| 00:01 | This is cellular neuroscience lecture seven. we discussed last time was the |
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| 00:08 | the Hippocampal circuit. We're basically getting some of the basics excitatory inhibitory circuitry |
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| 00:18 | we see in some of the most structures such as the hippo cameras. |
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| 00:25 | the best studied structure. Also the that you're seeing at the campus off |
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| 00:32 | circuits is what we call canonical That means that if you have the |
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| 00:39 | forward inhibition or inhibitory circuits surrounding excitatory that are communicating information longer distances, |
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| 00:47 | projection, excited parameter cells then you'll similar type of local network control, |
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| 00:54 | control in other parts of the like in the cortex neocortex. So |
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| 01:01 | have a campus, if you remember we have is we really have three |
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| 01:09 | of the excitatory cells. And those cells are distinguished only where they |
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| 01:17 | There's three layers we talked about stratum items stratum and stratum or Ians and |
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| 01:23 | did they express? Kyle bend in positive or they don't have some taliban |
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| 01:30 | C. B. Negative And they're by in this diagram from 10 years |
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| 01:37 | , 21 different subtypes of the inhibitory and these inhibitor in Iran's live in |
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| 01:44 | layers. They have a specific dendritic that's distinguishable one from another. And |
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| 01:51 | this diagram the yellow cups are the . So where are these inhibitory synapses |
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| 02:00 | some of them are formed on the some of them are formed on the |
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| 02:05 | in some rare cases they are formed the axons of the parameter cells. |
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| 02:11 | that parameter cells will talk to each . So excitation to excitation locally not |
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| 02:17 | projection but locally they'll communicate with each also they'll also talk to the inhibitory |
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| 02:24 | . So excitatory cells exciting inhibitory cells increase inhibition in the network and an |
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| 02:33 | source can communicate to each other. inhibitory cells communicating to inhibitory cells. |
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| 02:39 | we discussed these rules by which inhibitory typically inhibit. First of all there |
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| 02:47 | feedback inhibition and that's typically after the cell receives an input excitatory cell is |
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| 02:57 | . That excitatory cell will produce a of action potentials which will be communicated |
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| 03:03 | range outside of the C. One of the hippocampus. But at the |
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| 03:08 | time it's also going to stimulate a inhibitor in neuron. And that neuron |
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| 03:14 | the feedback fashion is going to inhibit problem. There's feed forward instead of |
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| 03:21 | , it's feed forward. In which the excitation excitatory inputs coming in. |
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| 03:28 | will excite these inhibitory cells first before excite the parameter cells and by exciting |
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| 03:35 | inhibitory cells first they will actually feed disinhibition and inhibit these excitatory cells in |
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| 03:43 | fashion. And in this third case lateral inhibition is described as something that |
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| 03:53 | autonomy autonomy segregation of neurons by suppressing similarly activated neighboring neurons. So you |
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| 04:02 | think about this if you want networks be precise spatially and temporally communicating that |
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| 04:12 | . Then in this situation excitation of neuron being excited and exciting inhibit ourselves |
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| 04:21 | there's inhibitory cells can inhibit nearby excitatory . So by this virtue you have |
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| 04:31 | inhibition on both sides. The signal is going to be really strong. |
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| 04:35 | output. The year is going to really strong too. And you have |
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| 04:40 | spatially separated and segregated that neuron from in the surrounding area that are built |
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| 04:47 | be inhibited. So a lot of , inhibitory neurons will have their synapses |
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| 04:57 | the so Mazz onto the proximal dendrites of the parameter cells and the selma's |
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| 05:07 | call this region para somatic region in around the selma base and there's some |
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| 05:14 | inhibitory cells that will target distal down . So there's a optical dendrites and |
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| 05:21 | on the parameter cells and the projections for example ol um cell. So |
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| 05:28 | basket cell on the left, the basket cell, we'll have a positioning |
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| 05:34 | it's perfectly positioned to do feed forward . And oh a lamb sell Oreos |
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| 05:44 | , another type of inhibitory cell. situated better to cater to feedback |
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| 05:54 | Just the way that the communication and connections are between the cells and of |
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| 06:00 | parameter cells are going to project that . Now the side of inhibitory projections |
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| 06:09 | where these inhibitory projections are targeting the cell will very much influence the integrative |
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| 06:19 | and how much influence they have on integrative properties. Integrative properties. Is |
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| 06:23 | all of the excitatory and inhibitory impacts going to get integrated by the soma |
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| 06:29 | the soma. That is exciting enough fire an action potential at the accident |
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| 06:34 | segment. So the closer you are the soma, the more direct impact |
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| 06:41 | have on the integrated properties and if inputs are located distantly you will have |
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| 06:48 | have much stronger inputs distantly in order exert the same effect on the basically |
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| 06:56 | integrative unit of the cell which is selma. Now this looks familiar now |
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| 07:09 | that you can see this image, see this parameter cells just turn them |
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| 07:13 | down. Sp stands for stratum dahlia layer S. R. For straddle |
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| 07:23 | Otto sl for stratum orients. So can see the parameter cells in this |
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| 07:30 | the basal dendrites are at the top the long optical dendrites are depicted at |
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| 07:35 | bottom. And we talked about different right? And we said that during |
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| 07:41 | different rhythms the way they're created is different cells will produce their action potentials |
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| 07:49 | a different oscillate ori cycle of this rhythm. And so this is an |
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| 07:55 | of the theta phase and theta rhythm the sharp wave of sharp ripple |
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| 08:05 | And what it shows you is wherever have read is the most intense neuronal |
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| 08:16 | . And what you can see is rhythm has a certain spatial temporal pattern |
