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00:02 | This is lecture nine of cellular Uh This is the first black |
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00:08 | Midterm. So this is sort of a second section of the course if |
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00:11 | starting. And although the syllabus notes we are going to talk about |
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00:17 | functional imaging, we're going to cover plasticity ah synaptic plasticity and I will |
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00:23 | that and adjust the syllabus as we on through the material in the next |
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00:29 | of lectures. But from early on person that postulated that there is plasticity |
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00:38 | neuronal connections and neuronal circuits was Ramona . In fact drew these arrows between |
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00:47 | indicating how the signals would flow, the neurons would communicate with each |
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00:52 | And he also suggested that those connections the way neurons communicate our plastic that |
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00:59 | can change with time and they can with activity. And so this term |
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01:07 | activity dependent plasticity that the plasticity or communication between the circuits and the adjustments |
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01:16 | that communication between individual neurons and neuronal whether strengthening it but weakening, it |
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01:25 | depends on activity, really depends on too. Uh plasticity is the most |
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01:37 | during their early brain development. We fact are born with a lot more |
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01:43 | in the brain that we end up in the adult brains, mature adult |
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01:49 | and in fact a lot of things the brain. During early developments, |
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01:55 | lot of circuits are interconnected and there a lot less specificity in these circuits |
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02:04 | connectivity between brain regions and so with with strengthening of certain synopsis and weakening |
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02:16 | away, driving away a lot of connections. You have sculpting of anatomy |
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02:26 | more precise wired circuits that are more like. And with sculpting of that |
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02:33 | you also have sculpting of the And as you sculpt the anatomy structure |
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02:41 | function. You also sculpt the the circuit, communication and even the |
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02:51 | with Mississippi. So plasticity is really for the early development and during early |
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03:02 | there is this period that is called period of development and during this critical |
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03:24 | of development, during early developmental stages are certain chemical trophic factors that allow |
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03:38 | high levels of plasticity to take place your brain matures, there is a |
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03:47 | expression of different molecules in the different trophic factors and during early development |
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03:55 | . A certain brain derived and other neurotrophic factors allow for these high levels |
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04:07 | elasticity to take place. So for and memory formation as we know, |
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04:16 | have to have normal experience normal exposure censor stimuli for a child, auditory |
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04:25 | Samata, sensors, stimuli in order that child and for that brain to |
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04:32 | normally. So these are experiences and are the most able to absorb and |
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04:40 | information also during that critical period of . If you think about early on |
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04:48 | is happening, you have the sorting the connections you have the sorting of |
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04:57 | connections. And then you have pruning the synopsis during this developmental stage that |
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05:12 | not going to be there because they not be as active or not as |
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05:18 | for their dog brains. So once have this process of pruning trophic |
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05:29 | sorting of the connections and that you liken in humans in the first few |
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05:36 | of life, when you're learning just to walk and to talk and to |
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05:43 | and things like that and then you the stage and language is a very |
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05:50 | example, you enter the stage, when you're learning a foreign language where |
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05:56 | most susceptible to picking up foreign language about three years of age. So |
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06:03 | earlier you start, the more likely will be fluent, bilingual, fluent |
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06:10 | you're talking about a foreign language. so if you look at the language |
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06:19 | and this is plasticity isn't you have levels of plasticity from this three years |
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06:29 | age and then the levels of plasticity down, it doesn't mean that you |
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06:36 | learn another language At the age of . But what's very likely Is if |
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06:43 | start learning a foreign language in you will show a stronger accent, |
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06:49 | motor commands and the plasticity and moving tongue in your mouth are not going |
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06:55 | be a skill, it's gonna take longer to learn the language. So |
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07:00 | can you can you're going to have spend a longer time and practice more |
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07:05 | order to pick up that line. when you think about plasticity is an |
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07:13 | plasticity and you think about critical period development, uh you have to think |
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07:20 | it's the right confluence of chemical environment allows for these synapses to undergo these |
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07:30 | based development, learning memory. And second, the reason why this is |
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07:39 | important is that it relates to the injury and loss of function equally. |
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07:46 | if you had a brain injury during period in early ages, you would |
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07:56 | a much better recovery of function or even full recovery of function. The |
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08:04 | the accident happens, the earlier the brain injury happens, the earlier for |
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08:09 | , if you're having a brain the earlier that surgical resection of the |
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08:16 | tissue happens, the greater chance there for recovery of function that's because the |
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08:24 | can reorganize and can form connections where has now lost, parts of the |
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08:32 | are lost or has damaged circuits that communicate. So if the child has |
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08:41 | surgery at this age, it's one . But if you have a brain |
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08:45 | in adults, there's inevitably a lot serious loss of function and less |
