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00:02 This is lecture nine of cellular Uh This is the first black

00:08 Midterm. So this is sort of a second section of the course if

00:11 starting. And although the syllabus notes we are going to talk about

00:17 functional imaging, we're going to cover plasticity ah synaptic plasticity and I will

00:23 that and adjust the syllabus as we on through the material in the next

00:29 of lectures. But from early on person that postulated that there is plasticity

00:38 neuronal connections and neuronal circuits was Ramona . In fact drew these arrows between

00:47 indicating how the signals would flow, the neurons would communicate with each

00:52 And he also suggested that those connections the way neurons communicate our plastic that

00:59 can change with time and they can with activity. And so this term

01:07 activity dependent plasticity that the plasticity or communication between the circuits and the adjustments

01:16 that communication between individual neurons and neuronal whether strengthening it but weakening, it

01:25 depends on activity, really depends on too. Uh plasticity is the most

01:37 during their early brain development. We fact are born with a lot more

01:43 in the brain that we end up in the adult brains, mature adult

01:49 and in fact a lot of things the brain. During early developments,

01:55 lot of circuits are interconnected and there a lot less specificity in these circuits

02:04 connectivity between brain regions and so with with strengthening of certain synopsis and weakening

02:16 away, driving away a lot of connections. You have sculpting of anatomy

02:26 more precise wired circuits that are more like. And with sculpting of that

02:33 you also have sculpting of the And as you sculpt the anatomy structure

02:41 function. You also sculpt the the circuit, communication and even the

02:51 with Mississippi. So plasticity is really for the early development and during early

03:02 there is this period that is called period of development and during this critical

03:24 of development, during early developmental stages are certain chemical trophic factors that allow

03:38 high levels of plasticity to take place your brain matures, there is a

03:47 expression of different molecules in the different trophic factors and during early development

03:55 . A certain brain derived and other neurotrophic factors allow for these high levels

04:07 elasticity to take place. So for and memory formation as we know,

04:16 have to have normal experience normal exposure censor stimuli for a child, auditory

04:25 Samata, sensors, stimuli in order that child and for that brain to

04:32 normally. So these are experiences and are the most able to absorb and

04:40 information also during that critical period of . If you think about early on

04:48 is happening, you have the sorting the connections you have the sorting of

04:57 connections. And then you have pruning the synopsis during this developmental stage that

05:12 not going to be there because they not be as active or not as

05:18 for their dog brains. So once have this process of pruning trophic

05:29 sorting of the connections and that you liken in humans in the first few

05:36 of life, when you're learning just to walk and to talk and to

05:43 and things like that and then you the stage and language is a very

05:50 example, you enter the stage, when you're learning a foreign language where

05:56 most susceptible to picking up foreign language about three years of age. So

06:03 earlier you start, the more likely will be fluent, bilingual, fluent

06:10 you're talking about a foreign language. so if you look at the language

06:19 and this is plasticity isn't you have levels of plasticity from this three years

06:29 age and then the levels of plasticity down, it doesn't mean that you

06:36 learn another language At the age of . But what's very likely Is if

06:43 start learning a foreign language in you will show a stronger accent,

06:49 motor commands and the plasticity and moving tongue in your mouth are not going

06:55 be a skill, it's gonna take longer to learn the language. So

07:00 can you can you're going to have spend a longer time and practice more

07:05 order to pick up that line. when you think about plasticity is an

07:13 plasticity and you think about critical period development, uh you have to think

07:20 it's the right confluence of chemical environment allows for these synapses to undergo these

07:30 based development, learning memory. And second, the reason why this is

07:39 important is that it relates to the injury and loss of function equally.

07:46 if you had a brain injury during period in early ages, you would

07:56 a much better recovery of function or even full recovery of function. The

08:04 the accident happens, the earlier the brain injury happens, the earlier for

08:09 , if you're having a brain the earlier that surgical resection of the

08:16 tissue happens, the greater chance there for recovery of function that's because the

08:24 can reorganize and can form connections where has now lost, parts of the

08:32 are lost or has damaged circuits that communicate. So if the child has

08:41 surgery at this age, it's one . But if you have a brain

08:45 in adults, there's inevitably a lot serious loss of function and less

08:53 And that is because you have passed sweet time window where the brain is

09:01 plastic and it takes longer and harder not at all, but the brain

09:07 and for the new synopsis to but it is still possible. So

09:13 not that in adults, there's no plasticity, it is just reduced and

09:18 environment has changed too. So when talk about plasticity, we talked about