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| 08:25 | certain map of activity over these three layers And that activity is divided between |
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| 08:36 | layers first pyramidal acted later orients and ready autumn active during the trough. |
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| 08:48 | during the actual very peak of the cycle, the blue is inhibition. |
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| 08:56 | what this shows you is a spatial pattern of activation across the layers. |
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| 09:03 | that ongoing oscillation of the theta rhythm theta phase on the right. You |
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| 09:10 | see that that image, even the image is very different and the rhythm |
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| 09:17 | very different in this case this is very fast sharp ripples rhythm. And |
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| 09:22 | can see majority of the peak signal in the parameter layer and most of |
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| 09:29 | peak signal is synchronized across three layers the same time. So you have |
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| 09:39 | blue and red represent minimal and maximal respectively. So in this case minimal |
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| 09:47 | blue and red is maximal inhibition. in this case we're looking at the |
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| 09:54 | of the inhibition across the legs but could be looking at the strength of |
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| 09:59 | . Also the figure is based on recorded and drug free rats or mice |
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| 10:05 | the exception of those the stratum The strata already adam input shows a |
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| 10:10 | increase during sharp wave ripples because the rate of the stratified cells but not |
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| 10:17 | of ivy cells increases. So you have to notice for the test of |
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| 10:22 | stratified cells versus ivy cells. But they're describing is basically because these different |
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| 10:29 | cells will fire different types of the . It influences the spatial temporal pattern |
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| 10:36 | the overall rhythm that is being Uh huh Some alarm cells and mice |
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| 10:46 | their firing way during sharp wave So, alum cell is something we |
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| 10:50 | in the previous slide here. This the alarm cell. But these two |
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| 10:55 | I'd like for you to know the cell because this is basically well, |
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| 11:00 | types of inhibition pretty much described. forward versus feedback basket cell is the |
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| 11:07 | that is per somatic inhibition and then lamb cell is the one that has |
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| 11:12 | dendrite inhibition. So computational lee, different. Their effect on the integrative |
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| 11:18 | of parameter salsa is different than their there in different phases. Data phase |
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| 11:24 | phase or sharp waves and ripples. going to be different as well. |
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| 11:30 | one more time, this is the , right? This is ripples |
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| 11:36 | And there are different types of You don't necessarily need to know what |
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| 11:42 | of cells they are. But in is parameter cell, this is a |
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| 11:47 | cell and green. This is all style and purple. So let's just |
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| 11:55 | on those three because we're talking about three cells and we're talking about so |
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| 12:00 | these cells behaving during the rhythm. cells fire at the very peak uh |
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| 12:09 | of the ripple rhythm. And so basket cells. So it seems that |
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| 12:15 | this rhythm during the very peak rhythm , you have synchronization across parameter cells |
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| 12:23 | their probability of firing increases tremendously. you have synchronization and very high probability |
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| 12:31 | firing and basket cells. But what alarm cells? Alarm cells during the |
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| 12:40 | center portion of this ripple are silent instead they have much higher probability of |
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| 12:51 | right preceding the largest amplitude phase of sharp ripples. And then following that |
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| 13:01 | . So those three cells synchronize at parts. Okay Now this is I'm |
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| 13:20 | skip this this diagram here but it 123456 cortical layers. And how do |
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| 13:28 | know remember? How do we know these are different cells that we're picking |
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| 13:32 | information from? And how do we this in Viva recordings we have to |
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| 13:38 | these sophisticated micro electors a lot of that we'll have multiple recording sites we |
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| 13:43 | to use triangulation. We have to typically more than one experimental technique to |
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| 13:49 | that you did record or picked up from. Elam cell versus basket cell |
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| 13:56 | parameter cell. Now, once you all of that information from those electors |
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| 14:00 | you can study the probability of firing these different cell subtypes and you can |
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| 14:07 | deriving what cells are active where during portion of the active ongoing rhythm oscillation |
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| 14:16 | the network. That's pretty neat because you look at E. G what |
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| 14:20 | talked about it's all filtered signal. have these waves. So how do |
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| 14:24 | get to the cellular underpinnings of what's on with that theater rhythm. And |
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| 14:30 | the only way you can do it have to record from as many cells |
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| 14:34 | possible. Individual cells recognize them as units based on their actual potential properties |
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| 14:41 | on the triangulation. And then you also do wholesale recordings of multiple cells |
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| 14:48 | vitro. And confirm that in Put the lectures in vivo, confirm |
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| 14:53 | in vivo. You know have a in Australia do the same work. |
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| 14:58 | he says yes I agree with you know about another cell that's active during |
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| 15:03 | rhythm. And that's how the scientific happens. And the solutions come about |
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| 15:09 | signals that you you know you observed . G. Signals being observed for |
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| 15:15 | of years. And what are the mechanisms of these different rhythms? Is |
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| 15:21 | emerging in the last 2030 years and emerging with our ability to subside different |
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| 15:29 | cells record from them, recognize them on their functional properties, member and |
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| 15:34 | and so on. And then figure what they contribute to different rhythm |
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| 15:42 | This is uh frequency spectral dynamics of E E. G. Because the |
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| 15:48 | would be so how do how did come up with these bands Of |
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| 15:54 | Right. Who said Why is it ? Who would give that cut off |
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| 15:59 | ? Why not 5-6? What about ? Why is why is gamma 32 |
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| 16:08 | 50. Slow gamma fast gamma is to 80. So what you do |
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| 16:16 | this is called spectral analysis where you frequency on the Y. Access. |