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08:53 | And that is because you have passed sweet time window where the brain is |
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09:01 | plastic and it takes longer and harder not at all, but the brain |
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09:07 | and for the new synopsis to but it is still possible. So |
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09:13 | not that in adults, there's no plasticity, it is just reduced and |
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09:18 | environment has changed too. So when talk about plasticity, we talked about |
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09:26 | ation strengthening of the synopsis and depression depression at the synapse activity gets depressed |
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09:34 | can lead to pruning or clipping essentially rid of the synapses. Let's say |
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09:41 | was no great expanse that are non . This is a normal synapse and |
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09:48 | have calcium levels here and sodium levels you have synaptic cleft and you have |
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09:57 | neural transmission. The action potential be pre synaptic terminal releases neurotransmitter. You |
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10:05 | influx of sodium and potassium sodium and . You flex of potassium. So |
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10:12 | talking about excitatory glutamate, ergic neural and then if you do something and |
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10:20 | is that something that causes synaptic What is it that causes the potentially |
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10:28 | ? I'll see you calcium exactly from physiological perspective. But when you're learning |
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10:34 | , what do you have to do order to learn it while you have |
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10:37 | repeat the same activity? You have study it over and over. Sometimes |
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10:41 | have to look up the terms you to have your friend test you through |
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10:45 | terms and equations and then you you because the synapses that are active, |
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10:52 | become potentially waited on physiological level. would see greater influx of sodium more |
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10:58 | polarization, greater influx of calcium which greater influence on the post synaptic activity |
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11:05 | they didn't do it experience, remember is also a secondary messenger. Right |
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11:10 | you look at this and you see now I'm seeing something else. I |
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11:13 | more receptor channels in the synapses. that's when you would recruit. It's |
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11:21 | way to strengthen that synapse or potentially . It's not just open more channels |
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11:27 | actually recruit more channels into that recruit them from extra synaptic spaces through |
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11:34 | diffusion through plasma membrane and recruit them receptor insertion receptor channels insertions from the |
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11:45 | of plaza into the plasma membranes. in depression you would see the |
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11:56 | you would see les de polarization. would see less calcium flux. You |
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12:04 | potentially see less of the excited to channels and serve it in some instances |
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12:11 | more inhibitory receptor channels inserted to dampen activity in that setup receptors impression. |
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12:29 | it's not just automatic prudent. Also . Right? You can depress the |
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12:37 | and we'll talk about it just like can strengthen the potential synopsis for a |
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12:41 | time. Which would be a short potentially ation and would be equivalent short |
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12:48 | memory. Something you learn quickly and forget you don't need to carry that |
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12:54 | long term and then there are long changes. So we'll talk about that |
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13:00 | a second. Um Hang on to question is a very good question. |
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13:07 | term changes would be something like a term memory information that you carry for |
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13:11 | long time. And there are several for this plasticity to occur. We |
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13:18 | are touching on some of these We talked about an M. |
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13:21 | A. Receptor. Very important because a coincidence detector. We're talking about |
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13:27 | influx because calcium is an intracellular We also mentioned side of skeletal |
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13:35 | So there would be underneath the There would be a rearrangement of cider |
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13:39 | elements to uh and this plasticity that talking about can happen on both excited |
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13:46 | an inhibitors analysis. So it's a bit more complicated. But in general |
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13:52 | you're depressing synapse it means it has activity. And if it gets depressed |
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13:58 | a very very very long time that's it gets pruned it gets general how |
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14:04 | that just depends on what it is you've learned what it is that you |
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14:13 | or where it is. Much easier forget. Uh Faces, names, |
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14:20 | , then functional things like piping like a bicycle like playing a sport you |
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14:28 | don't forget that you know. How I play tennis again? You know |
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14:31 | don't do that. So it's I know why but it's procedural and it |
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14:36 | motor skills. And maybe the coding different from just remembering the stories which |
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14:41 | semantic memory and hippocampus. If you is responsible for semantic memory formation and |
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14:49 | of semantic memory. Okay so wait I have to do is that you |
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14:57 | insert Gaba receptors in there. Or it only you can only recruit |
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15:03 | D. A. Mostly it's excited receptor insertion when we talk about it |
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15:09 | there's always exceptions to everything. And you cannot insert Gaba receptors you have |
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15:15 | cinnamon together receptors so you can recruit . There's there's ways the synapse will |
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15:20 | it most of the time when we about insertion is boosting the synapse through |
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15:26 | receptors and they seem to be most too from uh these receptor channels. |
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15:34 | you have those two strategies. And also has exceptions of being able to |
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15:40 | inserted as well. So we can that depression people is unimportant. |
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15:49 | No you can't assume that depression it an important depression is a part of |
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15:57 | of activity allowing you to remember certain better, wiping away things that you |
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16:03 | need And from emotional memory perspective depression you to move on because when you |