09:26 ation strengthening of the synopsis and depression depression at the synapse activity gets depressed

09:34 can lead to pruning or clipping essentially rid of the synapses. Let's say

09:41 was no great expanse that are non . This is a normal synapse and

09:48 have calcium levels here and sodium levels you have synaptic cleft and you have

09:57 neural transmission. The action potential be pre synaptic terminal releases neurotransmitter. You

10:05 influx of sodium and potassium sodium and . You flex of potassium. So

10:12 talking about excitatory glutamate, ergic neural and then if you do something and

10:20 is that something that causes synaptic What is it that causes the potentially

10:28 ? I'll see you calcium exactly from physiological perspective. But when you're learning

10:34 , what do you have to do order to learn it while you have

10:37 repeat the same activity? You have study it over and over. Sometimes

10:41 have to look up the terms you to have your friend test you through

10:45 terms and equations and then you you because the synapses that are active,

10:52 become potentially waited on physiological level. would see greater influx of sodium more

10:58 polarization, greater influx of calcium which greater influence on the post synaptic activity

11:05 they didn't do it experience, remember is also a secondary messenger. Right

11:10 you look at this and you see now I'm seeing something else. I

11:13 more receptor channels in the synapses. that's when you would recruit. It's

11:21 way to strengthen that synapse or potentially . It's not just open more channels

11:27 actually recruit more channels into that recruit them from extra synaptic spaces through

11:34 diffusion through plasma membrane and recruit them receptor insertion receptor channels insertions from the

11:45 of plaza into the plasma membranes. in depression you would see the

11:56 you would see les de polarization. would see less calcium flux. You

12:04 potentially see less of the excited to channels and serve it in some instances

12:11 more inhibitory receptor channels inserted to dampen activity in that setup receptors impression.

12:29 it's not just automatic prudent. Also . Right? You can depress the

12:37 and we'll talk about it just like can strengthen the potential synopsis for a

12:41 time. Which would be a short potentially ation and would be equivalent short

12:48 memory. Something you learn quickly and forget you don't need to carry that

12:54 long term and then there are long changes. So we'll talk about that

13:00 a second. Um Hang on to question is a very good question.

13:07 term changes would be something like a term memory information that you carry for

13:11 long time. And there are several for this plasticity to occur. We

13:18 are touching on some of these We talked about an M.

13:21 A. Receptor. Very important because a coincidence detector. We're talking about

13:27 influx because calcium is an intracellular We also mentioned side of skeletal

13:35 So there would be underneath the There would be a rearrangement of cider

13:39 elements to uh and this plasticity that talking about can happen on both excited

13:46 an inhibitors analysis. So it's a bit more complicated. But in general

13:52 you're depressing synapse it means it has activity. And if it gets depressed

13:58 a very very very long time that's it gets pruned it gets general how

14:04 that just depends on what it is you've learned what it is that you

14:13 or where it is. Much easier forget. Uh Faces, names,

14:20 , then functional things like piping like a bicycle like playing a sport you

14:28 don't forget that you know. How I play tennis again? You know

14:31 don't do that. So it's I know why but it's procedural and it

14:36 motor skills. And maybe the coding different from just remembering the stories which

14:41 semantic memory and hippocampus. If you is responsible for semantic memory formation and

14:49 of semantic memory. Okay so wait I have to do is that you

14:57 insert Gaba receptors in there. Or it only you can only recruit

15:03 D. A. Mostly it's excited receptor insertion when we talk about it

15:09 there's always exceptions to everything. And you cannot insert Gaba receptors you have

15:15 cinnamon together receptors so you can recruit . There's there's ways the synapse will

15:20 it most of the time when we about insertion is boosting the synapse through

15:26 receptors and they seem to be most too from uh these receptor channels.

15:34 you have those two strategies. And also has exceptions of being able to

15:40 inserted as well. So we can that depression people is unimportant.