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| 16:24 | this is low frequency Mhm. And can see that during R. |
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| 16:31 | M. Which is rapid eye movement . But this is how you could |
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| 16:36 | these E. G. Recordings. pick up low frequency signal here where |
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| 16:43 | see really dark. It says And waking arrows indicate volume conducted. |
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| 16:51 | frequency 7 to 9 hertz, oscillation the underlying IPO cameras, bottom furrier |
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| 16:59 | of lump epochs. We won't get into these details here but you're basically |
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| 17:06 | R. E. M. Slow sleep and exploration and you're basically extracting |
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| 17:15 | power. How much power the more there isn't that within that frequency range |
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| 17:23 | darker you will see the signal So on the Y axis you have |
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| 17:28 | on the X axis. You have in seconds, long duration 2000 seconds |
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| 17:36 | . And you're recording the E. . Activity. R. E. |
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| 17:40 | . Sleep slow wave and then wake and explore within that time period. |
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| 17:48 | . E. M. Has this in low frequency component, the 7 |
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| 17:53 | 9. But it also has the in the gamma range here. 30 |
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| 18:01 | 60 hertz right here. You see over time there's a lot of that |
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| 18:06 | that there's other frequencies on going anywhere seeing basically any gray here is the |
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| 18:13 | that indicates the strength that so there frequencies that are ongoing with these are |
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| 18:19 | frequencies during R. E. Sleep and during slow wave sleep you |
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| 18:23 | see it changes, you lose this frequency here. It's not not really |
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| 18:29 | prominent here anymore. And slow wave seems to be covering this broader range |
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| 18:36 | slow to about 2030 hertz. And active exploration. You engage the low |
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| 18:43 | the theater rhythm and then you engage fast gamma rhythm. So these kind |
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| 18:51 | a spectrograms off widened cortical L. . B. It's called local field |
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| 18:59 | recording. So in local field potential E. G. Recordings, your |
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| 19:05 | activity from the skull. Local field are extra cellular recordings that are going |
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| 19:14 | be picking up activity from thousands or of cells that are in the vicinity |
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| 19:21 | this recording electrode. So those are field potentials. And on the cellular |
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| 19:28 | there's a network response. So these not whole cell recordings are not single |
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| 19:32 | recordings. They're picking up activity from number of cells in the region of |
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| 19:39 | where you place that electorate. So you can confirm some of these frequencies |
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| 19:45 | some of these rhythms using extra cellular field potential recordings. But so this |
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| 19:53 | how we've come up with the segmentation these different rhythms and the system the |
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| 20:00 | system from really slow to really fast there is more power in these particular |
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| 20:08 | during different behavioral stays. And that's we equate now, different rhythm means |
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| 20:16 | different behavioral state. Okay, so excitation and inhibition, we wouldn't have |
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| 20:28 | rhythms and without excitation and inhibition and the cells being plastic and have the |
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| 20:44 | to have plasticity. We wouldn't be good at learning and forgetting things. |
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| 20:55 | this weekend I learned that there were unidentified flying objects that were shot down |
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| 21:06 | no threat to national security. Just . Why should there be a |
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| 21:13 | But there's a word alien that is mentioned and that is very, very |
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| 21:20 | . Just think as humans, we to think of the way we think |
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| 21:23 | maybe our brains are not plastic enough . So we get set in our |
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| 21:29 | ways of thinking that it's a spying. They're gonna do something |
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| 21:35 | And I'm just wondering if we had code of plasticity that introduced us to |
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| 21:42 | code of plasticity. We, as would be able to understand things differently |
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| 21:48 | maybe understand that maybe we're on the to like self destruction and that's why |
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| 21:53 | of these flying objects are coming around they're looking at us like ants that |
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| 21:59 | about to destroy and and pile that's affect the whole forest and they are |
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| 22:04 | of the forest. And so they're , we have to do something about |
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| 22:09 | and help them, you know, we had that discussion. So it's |
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| 22:15 | we have certain rules and ways and know, we're learning things because of |
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| 22:21 | way we are brought up our Will we know? But then if |
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| 22:27 | fed, you know, for 20 , there's no aliens, There's no |
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| 22:31 | . And then on year 20 there's congressional program study UFOs if we're seeing |
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| 22:36 | several unknown a weekend, you You know, it's it's it's |
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| 22:47 | So synoptic plasticity, What synaptic plasticity enables adaptive experience brain based brain |
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| 22:59 | learning and memory. Experience what we're to, what we believe in, |
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| 23:04 | we uh set, you know, say alien. We don't know what |
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| 23:08 | is. And then what if somebody you five years ago? You can |
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| 23:11 | alien, there's aliens all over, know, like well what happened to |
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| 23:15 | five years ago? It's progress. it's evolution. Things change. That's |
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| 23:22 | they always fluctuate around that line, they could be even periodic, but |
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| 23:26 | still moving forward. And it's experience it's adaptive. We have to adapt |
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| 23:33 | humans to learn. We have to as humans to forget. We also |
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| 23:39 | to repair the injury in the And plasticity contributes to injury repair and |
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| 23:50 | a lot of times to either halt disorders. So adapt to the circuits |
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| 23:57 | that are normal and try to tame neurological disease and disorders or they somehow |
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| 24:05 | participants in generating abnormal neurological activity And prison optically you release neurotransmitters posson |
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| 24:18 | . You have deep polarization through You have influx of calcium and a |
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| 24:24 | of this synoptic communication is happening at level of the dendrites and dendritic |
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| 24:31 | And if the synopses active and it being active. So this pre synaptic |