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16:12 | the synopsis that caused let's say a strong emotional response and maybe it was |
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16:18 | very negative emotional response. If your stored that information over time it would |
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16:25 | overwhelming. So depressing the synopsis and away the negative emotions is also a |
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16:33 | thing and in sculpting the activity and things. So if you think about |
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16:41 | ating is learning memorizing new things and can think of depression is forgetting to |
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16:48 | other things to be memorized or forgetting a protective mechanism? Very good |
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16:54 | So does that mean like people who to go post traumatic stress, Is |
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17:00 | into this depression or is it due or like damage? So don't confuse |
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17:08 | depression, which is a great question post traumatic stress disorder, which is |
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17:15 | , it has a syndrome of But you can also have clinical depression |
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17:20 | with the PTSD. Ah don't confuse with the physiological actions of potential rating |
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17:29 | of depressing the synopsis. But sometimes after a certain traumatic experience, they'll |
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17:36 | their blood ways. I guess that's I'm referring to. Like, |
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17:42 | And if they and if they don't have very difficult time psychologically. So |
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17:47 | they don't if they somehow cannot engage again, the chemical cast, if |
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17:54 | talking about that mediates this, it's just gaba and glutamate, it's all |
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18:03 | these other I mean there are it's serotonin norepinephrine and so on. |
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18:13 | it's it's quite complex in each That's what I'm wondering is if it's |
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18:21 | the brain is kind of forcing this depression like in terms of what we're |
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18:26 | about today or if there's been like generation from that trauma with both. |
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18:34 | , there's neural degeneration, but there's plasticity and there's a way to engage |
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18:40 | plasticity. But if there is also imbalance and you're missing some of these |
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18:46 | means that will contribute to plasticity and processes, then you can be in |
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18:51 | . And that's why when you talk depression with antidepressants, you will hear |
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18:55 | lot of the drugs are serotonin driven , PROzac actually the serotonin system, |
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19:02 | a common uh name for at that syndrome. So that tells you somehow |
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19:11 | is involved. Now if you have serotonin imbalance and you don't know that |
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19:16 | not being treated, you'd be just treated for gavel or glutamate somehow with |
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19:21 | kinds of the assassins or other then uh it's it's quite complex to |
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19:28 | it and if you don't have the elements you don't have the right |
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19:33 | So if you have a chemical imbalance strengthening you excited or inhibit third synopsis |
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19:38 | be affected. It may take longer to forget things. Years instead of |
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19:46 | or weeks. So. So the really important person in coining what we |
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19:56 | this modern day plasticity already. See this is probably gonna be two lectures |
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20:00 | plasticity is Donald Hebb. So Donald said when an axon of cell a |
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20:08 | and persistently takes part in firing that is when you repeatedly and persistently |
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20:17 | something, learn something, do Some growth process. Growth process something |
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20:24 | grown or metabolic change. Maybe more . Maybe some chemical is being synthesized |
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20:31 | place from one or both cells such the ace efficiency as one of the |
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20:37 | firing B is increased. So he essentially saying that there is so A |
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20:53 | the cell A. They're stopping to and it repeatedly and consistently sending the |
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21:02 | action potentials and releasing neurotransmitter onto the . You're saying that something happens in |
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21:14 | in the synapse here. Some process strengthens this input. Now this implies |
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21:24 | that if you had so see and L. C. Was not really |
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21:36 | . English widely active. Okay. implied here that the active synopsis would |
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21:49 | . And so the ones that fire choir together the ones the out of |
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22:16 | don't blink. Okay so fire Wire together there's activity that's firing |
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22:24 | Now that means also implies that Selby to be responsive to stimulus city. |
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22:32 | how is it responsive in house A. Going to know that Selby |
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22:36 | responded. So we'll go back and a little bit about the back propagating |
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22:40 | potential. And perhaps one of the important codes for plasticity despite them independent |
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22:49 | . So experimental support for heavy in after that. And neuroscience and neuropsychology |
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22:56 | psychology textbooks. It was called near in plasticity named after Donald have this |
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23:04 | psychologist. Experimental support for having plasticity stronger repeated activation of pre synaptic cell |
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23:12 | before spikes. And parse synaptic cell induces synaptic strengthening known as timing depends |
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23:18 | long term potentially ations and as the dependent plasticity will get the details of |
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23:24 | in a second. How did not propose a rule for the reverse spike |
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23:31 | order or for the back propagating So he didn't know the back propagating |
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23:36 | existed. But experiments indicated that many , repeated activation of pre synaptic cell |
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23:42 | immediately after post synaptic B leads the dependent long term depression all time independent |
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23:51 | term potential station. So you'll see that works together. These synaptic rules |
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23:56 | known as spike timing dependent plasticity. let's let's look a little bit of |
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24:03 | that means. So he claimed that , he basically explained what plasticity is |
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24:15 | we'll come back to spike time persistent in a second. So it's |
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24:19 | lot of times referred to as heavy plasticity. I think I took that |