15:49 No you can't assume that depression it an important depression is a part of

15:57 of activity allowing you to remember certain better, wiping away things that you

16:03 need And from emotional memory perspective depression you to move on because when you

16:12 the synopsis that caused let's say a strong emotional response and maybe it was

16:18 very negative emotional response. If your stored that information over time it would

16:25 overwhelming. So depressing the synopsis and away the negative emotions is also a

16:33 thing and in sculpting the activity and things. So if you think about

16:41 ating is learning memorizing new things and can think of depression is forgetting to

16:48 other things to be memorized or forgetting a protective mechanism? Very good

16:54 So does that mean like people who to go post traumatic stress, Is

17:00 into this depression or is it due or like damage? So don't confuse

17:08 depression, which is a great question post traumatic stress disorder, which is

17:15 , it has a syndrome of But you can also have clinical depression

17:20 with the PTSD. Ah don't confuse with the physiological actions of potential rating

17:29 of depressing the synopsis. But sometimes after a certain traumatic experience, they'll

17:36 their blood ways. I guess that's I'm referring to. Like,

17:42 And if they and if they don't have very difficult time psychologically. So

17:47 they don't if they somehow cannot engage again, the chemical cast, if

17:54 talking about that mediates this, it's just gaba and glutamate, it's all

18:03 these other I mean there are it's serotonin norepinephrine and so on.

18:13 it's it's quite complex in each That's what I'm wondering is if it's

18:21 the brain is kind of forcing this depression like in terms of what we're

18:26 about today or if there's been like generation from that trauma with both.

18:34 , there's neural degeneration, but there's plasticity and there's a way to engage

18:40 plasticity. But if there is also imbalance and you're missing some of these

18:46 means that will contribute to plasticity and processes, then you can be in

18:51 . And that's why when you talk depression with antidepressants, you will hear

18:55 lot of the drugs are serotonin driven , PROzac actually the serotonin system,

19:02 a common uh name for at that syndrome. So that tells you somehow

19:11 is involved. Now if you have serotonin imbalance and you don't know that

19:16 not being treated, you'd be just treated for gavel or glutamate somehow with

19:21 kinds of the assassins or other then uh it's it's quite complex to

19:28 it and if you don't have the elements you don't have the right

19:33 So if you have a chemical imbalance strengthening you excited or inhibit third synopsis

19:38 be affected. It may take longer to forget things. Years instead of

19:46 or weeks. So. So the really important person in coining what we

19:56 this modern day plasticity already. See this is probably gonna be two lectures

20:00 plasticity is Donald Hebb. So Donald said when an axon of cell a

20:08 and persistently takes part in firing that is when you repeatedly and persistently

20:17 something, learn something, do Some growth process. Growth process something

20:24 grown or metabolic change. Maybe more . Maybe some chemical is being synthesized

20:31 place from one or both cells such the ace efficiency as one of the

20:37 firing B is increased. So he essentially saying that there is so A

20:53 the cell A. They're stopping to and it repeatedly and consistently sending the

21:02 action potentials and releasing neurotransmitter onto the . You're saying that something happens in

21:14 in the synapse here. Some process strengthens this input. Now this implies

21:24 that if you had so see and L. C. Was not really

21:36 . English widely active. Okay. implied here that the active synopsis would

21:49 . And so the ones that fire choir together the ones the out of

22:16 don't blink. Okay so fire Wire together there's activity that's firing

22:24 Now that means also implies that Selby to be responsive to stimulus city.

22:32 how is it responsive in house A. Going to know that Selby

22:36 responded. So we'll go back and a little bit about the back propagating

22:40 potential. And perhaps one of the important codes for plasticity despite them independent

22:49 . So experimental support for heavy in after that. And neuroscience and neuropsychology

22:56 psychology textbooks. It was called near in plasticity named after Donald have this

23:04 psychologist. Experimental support for having plasticity stronger repeated activation of pre synaptic cell

23:12 before spikes. And parse synaptic cell induces synaptic strengthening known as timing depends

23:18 long term potentially ations and as the dependent plasticity will get the details of

23:24 in a second. How did not propose a rule for the reverse spike

23:31 order or for the back propagating So he didn't know the back propagating

23:36 existed. But experiments indicated that many , repeated activation of pre synaptic cell

23:42 immediately after post synaptic B leads the dependent long term depression all time independent

23:51 term potential station. So you'll see that works together. These synaptic rules

23:56 known as spike timing dependent plasticity. let's let's look a little bit of

24:03 that means. So he claimed that , he basically explained what plasticity is

24:15 we'll come back to spike time persistent in a second. So it's

24:19 lot of times referred to as heavy plasticity. I think I took that

24:24 a couple of pages on one of books and I believe I may have

24:29 that that in your class lecture supporting , mm hmm. So when you

24:35 about activation of one cell, the that we just looked at, that's

24:40 simple. But in reality you have and those neurons have reciprocal connections.