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| 24:40 | fires, fires and action potential releases this post synaptic neuron is getting d |
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| 24:47 | and it's reactive to the pre synaptic then this synapse may become potentially |
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| 24:56 | What does it mean potentially ated? you could actually have a greater number |
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| 25:02 | neurotransmitters that are being released. More neurotransmitter release of higher availability of the |
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| 25:11 | Or in number two you can have greater number of Pazin optic receptors that |
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| 25:18 | make available. And that would two in which that synapse can become |
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| 25:25 | So right off the bat that can pre synaptic mechanisms and there can be |
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| 25:32 | attic mechanisms. Well mostly focus on synaptic mechanisms of synaptic plasticity. But |
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| 25:39 | synopses now potentially ated. It strengthened in many cases you can even build |
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| 25:47 | develop new synopses, especially new dendritic . And if this synopsis strengthened now |
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| 25:56 | much smaller or less a stimulus may sufficient enough to get the same post |
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| 26:02 | response. If you increase the number receptors you can release the same amount |
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| 26:08 | neurotransmitters but your post synaptic response may much stronger. So potentially ation is |
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| 26:15 | cellular mechanism for learning for strengthening new . Uh and the cellular substrate for |
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| 26:27 | . Depression on the other hand would the opposite where you weaken the synopsis |
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| 26:33 | what you're seeing here in one and , you could have the opposite in |
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| 26:38 | depression situation, not enough neurotransmitters being or the post synaptic site doesn't contain |
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| 26:47 | of the post synaptic receptors, not much as it would like. And |
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| 26:52 | the response in that synapses weekend or , it's also a very important uh |
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| 27:01 | in the brain. Depression could then likened to forget it and forgetting is |
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| 27:10 | important mechanism of survival for human If you have a really bad personal |
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| 27:20 | physical experience, it is actually to advantage to get over things which is |
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| 27:30 | forgetting or changing the plasticity in the so that not as much of the |
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| 27:37 | spent on something especially negative. depression and forgetting is especially important for |
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| 27:46 | that have negative associations, negative emotions with. Right? Yes. |
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| 27:58 | But then you can call it up we'll talk about that in a |
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| 28:02 | So the person that really started talking synaptic plasticity was ramon alcohol. He |
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| 28:09 | doing the drawings of golgi stain neurons he showed that there is connection between |
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| 28:17 | with arrows. And he said that connections are not rigid. He described |
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| 28:24 | not set in stone. So they're and it was in the 19 |
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| 28:31 | So ra Monica Hall is in the of the 20th century. So another |
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| 28:36 | 40 years when this concept of synaptic starts coming about and starting to take |
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| 28:46 | cellular shape of explanation of what is . What does it look like |
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| 28:55 | There is no visualization of the there's no recording of L. |
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| 29:01 | P. Or potentially a shin or . T. D. Long term |
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| 29:06 | . So it comes from the work psychology donald Hebb when an accent of |
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| 29:14 | A repeatedly or persistently takes part in Selby. Some growth process or metabolic |
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| 29:23 | takes place in one or both such as a sufficiency as one of |
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| 29:30 | firing B. Is increased. So came up with his theory basically and |
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| 29:41 | it talks about how there is substantial for his work laid later for |
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| 29:49 | T. P. And L. . D. Potentially ation and depression |
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| 29:53 | did not explicitly propose a rule for reverse spike ordering. But experiments indicated |
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| 29:58 | many synapses repeated activation of pre synaptic A immediately after post synaptic cell |
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| 30:05 | Leads the timing dependent long term depression these are traffic rules are known as |
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| 30:11 | timing dependent plasticity. So we'll talk different types of plasticity but he did |
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| 30:18 | essentially that it's about communication between And B. It's about repeated |
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| 30:25 | Once that repeated firing. Something happens these cells to signal to strengthen and |
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| 30:32 | lot of explanation is also that the is important for pre synaptic and post |
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| 30:39 | cells to strengthen. To bind their together. The timing is important. |
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| 30:44 | the spike timing dependent plasticity becomes an subject matter in the 80s and |
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| 30:51 | mostly Mostly in the 90s. So and plasticity and this is a memory |
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| 31:06 | as it would be represented by. cell assembly and activity of that cell |
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| 31:16 | is like an engram. So cell simultaneously active neuron responding to the same |
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| 31:26 | . So let's say this is cell . Each one of these dots is |
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| 31:32 | cell and those cells are reciprocally connected each other and you will have a |
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| 31:39 | of reciprocal excitatory connections in the abdominal and the cortex and the hippocampus. |
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| 31:46 | you have a cell assembly here and is an external stimulus that specifically activates |
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| 31:54 | small network of cells and activation of cell assembly by the stimulus here. |
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| 32:04 | the stimulus happens there is reverberating continuous activation after the stimulus is |
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| 32:14 | Then he proposed So once the stimulus happening and it registered within the Ingraham |
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| 32:21 | a little bit of what we called activity in the assembly of the |
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| 32:27 | This reverberating activity will later named short plasticity or S. T. |
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| 32:36 | Now this is what you said about and modification strengthens the reciprocal connections between |
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| 32:44 | that are active at the same So according to this this heavy and |
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| 32:50 | would be a growth process that that the communication. The strengthened connections of |
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| 32:59 | self assembly contained the end ground with stimulus. So let's say this is |
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| 33:04 | donut. There's a stimulus for a and there's assembly of yourself that sees |
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| 33:09 | donut all the time. But at I didn't know what donut was. |