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24:24 | a couple of pages on one of books and I believe I may have |
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24:29 | that that in your class lecture supporting , mm hmm. So when you |
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24:35 | about activation of one cell, the that we just looked at, that's |
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24:40 | simple. But in reality you have and those neurons have reciprocal connections. |
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24:49 | if you have a certain connectivity, have a circuit. You have a |
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24:54 | neuronal network. And if you look these connections, there are certain rules |
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24:59 | the connections for the excitatory south. then hit the third sauce. We |
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25:02 | about some of these rules feedback feed individual lateral inhibition. We haven't talked |
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25:09 | . There is a summation of excitation so you have an external stimulus and |
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25:15 | stimulus is not just going to activate A and that one cell A. |
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25:21 | going to activate Selby most likely that stimulus is actually going to activate some |
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25:29 | of assembly of neurons. So this an input and that input, let's |
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25:36 | it in very plain. This is hamper. It's a circle. That |
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25:44 | is somehow going to get encoded by network of sauce and this network of |
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25:52 | as some sort of connectivity rules. cells are reciprocally connected in both directions |
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26:00 | other sources of communicating in just one . So if you have certain communication |
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26:08 | and then this assembly of selves or circuit, if you may response simultaneously |
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26:16 | this external stimuli and activation of the assembly by a stimulus boom boom boom |
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26:23 | boom. And what he is saying that if you have this external stimulus |
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26:30 | you activate the sole assembly but there's to be some levels of reverberating |
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26:39 | It's continuous activating the circuit following the stimulus activation. So he's saying that |
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26:50 | going to be some reverberating sort of . There's going to be something like |
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26:55 | is already primed So heavy and modification the reciprocal connections between nerves that are |
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27:04 | in the same time. So some these connections that were reciprocal and we're |
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27:12 | active. I'm gonna get strengthened now has become very strong. The strengthened |
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27:22 | of the cell assembly contained the n of the stimulus. So what was |
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27:30 | ? It was not an engram was of self structure on that structure. |
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27:38 | imposed strong stimulus which is function And now the synopsis plasticity happened And |
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27:50 | reciprocal cells that were activated with the . Now they have strengthened and they |
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28:00 | created an engram. So this would an engram. This isn't any ground |
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28:15 | the stimulus here. Maybe if you a different stimulus and it doesn't mean |
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28:21 | a visual stimulus but you can imagine can think about it as a visual |
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28:26 | that doesn't have to be a visual . So maybe if you presented a |
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28:32 | stimulus like this at the end ground look different. Huh? So the |
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28:46 | assembly may be the same right? I just tricked him added new |
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28:53 | But the same cell assembly is the . But one stimulus input imposes this |
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29:00 | a circle and other stimulus square imposes engram that looks more like a square |
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29:07 | something. It's representative of the external . So now you have the strengthened |
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29:17 | . They have the engram. After partial activation of the assembly leads to |
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29:24 | activation of the entire representation of that . So if our circle caused this |
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29:35 | gram here to be encoded and these become very strong. Now you actually |
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29:47 | even need to present the whole full but rather a certain fraction of that |
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29:56 | . So a weakened stimulus but still that circle but it's not as pronounced |
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30:06 | as it was before before it was this and like that. This is |
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30:11 | . Now you're presenting some very light of that stimulus. But guess what |
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30:17 | getting. You're engaging that same end . But when you did when you |
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30:23 | the ritual stimulus so now you have in the circuit and now you can |
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30:29 | the snap. Works much easier. example is you were studying something for |
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30:34 | long time and then all it takes it's just a second to look it |
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30:38 | before you reactivated the n grams and can take the test, remember |
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30:45 | So to generate the engram you may to repeat the stimulus and you repeat |
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30:50 | just like activity between A. And . And B. So it strengthens |
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30:56 | the same circuits. The same structure encode different anagrams. Of course this |
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31:02 | be repeating, receiving different stimulus. this reverberating activity. But how we |
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31:11 | to as STP for short term plasticity in this case short term potentially |
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31:39 | How does it look like on a a synoptic level? So here's an |
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31:44 | potential one and it causes the release neurotransmitter and produces the PSP two produces |
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31:56 | times second. Dp sp Okay third PSP four for the DSP. So |
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32:07 | you repeat this activity repeats the firing the activity and you're recording from the |
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32:12 | is the cell A. And you're from Selby. Then the release of |
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32:20 | activation of the synapse should now strengthen response and gradually increase the response in |
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32:28 | sentence calcium levels go up receptors get potential created. So the same |
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32:35 | the same strength, the same action will now be causing a much stronger |
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32:41 | response. And also on the pre side there will be changes as |
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32:47 | So this is reverberating activity And the circuit. The growth process consolidates the |
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32:54 | growth processes the plasticity, the plastic of the connections and then and graham |
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33:01 | . If you think about it then you can recall if you activate those |