24:49 if you have a certain connectivity, have a circuit. You have a

24:54 neuronal network. And if you look these connections, there are certain rules

24:59 the connections for the excitatory south. then hit the third sauce. We

25:02 about some of these rules feedback feed individual lateral inhibition. We haven't talked

25:09 . There is a summation of excitation so you have an external stimulus and

25:15 stimulus is not just going to activate A and that one cell A.

25:21 going to activate Selby most likely that stimulus is actually going to activate some

25:29 of assembly of neurons. So this an input and that input, let's

25:36 it in very plain. This is hamper. It's a circle. That

25:44 is somehow going to get encoded by network of sauce and this network of

25:52 as some sort of connectivity rules. cells are reciprocally connected in both directions

26:00 other sources of communicating in just one . So if you have certain communication

26:08 and then this assembly of selves or circuit, if you may response simultaneously

26:16 this external stimuli and activation of the assembly by a stimulus boom boom boom

26:23 boom. And what he is saying that if you have this external stimulus

26:30 you activate the sole assembly but there's to be some levels of reverberating

26:39 It's continuous activating the circuit following the stimulus activation. So he's saying that

26:50 going to be some reverberating sort of . There's going to be something like

26:55 is already primed So heavy and modification the reciprocal connections between nerves that are

27:04 in the same time. So some these connections that were reciprocal and we're

27:12 active. I'm gonna get strengthened now has become very strong. The strengthened

27:22 of the cell assembly contained the n of the stimulus. So what was

27:30 ? It was not an engram was of self structure on that structure.

27:38 imposed strong stimulus which is function And now the synopsis plasticity happened And

27:50 reciprocal cells that were activated with the . Now they have strengthened and they

28:00 created an engram. So this would an engram. This isn't any ground

28:15 the stimulus here. Maybe if you a different stimulus and it doesn't mean

28:21 a visual stimulus but you can imagine can think about it as a visual

28:26 that doesn't have to be a visual . So maybe if you presented a

28:32 stimulus like this at the end ground look different. Huh? So the

28:46 assembly may be the same right? I just tricked him added new

28:53 But the same cell assembly is the . But one stimulus input imposes this

29:00 a circle and other stimulus square imposes engram that looks more like a square

29:07 something. It's representative of the external . So now you have the strengthened

29:17 . They have the engram. After partial activation of the assembly leads to

29:24 activation of the entire representation of that . So if our circle caused this

29:35 gram here to be encoded and these become very strong. Now you actually

29:47 even need to present the whole full but rather a certain fraction of that

29:56 . So a weakened stimulus but still that circle but it's not as pronounced

30:06 as it was before before it was this and like that. This is

30:11 . Now you're presenting some very light of that stimulus. But guess what

30:17 getting. You're engaging that same end . But when you did when you

30:23 the ritual stimulus so now you have in the circuit and now you can

30:29 the snap. Works much easier. example is you were studying something for

30:34 long time and then all it takes it's just a second to look it

30:38 before you reactivated the n grams and can take the test, remember

30:45 So to generate the engram you may to repeat the stimulus and you repeat

30:50 just like activity between A. And . And B. So it strengthens

30:56 the same circuits. The same structure encode different anagrams. Of course this

31:02 be repeating, receiving different stimulus. this reverberating activity. But how we

31:11 to as STP for short term plasticity in this case short term potentially

31:39 How does it look like on a a synoptic level? So here's an

31:44 potential one and it causes the release neurotransmitter and produces the PSP two produces

31:56 times second. Dp sp Okay third PSP four for the DSP. So

32:07 you repeat this activity repeats the firing the activity and you're recording from the

32:12 is the cell A. And you're from Selby. Then the release of

32:20 activation of the synapse should now strengthen response and gradually increase the response in

32:28 sentence calcium levels go up receptors get potential created. So the same

32:35 the same strength, the same action will now be causing a much stronger

32:41 response. And also on the pre side there will be changes as

32:47 So this is reverberating activity And the circuit. The growth process consolidates the

32:54 growth processes the plasticity, the plastic of the connections and then and graham