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| 33:14 | you see the donut and it's also donut donut donut. Then there's information |
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| 33:21 | donut, there's a donut out there the world someplace. So next time |
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| 33:28 | shows you pieces of donut okay your and Graham says don't doesn't even need |
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| 33:37 | see the whole full donor. It's same stimulus, not external stimulus but |
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| 33:44 | incomplete and it's segmented but your association the cell and Graham after learning partial |
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| 33:51 | assembly leads to activation of the entire of the symbol circle or donut if |
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| 33:58 | may. So there has to be activity because he's talking about when an |
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| 34:07 | repeatedly or persistently. So that activity to be strong, has to be |
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| 34:13 | . Has to be persistent activity into network. And now you have this |
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| 34:20 | grim recall with just a partial A good example if you think about |
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| 34:27 | stimulus, there are these trivia games that song, A lot of really |
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| 34:35 | people. It takes 3, 4 . Sometimes you know maybe more than |
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| 34:43 | knows. Maybe you know 10 knows it's not a full song that the |
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| 34:48 | heard but what happens in the person's . They sing the song inside the |
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| 34:54 | . The lyrics come out and they recite it. So this is the |
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| 34:58 | is the Ingraham and this is how came about with explaining if he doesn't |
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| 35:04 | what that process is in the late . So you think that some metabolism |
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| 35:09 | persistent activity going on there. So engram was wide distribution among the cell |
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| 35:19 | . So there isn't one typically one where stimulant and association for n grams |
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| 35:28 | . Maybe you have several areas that recognize donut or will back up the |
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| 35:33 | gram of the donut or there are that are similar to donut, bagel |
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| 35:41 | donut and they will not be found the same place. It's not the |
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| 35:47 | assembly. Uh and this wide So you get wiped out the donut |
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| 35:54 | of your memory. You still can by by recognizing a circular piece of |
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| 36:00 | as something that you can eat. not be sweet, but then it's |
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| 36:04 | bagel. So it could involve the neurons involved in sensation perception. That |
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| 36:10 | that maybe some of these assemblies processing and bagel are gonna share some of |
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| 36:18 | components, cellular components to create. or so widely distributed. But there |
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| 36:28 | be overlapping activation of neurons. So neuron could be a part of the |
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| 36:32 | and bagel and graham and maybe bayonet . Who knows? So these are |
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| 36:44 | of the techniques that we typically used record cell activity. And this is |
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| 36:51 | the patch we put an electrode, talked about this, we can patch |
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| 36:56 | the south. And what's really cool that In the 90s the microscopy and |
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| 37:07 | recordings got pretty sophisticated where people started dendrites. So instead of just recording |
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| 37:17 | Selma's, people started recording from And then there were crazy that started |
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| 37:24 | from accidents Because the down drive is 1-2 micrometers in diameter. An axon |
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| 37:32 | typically one micrometer or less in diameter it's insulated, it's much more |
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| 37:39 | So why did we want to do recordings? Because we kind of wanted |
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| 37:44 | know what happens when the soma fires action potential? What happens in |
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| 37:48 | Down your idea if we were recording dendrite? So these are called dual |
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| 37:55 | recordings. It's the same cell with electrodes showing you in inflorescence too. |
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| 38:03 | huh. And so what we saw when we evoke an action potential here |
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| 38:15 | the soma. So this is from article that is in your reading materials |
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| 38:22 | blue, it's our somatic stimulation and . But what we do is in |
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| 38:30 | soma, we produce the action So what happens in the dendrite, |
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| 38:36 | know that once we produce the action , the point of the action potential |
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| 38:45 | gets generated here is to propagate down axon and then finally produce itself. |
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| 38:59 | the axon terminal where it's going to involved with neurotransmitter release. So this |
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| 39:06 | forward propagating spike gets produced here. gets reproduced in each note of randhir |
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| 39:16 | it gets reproduced here. And so function of the spike travel down the |
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| 39:22 | and cause neurotransmitter. And until we the ability to record from Denver as |
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| 39:30 | didn't know what was going on Denver adds, there was very much |
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| 39:34 | about, you know, stimulate the neurotransmitter release in the acts on record |
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| 39:41 | synaptic response at the level of the . And then these techniques come into |
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| 39:47 | . And the question was like, is the dendrite season in the actual |
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| 39:51 | was produced here. And I have electrode in the dendrite. What does |
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| 40:00 | done dried? See if this is an action potential here. What does |
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| 40:04 | done dried sea? And so there in the den dried portion of the |
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| 40:11 | that travels from here and at the of the dem ride, you'll report |
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| 40:17 | smaller deep polarization and it is back . This is forward propagating and this |
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| 40:26 | back propagated into the damn rise. signal coming from here is released neurotransmitter |
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| 40:38 | . It's back propagating action. So is pretty neat. We can record |
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| 40:58 | and uh back propagating spikes. So why does this become important? Because |
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| 41:05 | becomes important for for spike timing dependent is the main form of cellular |
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| 41:12 | Uh probably most advanced that we can to date unless this flying objects are |
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| 41:19 | help us. Um So what's happening . We talked about how there's a |
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| 41:31 | of inhibition that is paris somatic. there's a lot of inhibitory somatic neuro |
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| 41:37 | that happens around so much as a of excitation is actually excited to. |
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| 41:42 | synopsis are distilled a lot of So axon initial segment is the portion |
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| 41:50 | the axon that's responsible for generating the in the back propagating spike. It |