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33:05 | you just need a little trigger like said you just need a little trigger |
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33:09 | beginning of the equation, you can the rest of it. Whereas two |
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33:14 | ago you needed the whole equation in of you. So this is an |
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33:19 | recall. Hippocampus would be very very in recall. So hippocampus is very |
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33:26 | in encoding and formation of memories and . Where are these n grams that |
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33:32 | be storing different memories and encoding different . They're widely distributed throughout the |
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33:41 | And so it's very complex connectivity. we had a place where all of |
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33:45 | memories are stored that we can reach and stimulate and produce all your memories |
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33:52 | would be something else. But we have that. So the memories and |
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33:57 | n grams and cell assemblies that widely . And so if you're talking about |
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34:01 | grams for visual information there will be n grams in the visual cortex auditory |
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34:08 | . And then when you're talking about the census together, there will be |
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34:12 | grams that blend Information together visual auditory even the motor outputs. And we |
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34:19 | really understand what what shape or form 10 g are in. That's why |
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34:25 | need functional imaging both on the cellular whole grain levels. To really start |
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34:31 | that we have wide distribution among the assemblage. You have a lot of |
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34:39 | that would repeat. Quite often the will activates two nearby circuits. That |
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34:48 | to N grams that encode that It's a protective mechanism. So you |
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34:54 | recall. Maybe there's several ways you get to that Selby. If cell |
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35:00 | goes out, maybe you develop another could involve the same neurons involved in |
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35:11 | and perception. So sensations, perceptions things. And then when you think |
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35:20 | the thought processing or creation of new without external stimulus. When you're have |
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35:27 | eyes closed at night and you've just something in your head, what does |
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35:33 | come about? So there's some reverberating . There's some activity. There's some |
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35:38 | that are being engaged. There's some is there some some intrinsic the brain |
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35:48 | . There are these dynamic algorithms that intrinsic that now can generate new things |
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35:53 | we haven't learned. So when we about recording and performing spike timing dependent |
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36:04 | experiments, let's go back and revise we can do this whole self voltage |
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36:09 | recording experiments. And you can use clamp that you can use current clamps |
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36:20 | . This is a parameter style. an example of parameter style. You'd |
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36:27 | an infrared contrast microscopy to visualize So it's typically in the brain slice |
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36:34 | that if you're doing wholesale a patch recordings of significant dialysis, but you |
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36:40 | control number in potential really well. . And so this is the type |
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36:48 | the techniques that you would use originally record the back propagating action potential. |
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37:01 | is the principle of the back propagating potential. This is all leading us |
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37:12 | spike timing dependent position you have at axon initial segment here at the soma |
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37:24 | all of the stand rides a very location and the specialized location we're going |
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37:31 | produce forward propagating action potential and you're produce back propagating action potential and the |
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37:39 | propagating action potential is going to regenerated note of ranveer and then Dixon on |
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37:51 | . It's going to cost us neurotransmitter influx of calcium and deep polarization will |
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37:59 | the neurotransmitter release. This is forward actually attention. And it turns out |
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38:05 | the accident initial segment here Contains two of both educated sodium channels. One |
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38:11 | them is a low threshold, both sodium channel which is N. |
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38:16 | B 1.6 in the yellow zone. one is a high threshold Voltage gated |
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38:23 | channel which is n. a. . 1.2 and there's blue zone and |
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38:28 | you assume but the cell will be a lot of excitatory inputs into the |
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38:35 | of getting deep polarized. You also assume that a lot of the inhibitory |
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38:42 | just like in the hippocampal surface will targeting these excitatory cells. Let's say |
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38:47 | looking at the phenomenal cells. So have inhibitory emphasis here around the |
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38:53 | So in addition a lot of times have very tight control of the integrative |
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38:58 | of the selma and the integrative properties whether we're going to produce an action |
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39:04 | or not. That's what the selma especially the axon initial segment is going |
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39:09 | calculate. So you D polarized dumb you need a lot of deep polarization |
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39:16 | order for that deep polarization to reach axon initial segment. Because down rights |
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39:22 | some are not my eliminated and there's to be a significant leakage of current |
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39:26 | it's excited very current before it D acts on initial segment at the accident |
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39:33 | segment, the threshold for activation is lower. So you just need a |
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39:38 | bit of deep polarization there that's just way it is in order to activate |
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39:43 | voltage gated sodium channels. So if receiving distal excitatory inputs and those digital |
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39:49 | for infants happen to overcome the inhibition the south will be bombarded by excited |
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39:54 | inhibit your emphasis at the same If this green arrow in the form |
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39:58 | excitation and deep polarization overcomes the inhibition passes through into the axon initial |
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40:06 | it will actually bypass the m maybe zone because these are the channels that |
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40:13 | high threshold. That means that they high change in voltage in order to |
