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48:20 | positive charge on the inside of the membrane and the more positive the plasma |
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48:26 | on the inside becomes. This sensor getting repelled by positive charge entering into |
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48:34 | cellar. And by getting repelled, literally slides up through this three dimensional |
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48:42 | channel structure changes the confirmation of the And now causes the opening of the |
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48:50 | gates. So you will learn that are actually during the deep polarization here |
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49:00 | -60 to -40. If you were look at the sodium channel dynamics, |
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49:07 | will see that as soon as deep engages year, you have multiple sodium |
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49:13 | , you're represented by each trace. you have three channels And you have |
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49:19 | states of being for these channels noted , 2, 3, 4. |
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49:24 | , when you de polarize plasma numb and you record sodium channels because you |
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49:29 | voltage clamp and you can isolate individual currents. You see that these channels |
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49:36 | very fast, but they also close fast. So it's fast opening. |
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49:45 | it's fast inactivation of this channel. the channel is closed. It doesn't |
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49:52 | . You still have this persistent deep . The sodium channels they open transient |
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50:00 | and they closed fast opening and their . And that's why it doesn't reach |
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50:05 | equilibrium potential during the peak of the potential for for sodium here. |
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50:11 | because the channel is closed and the force decreases. So these channels close |
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50:18 | they actually have two gates. The two arms close like this are called |
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50:25 | gates. And this ball and chain out here, it's called inactivation |
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50:32 | So when the channel opens because of voltage because the voltage sensor slides open |
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50:38 | to deep polarization you receive positive D polarized. Now you're starting to |
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50:43 | the channels because the voltage sensor sliding sodium starts coming in. But as |
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50:49 | as sodium Russia's end through the this guy that ball on the swing |
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50:57 | , it doesn't wait and it So the sliding of that voltage sensor |
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51:04 | the channel. But the change in confirmation of that opening gate also causes |
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51:10 | conformational change in the swinging and the of the inactivation gate At that point |
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51:16 | number three the channel is inactivated. in order for the channel to open |
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51:22 | because it's enacted now it's plugged It's not conducting anything in order for |
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51:28 | channel to open again, you actually to deon activate it. Which means |
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51:33 | have to remove Inactivation Gates from the four Deion activated. Okay. and |
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51:43 | do that by releasing this member and from D polarized values back and to |
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51:49 | polarized values. Now when you have polarize the plasma membrane you now have |
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51:57 | voltage sensor that starts sliding back down the plasma membrane has negative charges starts |
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52:05 | back down as a sliding back It pushes out the inactivation gate and |
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52:11 | causes the activation. Get too close the number four position it's closed and |
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52:17 | to open again. You cannot go . It will not happen. You |
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52:24 | to deactivate and hyper polarize. That's during the absolute refractory period you cannot |
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52:29 | on that action potential. I have hyper polarized the plasma number in order |
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52:35 | produce another action potential which is during relative refractory period of the actual |
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52:42 | Great stuff. So when we come we're gonna talk about the patch clamp |
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52:48 | techniques. We already introduced a little about some of the recording techniques and |
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52:54 | actually watch some Simpsons. Um The the Simpsons as they explained some neuroscience |
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53:05 | us. We're gonna talk about brilliant Toshio Narahashi who studied the toxins and |
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53:15 | the definitive functions of vault educated sodium . So we'll talk a little bit |
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53:22 | pharmacology will basically finish talking about the potential. This is gonna be our |
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53:28 | lecture for the material and we will about the back propagating action potential. |
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53:35 | if you go in your lecture supporting , this is the slide that we're |
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53:43 | to discuss next lecture and you can it that much greater resolution with full |
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53:50 | . Explain, I'm just pointing it for you that it's there for |
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53:54 | so that when we go over that , we can fall back or you |
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53:58 | open it up and see it a resolution. So we'll leave it here |
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54:05 | . Remember all of these really important we discussed and and also the sodium |
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54:15 | , I would say the sodium channel and activation and activation would be probably |
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54:22 | The 4th and 5th most important concept we've discussed today. Thank you for |
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54:27 | here. Let's see. I'm gonna the recording here, mm |
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