33:01 . If you think about it then you can recall if you activate those

33:05 you just need a little trigger like said you just need a little trigger

33:09 beginning of the equation, you can the rest of it. Whereas two

33:14 ago you needed the whole equation in of you. So this is an

33:19 recall. Hippocampus would be very very in recall. So hippocampus is very

33:26 in encoding and formation of memories and . Where are these n grams that

33:32 be storing different memories and encoding different . They're widely distributed throughout the

33:41 And so it's very complex connectivity. we had a place where all of

33:45 memories are stored that we can reach and stimulate and produce all your memories

33:52 would be something else. But we have that. So the memories and

33:57 n grams and cell assemblies that widely . And so if you're talking about

34:01 grams for visual information there will be n grams in the visual cortex auditory

34:08 . And then when you're talking about the census together, there will be

34:12 grams that blend Information together visual auditory even the motor outputs. And we

34:19 really understand what what shape or form 10 g are in. That's why

34:25 need functional imaging both on the cellular whole grain levels. To really start

34:31 that we have wide distribution among the assemblage. You have a lot of

34:39 that would repeat. Quite often the will activates two nearby circuits. That

34:48 to N grams that encode that It's a protective mechanism. So you

34:54 recall. Maybe there's several ways you get to that Selby. If cell

35:00 goes out, maybe you develop another could involve the same neurons involved in

35:11 and perception. So sensations, perceptions things. And then when you think

35:20 the thought processing or creation of new without external stimulus. When you're have

35:27 eyes closed at night and you've just something in your head, what does

35:33 come about? So there's some reverberating . There's some activity. There's some

35:38 that are being engaged. There's some is there some some intrinsic the brain

35:48 . There are these dynamic algorithms that intrinsic that now can generate new things

35:53 we haven't learned. So when we about recording and performing spike timing dependent

36:04 experiments, let's go back and revise we can do this whole self voltage

36:09 recording experiments. And you can use clamp that you can use current clamps

36:20 . This is a parameter style. an example of parameter style. You'd

36:27 an infrared contrast microscopy to visualize So it's typically in the brain slice

36:34 that if you're doing wholesale a patch recordings of significant dialysis, but you

36:40 control number in potential really well. . And so this is the type

36:48 the techniques that you would use originally record the back propagating action potential.

37:01 is the principle of the back propagating potential. This is all leading us

37:12 spike timing dependent position you have at axon initial segment here at the soma

37:24 all of the stand rides a very location and the specialized location we're going

37:31 produce forward propagating action potential and you're produce back propagating action potential and the

37:39 propagating action potential is going to regenerated note of ranveer and then Dixon on

37:51 . It's going to cost us neurotransmitter influx of calcium and deep polarization will

37:59 the neurotransmitter release. This is forward actually attention. And it turns out

38:05 the accident initial segment here Contains two of both educated sodium channels. One

38:11 them is a low threshold, both sodium channel which is N.

38:16 B 1.6 in the yellow zone. one is a high threshold Voltage gated

38:23 channel which is n. a. . 1.2 and there's blue zone and

38:28 you assume but the cell will be a lot of excitatory inputs into the

38:35 of getting deep polarized. You also assume that a lot of the inhibitory

38:42 just like in the hippocampal surface will targeting these excitatory cells. Let's say

38:47 looking at the phenomenal cells. So have inhibitory emphasis here around the

38:53 So in addition a lot of times have very tight control of the integrative

38:58 of the selma and the integrative properties whether we're going to produce an action

39:04 or not. That's what the selma especially the axon initial segment is going

39:09 calculate. So you D polarized dumb you need a lot of deep polarization

39:16 order for that deep polarization to reach axon initial segment. Because down rights

39:22 some are not my eliminated and there's to be a significant leakage of current

39:26 it's excited very current before it D acts on initial segment at the accident

39:33 segment, the threshold for activation is lower. So you just need a

39:38 bit of deep polarization there that's just way it is in order to activate

39:43 voltage gated sodium channels. So if receiving distal excitatory inputs and those digital

39:49 for infants happen to overcome the inhibition the south will be bombarded by excited

39:54 inhibit your emphasis at the same If this green arrow in the form

39:58 excitation and deep polarization overcomes the inhibition passes through into the axon initial

40:06 it will actually bypass the m maybe zone because these are the channels that

40:13 high threshold. That means that they high change in voltage in order to

40:19 . So and maybe 1.2 channels I'm going to open Instead and maybe 1.6

40:25 are going to open And NAV 1.6 are going to produce the forward propagating

40:31 potential. And that is going to the chemical neurotransmitter release of the senators

40:39 these. And maybe 1.6 channels. low threshold voltage gated sodium channels.