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40:19 | . So and maybe 1.2 channels I'm going to open Instead and maybe 1.6 |
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40:25 | are going to open And NAV 1.6 are going to produce the forward propagating |
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40:31 | potential. And that is going to the chemical neurotransmitter release of the senators |
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40:39 | these. And maybe 1.6 channels. low threshold voltage gated sodium channels. |
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40:44 | they don't need much of the deep of this green arrow. And they |
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40:50 | this explosion in the form of actual and propagates forward. While that explosion |
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40:57 | in addition to this already existing excited input in the form of the green |
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41:02 | . Now you have the summation Of excitation and the deep polarization that is |
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41:07 | in the membrane through an 81.6 And summation of the input and the excitation |
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41:14 | an 81.6. It's now enough of high enough of the voltage to open |
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41:19 | high threshold And maybe 1.2. And these high threshold channels open up to |
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41:26 | back propagating action potential, that back action potential is going to flux. |
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41:32 | positive current back into the soma and into the dendrites and then to |
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41:38 | So the function of the back propagating potential is very different. And the |
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41:43 | of the back propagating action potential primarily with spike timing dependent plasticity, plasticity |
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41:52 | the aca synopsis in general. So very different functions. But how would |
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41:58 | record that? So you would record we detected back propagating action potentials, |
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42:05 | me, but neuroscientists by doing dual patch clamp recordings on the same |
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42:12 | So you would patch clamp the selma you would patch clamp the dendrite. |
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42:18 | when an action potential was recorded at level of the selma there was a |
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42:23 | small blip representation of fat that got up in the done tracked. And |
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42:28 | what made scientists wonder, what is ? So, you did a dual |
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42:35 | from the dendrite and the selma. in the soma. Mhm. You |
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42:41 | this large action potential and in the right, your electrode picked up this |
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42:48 | back propagating action potential. And every you record a spike in the |
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42:54 | which is forward propagating spike. To the back propagating spike, every time |
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43:00 | a forward propagating spike there's back propagating . So, it makes scientists wonder |
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43:10 | is that? Why is it It's easy to say, we know |
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43:14 | the forward propagating spike? Is that to release the neurotransmitter. So why |
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43:19 | we have that back propagating spike. is an example of what these chases |
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43:25 | look like. So you have dendrite electrode here and you have blue electrode |
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43:36 | in the selma. And so you this very large deep polarization in the |
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43:44 | . And you see a fraction of deep polarization in the in the dem |
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43:49 | . Right? So now you can that this is the green is the |
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43:59 | action potential. And if you enlarge you can always see that there is |
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44:04 | little delay so that the dendritic action in the peak of the dendritic action |
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44:10 | is delayed to the somatic action Well in B. You have |
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44:20 | S. P. S. Involved synaptic stimulation followed by back propagating action |
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44:27 | . So what's happening here is that you vote E. P. |
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44:33 | P. S. With a synoptic ? This is a stimulating electron. |
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44:38 | let's say you're stimulating shopper collaterals. so in this green one you will |
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44:45 | up the PSP The synaptic potential Alright you will cause the deep polarization |
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44:54 | and you will have the ps ps ps are large enough from the |
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45:00 | The green traces the PSP's right? the level of the selma you will |
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45:07 | an action potential. U. P. S. P. S |
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45:10 | the level of the soma. This the PSP. Remember that? This |
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45:19 | excitatory personality potential DSP. It can to an action potential, right? |
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45:29 | you're recording from done right? When record from done right, you stimulate |
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45:33 | fibers, you record very robust e in green. You're not seeing a |
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45:40 | robust PSP in blue because your synapses adapter. Called downgrades. If you |
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45:49 | the synapses going into the selma, would see a very robust response and |
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45:55 | in blue. But they're coming And with this green electrode boom, |
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46:00 | pick up the PSP and then in blue electrode, the next thing you |
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46:05 | up, boom, it started an potential and then a millisecond or two |
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46:09 | . Boom. There's a back propagating that I've picked up. So one |
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46:15 | , this is not repeated stimulus that to the sedans is one stimulus boom |
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46:26 | . Glutamate release an optical done It means in the done dry, |
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46:30 | polarization in the selma it means deep that's strong enough reaches the threshold, |
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46:36 | generating forward propagating action potential. And dendrite. Now, except the back |
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46:42 | action in the country. So. you have on the on the on |
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46:50 | bottom here measurement of the conduction velocity back propagation by time differences between the |
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47:00 | of the somatic and dendritic action potentials various locations of the dendritic recording |
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47:08 | So it tells you the latency over . It's very fast, Right? |
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47:16 | get milliseconds within milliseconds, you can up the signal flowing within 100 micrometers |
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47:23 | space and 100 micrometers. Is this 10 micrometers in diameter but hundreds and |
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47:30 | axons especially can be very, very . So does everybody understand this is |
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47:36 | we discovered the back propagating action This is why you would have this |