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| 41:57 | the forward propagating spike by opening A. V voltage gated sodium channel |
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| 42:06 | which is low threshold channel. And means it requires low levels of |
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| 42:13 | And this n. is actually going initiate the forward propagating action potential which |
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| 42:19 | cause the neurotransmitter release. And these . a. d. 1.2 stand |
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| 42:26 | voltage gated sodium channel 1.2 which is high threshold. So it requires more |
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| 42:35 | polarization and it will only get activated the action potential gets produced by |
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| 42:42 | a. d. 1.6. And these n. channels and the influx |
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| 42:49 | sodium through them will generate the back action potential. And you can see |
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| 42:57 | that back propagating action potential is going be much smaller than the forward propagating |
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| 43:03 | potential. It's actually going to died over distance too because down rights and |
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| 43:10 | most are not insulated like axon So because the Navy will we do |
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| 43:20 | were bypassed by the initial synoptic deep there available for activation. So after |
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| 43:26 | channels have been activated, these channels available for activation and that's what produces |
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| 43:32 | back propagating action. So excellent initial will contain high densities of voltage gated |
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| 43:40 | channels and potassium channels. The influx sodium will cause the deep polarization during |
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| 43:45 | action potential. And the forward spike produced by low threshold both educated sodium |
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| 43:52 | and the back propagating spike is produced high threshold. Both educated sodium |
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| 43:57 | Both are located within about the same of the excellent initial segment of the |
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| 44:16 | . Okay, so you can have electrodes in the dendrite if you want |
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| 44:23 | and see how the signal deteriorates from selma's all the way into the distal |
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| 44:30 | . When you produce an action Leave this article is in your |
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| 44:48 | Gonna make sure it's in your But it talks about spike timing dependent |
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| 44:55 | and why am I talking about spike dependent plasticity. It's It is a |
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| 45:00 | cellular model for behavioral learning and memory rich computational properties. So let's try |
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| 45:10 | understand it before we understand what all this is. And we need these |
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| 45:15 | in order to understand the spike timing neurons. Spike timing and dendrites. |
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| 45:20 | the amplitude of that deep polarization and rights, not just axonal terminal. |
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| 45:27 | let's go back to the original studies mechanisms our hostess city and after half |
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| 45:45 | these population of and Graham reverberating activity 1940s 1950s then people started targeting shop |
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| 46:02 | collaterals. This was the main top that goes from C. A. |
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| 46:07 | in the hippocampus to see one area you have a lot of the parameter |
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| 46:16 | . Uh huh. C. This is super collateral projections. And |
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| 46:27 | way that that experiments were done where was a stimulating electrode on these shopper |
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| 46:42 | and there was a local field potential which is picking up activity. If |
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| 46:51 | put it in the parameter cell layer to 90% of the cells from Parameter |
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| 46:59 | . So you produce little stimulation You shocked these fibers electrically with a |
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| 47:09 | electrode. And what you do is cause the release of the neurotransmitter |
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| 47:17 | And with this local field potential you up a small signal so you stimulate |
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| 47:27 | and then you record this is your and this is your reporting. So |
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| 47:35 | called local field potential recordings in the by stimulating the shop of collaterals recording |
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| 47:42 | single cell recording network activity. Okay now we can look at it this |
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| 48:11 | this is amplitude. Hey miller balls say of the local field potential. |
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| 48:27 | ? And this is baseline. So time you stimulate you record your |
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| 48:37 | Okay and every 15 seconds you stimulate record a response and there's a little |
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| 48:44 | of variability in this response. But all lingers around this baseline. You |
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| 48:52 | stimulate every 15 seconds And you do because it takes about 12 seconds for |
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| 49:02 | to fully re establish themselves with neurotransmitter you get this stable local field attention |
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| 49:12 | then people lost the squash. And if we deliver different frequencies stimuli to |
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| 49:19 | network of cells? Is it going change the attitude of the local field |
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| 49:27 | ? This access we have time. so people come up with a number |
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| 49:35 | stimuli in this this is like can likened to condition it. So now |
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| 49:51 | gonna produce some different stimuli. Instead just sampling the baseline every 15 seconds |
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| 49:56 | recording field potential, you're gonna do different for a minute or two or |
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| 50:01 | minutes. And that different at first very high frequency stimuli. Okay that |
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| 50:11 | repeated and there were one second so long high frequency stimulated were |
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| 50:19 | Following that You go back to sampling 15 seconds again And this is 100 |
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| 50:31 | stimuli that gets repeated through this electrodes of the single stimulus. And sampling |
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| 50:38 | single stimulus and sample you jolt this frequency and you repeat it. We |
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| 50:46 | trains of high frequency activity. And you go back to the same. |
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| 50:52 | well let's see what happens because now imitated some sort of encoding of an |
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| 50:58 | and this local cellular network. Let's what happens. And people discovered that |
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| 51:04 | this is 100% baseline. They discovered the signals would potentially eight and they |
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| 51:13 | stay potentiality ID. Or increased in for a long time so it can |
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| 51:21 | potentially ated and stay like this for . So people were wow this is |
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| 51:33 | cool because we are potential rating the . There's something very special. And |
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| 51:41 | me people played with different frequencies. played with you know 20 hertz and |
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| 51:48 | hertz. And it calls different things 100 hertz in this capital start but |
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| 51:53 | to have been very effective. It a long term change and potential hated |