40:44 they don't need much of the deep of this green arrow. And they

40:50 this explosion in the form of actual and propagates forward. While that explosion

40:57 in addition to this already existing excited input in the form of the green

41:02 . Now you have the summation Of excitation and the deep polarization that is

41:07 in the membrane through an 81.6 And summation of the input and the excitation

41:14 an 81.6. It's now enough of high enough of the voltage to open

41:19 high threshold And maybe 1.2. And these high threshold channels open up to

41:26 back propagating action potential, that back action potential is going to flux.

41:32 positive current back into the soma and into the dendrites and then to

41:38 So the function of the back propagating potential is very different. And the

41:43 of the back propagating action potential primarily with spike timing dependent plasticity, plasticity

41:52 the aca synopsis in general. So very different functions. But how would

41:58 record that? So you would record we detected back propagating action potentials,

42:05 me, but neuroscientists by doing dual patch clamp recordings on the same

42:12 So you would patch clamp the selma you would patch clamp the dendrite.

42:18 when an action potential was recorded at level of the selma there was a

42:23 small blip representation of fat that got up in the done tracked. And

42:28 what made scientists wonder, what is ? So, you did a dual

42:35 from the dendrite and the selma. in the soma. Mhm. You

42:41 this large action potential and in the right, your electrode picked up this

42:48 back propagating action potential. And every you record a spike in the

42:54 which is forward propagating spike. To the back propagating spike, every time

43:00 a forward propagating spike there's back propagating . So, it makes scientists wonder

43:10 is that? Why is it It's easy to say, we know

43:14 the forward propagating spike? Is that to release the neurotransmitter. So why

43:19 we have that back propagating spike. is an example of what these chases

43:25 look like. So you have dendrite electrode here and you have blue electrode

43:36 in the selma. And so you this very large deep polarization in the

43:44 . And you see a fraction of deep polarization in the in the dem

43:49 . Right? So now you can that this is the green is the

43:59 action potential. And if you enlarge you can always see that there is

44:04 little delay so that the dendritic action in the peak of the dendritic action

44:10 is delayed to the somatic action Well in B. You have

44:20 S. P. S. Involved synaptic stimulation followed by back propagating action

44:27 . So what's happening here is that you vote E. P.

44:33 P. S. With a synoptic ? This is a stimulating electron.

44:38 let's say you're stimulating shopper collaterals. so in this green one you will

44:45 up the PSP The synaptic potential Alright you will cause the deep polarization

44:54 and you will have the ps ps ps are large enough from the

45:00 The green traces the PSP's right? the level of the selma you will

45:07 an action potential. U. P. S. P. S

45:10 the level of the soma. This the PSP. Remember that? This

45:19 excitatory personality potential DSP. It can to an action potential, right?

45:29 you're recording from done right? When record from done right, you stimulate

45:33 fibers, you record very robust e in green. You're not seeing a

45:40 robust PSP in blue because your synapses adapter. Called downgrades. If you

45:49 the synapses going into the selma, would see a very robust response and

45:55 in blue. But they're coming And with this green electrode boom,

46:00 pick up the PSP and then in blue electrode, the next thing you

46:05 up, boom, it started an potential and then a millisecond or two

46:09 . Boom. There's a back propagating that I've picked up. So one

46:15 , this is not repeated stimulus that to the sedans is one stimulus boom

46:26 . Glutamate release an optical done It means in the done dry,

46:30 polarization in the selma it means deep that's strong enough reaches the threshold,

46:36 generating forward propagating action potential. And dendrite. Now, except the back

46:42 action in the country. So. you have on the on the on

46:50 bottom here measurement of the conduction velocity back propagation by time differences between the

47:00 of the somatic and dendritic action potentials various locations of the dendritic recording

47:08 So it tells you the latency over . It's very fast, Right?

47:16 get milliseconds within milliseconds, you can up the signal flowing within 100 micrometers

47:23 space and 100 micrometers. Is this 10 micrometers in diameter but hundreds and

47:30 axons especially can be very, very . So does everybody understand this is

47:36 we discovered the back propagating action This is why you would have this

47:40 and then drive it with the cap activity. Someone would produce the

47:45 But that's spiked with backwash back propagate you will pick it up also at

47:49 level of the dendrite. So then knew there's something going on here.