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47:40 | and then drive it with the cap activity. Someone would produce the |
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47:45 | But that's spiked with backwash back propagate you will pick it up also at |
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47:49 | level of the dendrite. So then knew there's something going on here. |
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47:55 | then that whole principle of spike timing came into into light and became very |
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48:07 | . So here's another interesting experiment. have three electrodes in the selma in |
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48:15 | done right. And then another optical right? So this is layer one |
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48:21 | the neocortex. This is layers 3, 4 and layer five. |
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48:28 | you have an a also reporting from same Parameter sound with three independent 5 |
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48:40 | . Middle panel shows somatic black and propagating action potentials in red lower panel |
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48:50 | that the burst of three somatic action is to vote by combined somatic and |
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48:54 | dirty current injections supplied within a short window time courses of somatic and dirty |
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49:00 | injections are shown below voltage traces. there is a little delay and then |
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49:07 | summation and the frequency of the action can influence very much the back propagation |
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49:13 | that signal? Ah This is a good article that I have in your |
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49:25 | neuromodulation of spike timing dependent plasticity present future. So when we talk |
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49:32 | plasticity in general and when we talk the signaling spill of the neurotransmitter back |
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49:40 | action potential. We actually are talking cellular substrates. These are cellular substrates |
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49:48 | plasticity, cellular substrates of learning and , cellular model of behavioral learning and |
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49:56 | with rich computational properties. There's a precision for the spike farming and we |
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50:06 | a lot of very slow activity also don't understand how that works very |
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50:13 | And if you think about excitatory synopsis inhibitory synopsis minus, life is pretty |
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50:21 | , awesome minus. So when you the means when you introduce the serotonin |
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50:26 | norepinephrine societal Collins neuromodulation of these So what are some of the plasticity |
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50:35 | ? The first rule is the rate rule. Okay. And it's emerged |
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50:43 | the 1970s and it was actually done this really cool. See a one |
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50:54 | of the Hippocampus with the schaffer collaterals being stimulated that project onto the pyramidal |
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51:08 | . Okay. And this drama to cells are very densely populated and strike |
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51:18 | through on the dollar. And so the 70s scientists and stuck these large |
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51:26 | cellular electorates if we're picking up activity many cells in the area, not |
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51:32 | intracellular electorates. And they said okay let's see if we can strengthen the |
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51:39 | by stimulating this pathway the shop. collateral possible. Yeah. And they |
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51:48 | two types of the stimulations first. did short term short turns of stimulation |
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52:02 | looks something like this and lasted maybe milliseconds. And they repeat these trains |
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52:14 | stimulation. Mhm. Every 15 And they would record the post synaptic |
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52:27 | . And they would see the response increased in amplitude. And they call |
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52:35 | facilitation. Or potentially ation. It's to as facilitation because the previous |
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52:47 | P. S. P. Promotes larger and larger facilitates a larger |
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52:56 | So that was pretty cool. They this pattern here in certain frequency let's |
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53:03 | this was it 10 hertz. Can see this Increased growth and this is |
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53:14 | Hz is not the number that you have to remember. And then they |
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53:20 | the same experiment. But instead of 10 hertz stimulus and produce the same |
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53:34 | But 40 Hz stimulus and what they is something that looked like this where |
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53:45 | initial response by somatic response of the was facilitation or the strengthening of the |
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53:58 | . But very obviously as the strain on it was depression of the |
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54:06 | So this is depression of the signal the strain of activity. So that |
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54:20 | the scientists that this bursts of activity on frequency can produce these facilitate torrey |
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54:26 | depressing short term forms of plasticity that within the actual train of stimulation. |
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54:35 | then they would say let's introduce something faster like 100 hertz and they're |
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54:51 | We saw it was pretty much depression the initial E PSP We saw a |
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55:01 | . So these different frequencies of acts activation and this facilitation and distraction during |
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55:07 | short stimulus let's say the stimulus is um 50 milliseconds, 100 milliseconds. |
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55:20 | stimulus. You have the facilitation and have the depression. This is what |
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55:26 | think is the reverberating activity in that that happened. I was trying to |
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55:33 | with the reverberating activity that the engaged and why would there be a |
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55:39 | There's potentially increases in calcium and calcium be promoting stronger post synaptic response. |
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55:49 | at this frequency you can recruit recruit but guess what? You can also |
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55:59 | receptors from the synopsis and by removing from the synopsis you can depress synopsis |
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56:08 | so what happens here? You have you potentially have a lot of influx |
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56:14 | calcium and maybe on that first burst exhausted it and you don't have enough |
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56:20 | calcium levels are going down okay and this particular frequency somehow doesn't work very |
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56:31 | with receptors either opening or closing of receptors or the number of the receptors |
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56:36 | are synopsis. So what's happening here we have a certain pre synaptic frequency |
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56:46 | can encode certain reverberating persistent activity promoting growth facilitation or promoting the weakening of |
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56:53 | signal. Depression depending on the frequency on the circuit depending on the |