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| 52:00 | . You're not talking about a single earlier with the potential hated signal to |
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| 52:04 | what we would call the engram in hat wow So now this conditioning can |
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| 52:19 | different and instead of 100 hertz this here you can repeat it but instead |
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| 52:28 | gonna produce stimuli once every second. 100 Hz. Because this potentially |
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| 52:39 | The question is if I do this stimulus of one hertz What does it |
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| 52:47 | ? This conditioning is it do the thing potentially eight. And they've discovered |
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| 52:52 | this protocol to process the synopsis causes is called long term potentially ation or |
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| 53:05 | and this is called long term depression L. T. D. So |
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| 53:11 | can imagine how exciting this was because have found a code for ballistics city |
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| 53:23 | it seems to be pretty simple. frequency depressed I frequency 100 herds potentially |
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| 53:32 | . And so this became a rate and there's some truth to it. |
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| 53:39 | rate and stimulation can resolve in either ation or depression. L. |
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| 53:47 | P. Or L. T. . However it is not as simple |
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| 53:50 | one hurts. Does this 100 Does this all the time and all |
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| 53:54 | circuits. It depends on the circuits specifically addressing this in the shop and |
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| 54:00 | in the C. Three to One. Because that's where people did |
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| 54:04 | lot of these studies and that's why lot of electro physiologists for the next |
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| 54:08 | years went back in the same circuit the hippocampus because there were glimpses of |
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| 54:14 | for the rate code or the stimulus of the stimulus, the response and |
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| 54:19 | potentially ation. Okay then we are something here because this conditioning response |
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| 54:31 | This conditioning stimulus which you produce as experimenter but you're trying to mimic something |
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| 54:39 | . Have said that during this conditioning there's something going on right? You |
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| 54:47 | about reverberating activity. So if this long term potentially ation or long term |
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| 54:57 | that means that whatever stimulus conditioning stimulus produced here caused a long term change |
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| 55:06 | the synaptic functioning in this network long increase long term decrease and it persisted |
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| 55:12 | hours and this actually can persist for and weeks. So certain stimuli once |
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| 55:20 | activate those N grams they can That minimal activation. That's how you |
|
| 55:26 | . Well on the test you still the reverberating buzzing activity. You hit |
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| 55:32 | it with accused and the questions on test and you recall the in |
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| 55:37 | you tried to do it four months you can't because you're in a different |
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| 55:42 | and your activity is no longer Now if you went back and stimulated |
|
| 55:47 | same engram a couple of times boom be back on top again. You |
|
| 55:52 | recall it unless it's been too long it's really complicated or you just studied |
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| 55:57 | for you know to get a grade get over it. So but so |
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| 56:01 | you have this long term but what happening during the conditioning stimulus reverberating |
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| 56:11 | And it turns out that certain cells certain pathways during this 100 hertz stimulation |
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| 56:22 | keep increasing and increasing and increasing In polarization. So this is 100 heart |
|
| 56:32 | . Okay you just start increasing in deep polarization. So this is called |
|
| 56:48 | . Okay thank you. That can in hippocampus. That can happen in |
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| 56:54 | cortex and by the way everything that talking about. So it was discovered |
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| 56:58 | hippocampus and studied in hippocampus. Yes can evoke ltp in visual cortex if |
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| 57:04 | do 100 hertz in certain back So where and how these rules apply |
|
| 57:11 | what circuits is still under investigation. we're just basically getting a glimpse of |
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| 57:16 | cellular rules of how they how things . So you have facilitation. But |
|
| 57:21 | what? Like you said in what that happens because in another circuit the |
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| 57:27 | 100 hertz stimulus that you're getting here cause a short term depression. So |
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| 57:41 | same duration, the same 100 hertz . But at the end you've actually |
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| 57:47 | the signal and made it much smaller it was at the initial phases |
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| 57:53 | Now your signal is much smaller. so this is what is happening during |
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| 57:58 | conditioning stimulus. This is sort of reverberating activity according to have, which |
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| 58:06 | now call short term plasticity, short plasticity STP versus long term plasticity, |
|
| 58:17 | term facilitation, short term depression. , so this is short term |
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| 58:24 | This is short term depression. This only during the stimulus and this stimulus |
|
| 58:31 | conditioning stimulus as for Minutes Let's say minutes. This information, facilitation depression |
|
| 58:40 | for minutes typically. What's a good phone number? 7137431618. Okay, |
|
| 58:47 | , dialed it minutes later, no . 71374316.85 minutes later, What was |
|
| 58:56 | again? 7137431 What? So you remember and that's only lasting there per |
|
| 59:05 | . So during that stimulus, that and you're being stimulated, remember this |
|
| 59:10 | now you're gonna dial it but it's relevant for you five or 10 minutes |
|
| 59:14 | . So maybe that stimulus wasn't strong and didn't encoded long term just encoded |
|
| 59:22 | facilitated for you to remember a short or forget it short term too And |
|
| 59:28 | what you would have another number coming your head and you will be suppressing |
|
| 59:33 | information from the (713) 743 1618. so now we understand that there are |
|
| 59:42 | term and short term plasticity. Short plasticity can be likened to short term |
|
| 59:49 | . You meet people know their you forget their names unless you're meeting |
|
| 59:54 | over and over and over then they're they're finding their way to long term |
|
| 59:58 | . They are no longer here and conditioning stimulus then you can be |
|
| 60:05 | Your name is B. Brand That's right. Brandon be in that |
|
| 60:10 | the Brandon and grand. So this what these field potentials would look like |
|
| 60:18 | the stimulation of the of the network this schaffer collaterals cyclists does happen as |
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| 60:32 | either get locked in that moment of we can be the hyper aggressive with |
|
| 60:39 | shut down completely. I don't know it was the real parallel to but |
|
| 60:43 | was such a thing of like this potentially ation trauma where you simply cannot |
|
| 60:51 | alarm the symptoms. And for for someone around like loud violence, |
|
| 60:57 | are veterans struggle with triggers. That does that that behavior of whether someone |
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| 61:04 | hyper aggressive to that becomes completely shut and points out, is there a |
|
| 61:11 | to it being this long term But even though it's longer, potentially |
|
| 61:16 | that depend on the network that depends the behavior to determine. But I |
|
| 61:20 | know if that's if you repeat it this is what happens with the traumatic |
|
| 61:29 | . We're talking about veterans ptsd you , you know, people having to |
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| 61:33 | the bomb shelter and brace for then it will be there long term |
|
| 61:41 | now how that happens when people shutting . It's almost a protective mechanism to |