47:55 then that whole principle of spike timing came into into light and became very

48:07 . So here's another interesting experiment. have three electrodes in the selma in

48:15 done right. And then another optical right? So this is layer one

48:21 the neocortex. This is layers 3, 4 and layer five.

48:28 you have an a also reporting from same Parameter sound with three independent 5

48:40 . Middle panel shows somatic black and propagating action potentials in red lower panel

48:50 that the burst of three somatic action is to vote by combined somatic and

48:54 dirty current injections supplied within a short window time courses of somatic and dirty

49:00 injections are shown below voltage traces. there is a little delay and then

49:07 summation and the frequency of the action can influence very much the back propagation

49:13 that signal? Ah This is a good article that I have in your

49:25 neuromodulation of spike timing dependent plasticity present future. So when we talk

49:32 plasticity in general and when we talk the signaling spill of the neurotransmitter back

49:40 action potential. We actually are talking cellular substrates. These are cellular substrates

49:48 plasticity, cellular substrates of learning and , cellular model of behavioral learning and

49:56 with rich computational properties. There's a precision for the spike farming and we

50:06 a lot of very slow activity also don't understand how that works very

50:13 And if you think about excitatory synopsis inhibitory synopsis minus, life is pretty

50:21 , awesome minus. So when you the means when you introduce the serotonin

50:26 norepinephrine societal Collins neuromodulation of these So what are some of the plasticity

50:35 ? The first rule is the rate rule. Okay. And it's emerged

50:43 the 1970s and it was actually done this really cool. See a one

50:54 of the Hippocampus with the schaffer collaterals being stimulated that project onto the pyramidal

51:08 . Okay. And this drama to cells are very densely populated and strike

51:18 through on the dollar. And so the 70s scientists and stuck these large

51:26 cellular electorates if we're picking up activity many cells in the area, not

51:32 intracellular electorates. And they said okay let's see if we can strengthen the

51:39 by stimulating this pathway the shop. collateral possible. Yeah. And they

51:48 two types of the stimulations first. did short term short turns of stimulation

52:02 looks something like this and lasted maybe milliseconds. And they repeat these trains

52:14 stimulation. Mhm. Every 15 And they would record the post synaptic

52:27 . And they would see the response increased in amplitude. And they call

52:35 facilitation. Or potentially ation. It's to as facilitation because the previous

52:47 P. S. P. Promotes larger and larger facilitates a larger

52:56 So that was pretty cool. They this pattern here in certain frequency let's

53:03 this was it 10 hertz. Can see this Increased growth and this is

53:14 Hz is not the number that you have to remember. And then they

53:20 the same experiment. But instead of 10 hertz stimulus and produce the same

53:34 But 40 Hz stimulus and what they is something that looked like this where

53:45 initial response by somatic response of the was facilitation or the strengthening of the

53:58 . But very obviously as the strain on it was depression of the

54:06 So this is depression of the signal the strain of activity. So that

54:20 the scientists that this bursts of activity on frequency can produce these facilitate torrey

54:26 depressing short term forms of plasticity that within the actual train of stimulation.

54:35 then they would say let's introduce something faster like 100 hertz and they're

54:51 We saw it was pretty much depression the initial E PSP We saw a

55:01 . So these different frequencies of acts activation and this facilitation and distraction during

55:07 short stimulus let's say the stimulus is um 50 milliseconds, 100 milliseconds.

55:20 stimulus. You have the facilitation and have the depression. This is what

55:26 think is the reverberating activity in that that happened. I was trying to

55:33 with the reverberating activity that the engaged and why would there be a

55:39 There's potentially increases in calcium and calcium be promoting stronger post synaptic response.

55:49 at this frequency you can recruit recruit but guess what? You can also

55:59 receptors from the synopsis and by removing from the synopsis you can depress synopsis

56:08 so what happens here? You have you potentially have a lot of influx

56:14 calcium and maybe on that first burst exhausted it and you don't have enough

56:20 calcium levels are going down okay and this particular frequency somehow doesn't work very

56:31 with receptors either opening or closing of receptors or the number of the receptors

56:36 are synopsis. So what's happening here we have a certain pre synaptic frequency

56:46 can encode certain reverberating persistent activity promoting growth facilitation or promoting the weakening of

56:53 signal. Depression depending on the frequency on the circuit depending on the

56:59 But let's say this is one of examples of short term plasticity facilitation and

