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BIOL 6397 Cell Neuroscience Mo Wed 1-2.30pm - CELLULAR NEURO Lecture 10 Plasticity II
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00:01 Okay this is cellular neuroscience. Lecture . And we're going to continue talking
00:07 the plasticity neuronal plasticity. The rules this plasticity and the structures that we've
00:16 discussed. And continue discussing where this happens. Fortunately this is not very
00:22 . But we talked about short term short term plasticity. And we talked
00:30 long term plasticity under short term We talked about facilitation for depression.
00:42 for a long term plasticity we introduced started talking about long term potential
00:50 Well you can see oh did I because I appreciate it. So it's
01:07 of a here also actually I don't to drive. I can show it
01:11 you. So for long term plasticity have long term potentially ation the long
01:18 depression. And this is what we the rate cut. And we talked
01:23 how if you had one hertz frequency to these fibers In c.
01:30 one that you would good L. . D. And if you had
01:37 hertz jolts of stimulation along the same in C. A. One of
01:44 hippocampus you will get LTP. And this understanding of a rate code that
01:53 frequencies in code for memorizing information encoding the synopsis and continuous low frequency stimulation
02:03 weakens the synopsis of causes L. . D. Okay so that's uh
02:10 a simple kind of a nice explanation it's definitely incomplete. But then you
02:18 say so why did it persist? people did these experiments and the slices
02:26 the hippocampus. The C. one Schaffer collaterals in months. And then
02:33 did it in rats and then they to get some human tissue in the
02:40 after the surgery. And they did in humans. And they saw that
02:47 something to this role that every time would call the tissue with high frequency
02:53 that there would be a continuous sustained increased response within the same circuit.
03:00 that is exactly what donald have talked is a sustained process sustained response that
03:08 the in ground. So spike timing plasticity it's described here when enough synapses
03:18 active at the same time. The in optic nerve will be d polarized
03:22 to fire an action potential. So of these studies that we discussed here
03:29 looking at the size of excitatory post potentials were shocking. The fibers that
03:38 coming onto the cell of interest. and we are reporting from the cell
03:45 interest E. P. S. . S. If we're recording intracellular
03:49 for whole cell recordings. And we can record activity from multiple cells in
03:56 network here by placing an extra cellular electrode and picking up what is known
04:04 field E. PSP. Which is that is representative of many cells in
04:12 area of response of many cells in area. So an E.
04:17 S. B. Refers to a extra excitatory pasta not the potential
04:25 And it's a great response. It be smaller in size and the larger
04:29 size. You can be plastic and . This is the strength of the
04:34 ax E. P. S. . S. Can actually reach the
04:40 . Okay. They can reach that -45 million bald membrane potential threshold for
04:48 potential. And if the PSP strong ethical generating action for touching. So
04:57 that means is that in order for to generate a posse synaptic response,
05:05 is going to happen is that if shocking, let's say this is your
05:12 , mm hmm. And you're shocking fibers with electricity. And let's say
05:22 activate in very simple terms one synapse one synapse in C. N.
05:34 . produces approximately 0.5 million volt. PSP. Okay and the threshold,
05:50 say you wouldn't mind the 65 This is a very small the
05:58 If you activate it once in apps the release here and the signal that
06:04 recording is coming from this salary here the threshold for action potential is over
06:11 -45 kilovolts. And so it's not to activate. Once enough you have
06:20 activate many synapses. You have to multiple icicles. Many many many synopses
06:33 now summit. It's a great response . That's great. I remember at
06:43 same time these neurons and the stimulation turn on these inhibitory circuits that we
06:48 about feed forward inhibitory surface will be and making this response smaller feedback inhibitory
06:59 are going to be making this response . Alright so there's constant this
07:06 Even when you stimulate the shaft of and you're stimulating this major excitatory
07:14 It'll axons you know the anatomy from . A. Three coming in those
07:18 accents through schaffer collaterals. So you're that you are mostly submitting the excited
07:26 her response. And if you someday you some ain't enough, if you
07:33 enough of the synapses you will reach threshold but the action potential. So
07:44 is exactly what is being talked about that this is a single synapse.
07:51 Melon balls. Central nervous system synopses not very reliable. You need to
07:59 tens of the synapses, tens of fibers, axonal fibers and synapses in
08:05 to reach the action potential. Person . So when enough synapses are active
08:13 the same time the post synaptic neuron be d polarized efficiently to fire an
08:17 potential. Donald have proposed that each synapse grows a little stronger when it
08:23 participates in the firing of the post neuron, meaning that there is an
08:29 and there is no response. Post responses. This relationship is not very
08:34 . The phenomenon of LTP comes close satisfying heads ideal. The synapse gets
08:39 when the glutamate released by the pre terminals binds to post synaptic NMDA receptors
08:44 the process synaptic membrane is too polarized enough to displace magnesium block from an
08:50 . D. A receptor channel. there's no influx of sodium and
08:56 If there is a role is there a role for prostatic action potential in
09:01 strong deep polarization. The first evidence appropriate timing Of post synaptic action
09:07 Mind be important for DP was obtained the early 1980s. They found that
09:12 occurred in the post synaptic action potential simultaneously with or slightly after pre synaptic
09:19 of glutamate. So what are You can you can you can read
09:27 on your own through this page. not gonna read through everything but I've
09:32 explained this basic principle here is that you have a meaningful relationship you have
09:38 have a strong enough of the activation that cell or that network and you
09:43 for that cell or that network to with an action potential. So that's
09:48 basic principle. Now the second thing you expect is you expect that self
09:53 respond with an action potential fairly And this is where the spike timing
10:00 timing between when there is activation of pre synaptic signal and how long does
10:05 take for this post synaptic cell to polarize enough to produce an action potential
10:10 this time period two milliseconds five There's a synoptic delay. So between
10:16 time when you release neurotransmitter here it across the synapse bind stamp and India
10:23 receptors de polarize the cell. We're about 5, 10 milliseconds, 50
10:28 delay. Now this is still right? But what if the cell
10:34 doesn't respond for 100 milliseconds? It's times longer than the usual communication.