|
| 61:49 | that is maybe the opposite of depressing memories and and and and you |
|
| 61:58 | it's a it's a it's a it's psychological, it's a mental process |
|
| 62:03 | But yeah, but also Yeah, . And people fall within certain dynamic |
|
| 62:14 | , just like somewhere better learners, learners, others take forever to |
|
| 62:18 | But then once they do they're maybe at the quicker learners. Like it's |
|
| 62:23 | it's different. Um but it's a a good way to think about |
|
| 62:27 | Now, if you may recall last , we watched the video by Ramachandran |
|
| 62:35 | he talked about learned paralysis which is phantom limb phantom limbs and go and |
|
| 62:44 | with physical injury, what's happening. had physical injury. You went through |
|
| 62:51 | massive conditioning stimulus in this case your sensory brains and not a sensory |
|
| 63:00 | what is it gonna do? You that's that phantom limb and phantom pain |
|
| 63:07 | learned paralysis because the arm is no there the pain is no longer |
|
| 63:12 | That's what's phantom but your brain thinks there. So yeah so it is |
|
| 63:18 | learned component both in physical injury or mental injury. Same conditions, same |
|
| 63:27 | still behave same condition within the same . It's different connectivity. Yeah that's |
|
| 63:40 | we're slightly different splice variants, synaptic of each other. Uh So there |
|
| 63:50 | a certain dynamic range by which people know will operate uh physically and mentally |
|
| 63:57 | try to you know deal with us to speak. You know. Uh |
|
| 64:05 | is also like an illustration here for you can see that during this fast |
|
| 64:10 | of stimulation. This is an individual field potential. And during the stimulus |
|
| 64:16 | can see that the yield potential is small so it's getting depressed. So |
|
| 64:22 | is just an illustration of what's happening this. For odd activity stimulation you |
|
| 64:30 | a gradual decrease in local may be by depression or maybe followed by potentially |
|
| 64:37 | because the outcome of the short term does not mean that it's gonna be |
|
| 64:43 | same outcome of the meaning that during stimulus you may depress the network during |
|
| 64:49 | stimulus. But then once you come to normal mode of operation, whoa |
|
| 64:55 | It shows an increase. There are situations where you will see a strong |
|
| 65:01 | and instead of getting LTP right away may get L. T. |
|
| 65:06 | For 10 minutes and then followed by . T. P. So you |
|
| 65:12 | depress the network and then so there's iterations of how this can happen. |
|
| 65:17 | is no linear relationship between what's happening the actual train of stimulus and whether |
|
| 65:24 | going to be. So during facilitation you may end up with a network |
|
| 65:29 | long term depressed. Yeah so short versus long term they're they're different different |
|
| 65:37 | different circuits were just trying to understand . Now. This is from the |
|
| 65:45 | book. Synoptic plasticity, timing is . So when enough synopses are active |
|
| 65:52 | the same time the past synaptic neuron be D polarized efficiently to fire an |
|
| 65:58 | potential nominal. Have proposed that each synapse grows a little stronger when it |
|
| 66:04 | participates in the firing of pasta haptic . The phenomenon of LTP comes close |
|
| 66:10 | satisfying heads ideal. Right ever since came out with that. And ground |
|
| 66:16 | like well how does it work? stimulate this, we get facilitation |
|
| 66:20 | Ation depression, What sells and so . So there's a whole uh thing |
|
| 66:31 | and this whole discussion of concerns, timing and how spike timing is very |
|
| 66:39 | for plasticity. In other words this a rate code, high frequency |
|
| 66:49 | Intensification, depression, low frequency Long term potential patient depression. But |
|
| 66:56 | mentioned to you earlier that what is I should take a picture for folks |
|
| 67:02 | are not here. The pre synaptic fires and the post synaptic neuron |
|
| 67:35 | This is pre synaptic action potential. pre synaptic and post synaptic you get |
|
| 67:44 | or boston optic potential for E. . S. P. It's a |
|
| 67:47 | response that you record post synaptic lee an electrode here. So now if |
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| 67:58 | stimulus is strong enough, what's going happen is the cell will produce the |
|
| 68:05 | potential. The self produces the action and it's going to cause their transmitter |
|
| 68:14 | down the axon. Yeah if the potential gets generated here this post synaptic |
|
| 68:25 | from the recordings you can record with propagating spike. So what becomes really |
|
| 68:38 | is these two cells are communicating to other. This is pre synaptic cells |
|
| 68:43 | to post synaptic cell in any You say something and you wait for |
|
| 68:50 | response. And the timing is important human verbal communication. Hello. And |
|
| 68:58 | expect that within less than a second will nod their head say hello. |
|
| 69:03 | it takes 23 seconds to start wondering the person heard you? 10 seconds |
|
| 69:08 | they pissed at you or something and it's irrelevant. So five minutes later |
|
| 69:16 | know you said hello, how are doing? You don't get a |
|
| 69:20 | Five minutes later a person says You look good what you forgot what |
|
| 69:25 | asked. So this this communication and is like not relevant anymore. So |
|
| 69:32 | can translate this into the neuronal cellular except that this is happening on the |
|
| 69:38 | of milliseconds. So this cell is and this cell never responds. Never |
|
| 69:45 | an action potential and never produces a propagating spike. This cell says the |
|
| 69:51 | with you. This is meaningless communication . And this response for neurons has |
|
| 69:56 | happen within 10 milliseconds. Or so pre synaptic cell inspiring post synaptic cell |
|
| 70:04 | and has back propagating spike the pre cell and the post synaptic activity now |
|
| 70:10 | their activity. Their binding it together synaptic synaptic character, pre synaptic synaptic |
|
| 70:18 | . So the spike timing the interactions wonderful synaptic cell fire. When the |
|
| 70:25 | synaptic self produced action potential in the propagating spike becomes very very important. |
|
| 70:31 | it becomes a new rule in plasticity learning which we call spike timing dependent |
|
| 70:40 | . Uh And here I jumped in term versus long term post synaptic versus |
|
| 70:46 | synaptic. But this is another mode learning. So what we learned today |
|
| 71:00 | I think that I'm out of time sufficiently. And we have a lot |
|
| 71:06 | cover for this plasticity lecture. So will leave what we learn uh for |
|
| 71:13 | exam up until now and then. new information will cover from the second |
|
| 71:19 | . I guess it took me longer explain this that I thought but what |
|
| 71:23 | some of the important things we learned we learned about plasticity. We learned |
|
| 71:29 | the in ground it. We learned the rate code LT. P. |
|
| 71:36 | L. T. D. Now me just show you one diagram here |
|
| 71:41 | address this. Yeah you asked Same network, same stimulus, Same |
|
| 71:52 | different stimulus. In one case we depression and one in another case we |
|
| 71:57 | potentially ation what's different. And so really good explanation is based on the |
|
| 72:06 | of calcium through an M. A. Receptor. Remember we said |
|
| 72:09 | an M. D. A receptor a coincidence detector, it allows for |
|
| 72:14 | to flux in and high frequency HFS produces high levels of calcium influx |
|
| 72:22 | that high calcium level turned on the kindnesses which was four late proteins in |
|
| 72:31 | of L. D. P. low frequency stimulation. Low levels of |
|
| 72:37 | . You actually facilitate protein phosphate Um phosphor relate synaptic proteins in your |
|
| 72:46 | L. T. D. So basically a rate code explain it based |
|
| 72:52 | the calcium dynamics. It's one possibility which you can explain it. So |
|
| 72:58 | is rape culture that we weren't. also learned that there is short term |
|
| 73:03 | sdp versus long term plasticity that we facilitation, short term facilitation, short |
|
| 73:10 | depression. And we have long term ation long term depression. We also |
|
| 73:16 | that the timing is everything actually for and the truth and the way the |
|
| 73:24 | code. The information falls in between spike timing and the rate codes. |
|
| 73:32 | really a combination of both. So actually do encode, learn information using |
|
| 73:38 | of these. But the rate code to be incorporated within spike timing and |
|
| 73:44 | this communication and the response. thank you very much. Uh I |
|
| 73:53 | talking about this stuff because we don't it really well and uh hopefully you |
|
| 74:05 | understand it better as more information comes in the next couple of decades. |
|
| 74:13 | think about it. 49 have thinks the psychology and Graham, There's not |
|
| 74:20 | voltage clamp in 49. So you these dendritic recordings in the 90s. |
|
| 74:28 | when I went to graduate school, recorded from down drive that was like |
|
| 74:35 | thing to do. And then we playing around with these frequencies in the |
|
| 74:41 | and local field potential is in the and then do all cell recordings and |
|
| 74:47 | timing in the nineties. This is progress every two decades or so. |
|
| 74:52 | reveal sort of a new learning rule which the brain functions. So that's |
|
| 74:57 | cool. That's why there will be rules in another two decades. |
|
| 75:01 | I'll see everyone on zoom on It's |
|