57:07 . Now the other set of experiments these guys did in the 70's we

57:16 the same Shopper collaterals see one area in this case they produced very high

57:30 yeah 100 hertz For about 1/2. repeated it every 15 seconds from they

57:50 it. And let's say they repeated activity multiple times 10 times 15 times

58:00 times five minute period. Where every seconds there is massive stimulation and high

58:09 of these fibers onto the parameter all . And you're recording extra cellular early

58:17 activity 400 salad that were either way you do this stimulus you produce one

58:28 and your recording PSP 15 seconds later produce another stimulus. You recorded PSP

58:36 then you decide to turn on this protocol that is repeated. Okay so

58:44 say this goes on for about five . It's like me hammering into your

58:50 on a spike timing dependent plasticity, timing dependent plasticity. And then after

58:56 gone through this five minutes I say timing dependent plasticity. So what happens

59:04 this five minutes is now you'll instead a train you'll produce that single stimulus

59:11 and the response that you're recording The ep sp response that you're recording

59:18 will now be markedly increased. So have just potentially ated that. Okay

59:28 if you now recorded this over So this is your E.

59:43 S. P. Amplitude and millet . It can be slow or amplitude

59:53 slope. Also it is indicative and sometimes better measures, measured the slope

60:00 the rising gps speed on that. complicated and you look at time.

60:06 . And this is your control and is where you're producing single stimuli Every

60:16 seconds. And this is where you your conditioner and you're producing this very

60:29 frequency stimuli that 100 hertz every 15 . You're shocking the circuit. So

60:41 hammered. Now you go back and let's say so this is spike in

60:46 response. Spike spike and response spike persists. Spike timing dependent plasticity.

60:55 I said spike, despite battling development much stronger response. So you will

61:02 an increase in amplitude when you now . So if the E.

61:08 S. D. On average, this side here in the PSP is

61:11 to be on this size. And increase in the amplitude can last and

61:17 can last for hours and so this long term potentially ation. So this

61:26 how people thought, okay this is strong stimulus, 100 hertz, very

61:32 frequency. It causes potentially asian models guys, you know, reading my

61:37 here. So what happens if we do the opposite instead of this very

61:47 frequency At 100 Hz. We're going produce this very annoying frequency stimulation was

62:02 . That one hurts and we're gonna that again here. Very annoying and

62:10 that again here. Very annoying. then we're gonna test what happens to

62:15 ep sp. And as we're doing one hurts stimulations and maybe the protocol

62:23 a little different. You're doing one . So it's one second. You

62:27 do a ton of hurts but something . So you can do do do

62:32 repeat that stimulus? You task for PSP. And all of a sudden

62:37 discover that the size of that P. S. B. Has

62:44 . And so now you have long depression and this is the depressed the

62:55 . And this long term depression can last for hours for days and this

63:04 term depression. If the synopsis are dampened activity will cause the pruning and

63:11 driving away of the synopsis that are active. So this is how the

63:20 code came about and it was High frequency engaging synapses ltp low frequencies

63:28 . T. D. Everybody's What's happening during high frequencies a lot

63:32 calcium goes in. Alright, lots plasticity. What happens when you have

63:37 slow stimulation? Little calcium. Little depression. So that was dominating the

63:45 field and the cellular understanding of these for a good two decades 70s and

63:51 until in the 90s we started doing types of experiments. Dual wholesale patch

63:58 experiments and in particular dendritic recordings. if people got really good at patching

64:05 In the 70s and the 80's People getting really good at patching done drives

64:12 in the 90s and you don't see papers and the British recordings until the

64:16 . This is fresh stop. so now I have this excerpt they're

64:23 have and the spike timing dependent plasticity would encourage for you to look at

64:27 and then we're going to look at pre synaptic posse. Synaptic changes take

64:33 in the elasticity. L. D. L. D.

64:37 Mechanism and spike timing dependent plasticity. I suspect that we'll probably spend another

64:43 an hour to 45 minutes in understanding . But I think it's just a

64:47 cool subjects to understand to know to about and these are the rules.

64:53 we learned two major rules. The term rules, facilitation and depression during

64:58 actual stimulation train. And then we what happens in the long term rules

65:05 you stimulate the circuit with high frequency low frequency. And this is called

65:09 rate code. So we then had rudimentary understanding when we introduced the back

65:16 action potentials were then understood the spiked independent code despite time independent.

65:23 I'll end here and I actually I

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