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56:59 | But let's say this is one of examples of short term plasticity facilitation and |
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57:07 | . Now the other set of experiments these guys did in the 70's we |
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57:16 | the same Shopper collaterals see one area in this case they produced very high |
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57:30 | yeah 100 hertz For about 1/2. repeated it every 15 seconds from they |
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57:50 | it. And let's say they repeated activity multiple times 10 times 15 times |
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58:00 | times five minute period. Where every seconds there is massive stimulation and high |
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58:09 | of these fibers onto the parameter all . And you're recording extra cellular early |
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58:17 | activity 400 salad that were either way you do this stimulus you produce one |
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58:28 | and your recording PSP 15 seconds later produce another stimulus. You recorded PSP |
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58:36 | then you decide to turn on this protocol that is repeated. Okay so |
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58:44 | say this goes on for about five . It's like me hammering into your |
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58:50 | on a spike timing dependent plasticity, timing dependent plasticity. And then after |
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58:56 | gone through this five minutes I say timing dependent plasticity. So what happens |
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59:04 | this five minutes is now you'll instead a train you'll produce that single stimulus |
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59:11 | and the response that you're recording The ep sp response that you're recording |
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59:18 | will now be markedly increased. So have just potentially ated that. Okay |
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59:28 | if you now recorded this over So this is your E. |
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59:43 | S. P. Amplitude and millet . It can be slow or amplitude |
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59:53 | slope. Also it is indicative and sometimes better measures, measured the slope |
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60:00 | the rising gps speed on that. complicated and you look at time. |
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60:06 | . And this is your control and is where you're producing single stimuli Every |
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60:16 | seconds. And this is where you your conditioner and you're producing this very |
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60:29 | frequency stimuli that 100 hertz every 15 . You're shocking the circuit. So |
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60:41 | hammered. Now you go back and let's say so this is spike in |
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60:46 | response. Spike spike and response spike persists. Spike timing dependent plasticity. |
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60:55 | I said spike, despite battling development much stronger response. So you will |
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61:02 | an increase in amplitude when you now . So if the E. |
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61:08 | S. D. On average, this side here in the PSP is |
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61:11 | to be on this size. And increase in the amplitude can last and |
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61:17 | can last for hours and so this long term potentially ation. So this |
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61:26 | how people thought, okay this is strong stimulus, 100 hertz, very |
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61:32 | frequency. It causes potentially asian models guys, you know, reading my |
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61:37 | here. So what happens if we do the opposite instead of this very |
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61:47 | frequency At 100 Hz. We're going produce this very annoying frequency stimulation was |
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62:02 | . That one hurts and we're gonna that again here. Very annoying and |
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62:10 | that again here. Very annoying. then we're gonna test what happens to |
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62:15 | ep sp. And as we're doing one hurts stimulations and maybe the protocol |
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62:23 | a little different. You're doing one . So it's one second. You |
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62:27 | do a ton of hurts but something . So you can do do do |
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62:32 | repeat that stimulus? You task for PSP. And all of a sudden |
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62:37 | discover that the size of that P. S. B. Has |
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62:44 | . And so now you have long depression and this is the depressed the |
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62:55 | . And this long term depression can last for hours for days and this |
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63:04 | term depression. If the synopsis are dampened activity will cause the pruning and |
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63:11 | driving away of the synopsis that are active. So this is how the |
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63:20 | code came about and it was High frequency engaging synapses ltp low frequencies |
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63:28 | . T. D. Everybody's What's happening during high frequencies a lot |
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63:32 | calcium goes in. Alright, lots plasticity. What happens when you have |
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63:37 | slow stimulation? Little calcium. Little depression. So that was dominating the |
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63:45 | field and the cellular understanding of these for a good two decades 70s and |
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63:51 | until in the 90s we started doing types of experiments. Dual wholesale patch |
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63:58 | experiments and in particular dendritic recordings. if people got really good at patching |
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64:05 | In the 70s and the 80's People getting really good at patching done drives |
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64:12 | in the 90s and you don't see papers and the British recordings until the |
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64:16 | . This is fresh stop. so now I have this excerpt they're |
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64:23 | have and the spike timing dependent plasticity would encourage for you to look at |
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64:27 | and then we're going to look at pre synaptic posse. Synaptic changes take |
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64:33 | in the elasticity. L. D. L. D. |
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64:37 | Mechanism and spike timing dependent plasticity. I suspect that we'll probably spend another |
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64:43 | an hour to 45 minutes in understanding . But I think it's just a |
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64:47 | cool subjects to understand to know to about and these are the rules. |
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64:53 | we learned two major rules. The term rules, facilitation and depression during |
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64:58 | actual stimulation train. And then we what happens in the long term rules |
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65:05 | you stimulate the circuit with high frequency low frequency. And this is called |
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65:09 | rate code. So we then had rudimentary understanding when we introduced the back |
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65:16 | action potentials were then understood the spiked independent code despite time independent. |
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65:23 | I'll end here and I actually I |
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