10:42 should take place. So what happens you're listening to somebody and all of
10:47 sudden they stopped talking and they talk we their their their frequency of talking
10:54 down 10 times 10 times less than they were talking about. It's very
11:00 it still meaningful? Is that at point there is you lose attention.
11:07 now mechanisms of short term plasticity. let's before we talk a lot about
11:12 counting dependent plasticity and more about this term plasticity as well. Let's talk
11:18 the mechanisms. So on the pre side you can have increases in calcium
11:25 in the pre synaptic terminals. You also prime the neurotransmitter vesicles so that
11:35 more available. And by priming and them closer to the active pre synoptic
11:44 . You are facilitating the fusion dynamics that bicycle to the pre synaptic memory
11:51 messenger control. Pre synaptic lee. there is uh pre synaptic lee that
11:59 looked at the retrograde controlled by the messenger. When we looked at gaba
12:05 we said that if you have pre gaba b they're called order receptors.
12:10 this is in the case of So you can pre synaptic lee through
12:14 retrograde messenger activation. You can also retrograde signaling through endocannabinoid. So other
12:24 that may exit personality thickly. And in the cannabinoids, those are lipid
12:31 neurotransmitters. Those are gasses and they travel prison optically and control neurotransmitter release
12:39 promote neurotransmitter release either way that regulation neurotransmitter pops. So once neurotransmitters in
12:47 synoptic cloth that gets re uptake in into the pre synaptic plot. Once
12:54 is in the pre synaptic terminal, the in the in the in axonal
13:00 it gets transported into the vesicles. you have the cellular transporters for
13:06 You have the secular transporters. And are all of the strategies that the
13:11 would use. For example, if was a cell and I needed to
13:15 my pre synaptic output, I would give me more calcium voltage gated,
13:22 calcium channels. The cell, I'm to send the signal to the soma
13:26 more voltage gated calcium channels, more gated calcium channels. And then maybe
13:31 gonna get more voltage gated counsel Charles . Now I have a better chance
13:37 every time there is a stimulation to of a circular release. So all
13:41 these strategies would play into how you cause this facilitation and depression of course
13:49 you're facilitating something, there's a possibility this train of stimulation if you're increasing
13:55 signal and facilitating that maybe calcium levels going up each time. Maybe there
14:04 something else, There's better fusion of vesicles present, optical too. But
14:10 also saw that during the stimulant you have short term depression. So what
14:17 happening there? And it's very likely maybe at this synopsis and the dynamics
14:23 those synopses are different and this synopsis of slowly building up calcium. Like
14:29 the case of facilitation they may actually all of the calcium at once causing
14:39 lack of calcium not released. I'm but but but but there's going to
14:44 larger influx of calcium and then there's to be less of calcium. Maybe
14:48 local extra cellular stores of calcium gets quickly depleted or maybe it's the volt
14:54 costume channels that have different properties and somehow slowing down the costume influx instead
15:01 speeding it up. So there's that where you have depression, calcium is
15:07 one of the culprits. Deep polarization another one of course. Post synaptic
15:14 , post synaptic lee. What's very is an M. D. A
15:19 . XYZ coincidence detectors boston optically we have ion channel redistribution. We talked
15:27 how extra synaptic channels can come into synapse. We talked about channel
15:33 We also talked about internal internalization of channels. So just like they can
15:39 inserted when there is more demand for channels let's say in the synapse the
15:45 way in the synapse that is not functional and its function is going away
15:51 cell body and the cell overall is to compute is that post still important
15:57 should I eliminate that post over there synapse slowly and strengthen the other one
16:05 door that seems to be more active important. So when you do that
16:09 you would end those potatoes and you internalize receptors from the synopses such as
16:15 receptors um production and release of retrograde . So post synaptic lee you can
16:23 messengers and you can boost their production you can boost the release post synaptic
16:30 too dependent on the levels of pre activity. And that post synaptic boost
16:35 be persistent and that post synaptic boost contribute to to to basically the
16:43 Uh this case if you're boosting So what is our understanding, our
16:58 on on tapas like our understanding of of high frequency synaptic transmission and you
17:06 see that You know, we thought things in the 90s and early 2000s
17:11 pretty much confined to the synapse, know that the things were happening
17:18 So we were just measuring the number receptor channels that's the cost and we
17:23 there is some sort of an internalization that can happen. Then we realized
17:28 is lateral diffusion and you can have uh internalization insertion of the receptors and
17:35 diffusion into this announce and then there this extra synaptic exchange that is happening
17:43 so the receptors that are not even the synapse now they can get either
17:47 extra synaptic lee internalized and inserted into synopsis. How long do these processes
17:54 ? So when we talk about short plasticity, facilitation, short term
18:00 short term facilitation, we're talking about , talking about seconds, things that
18:05 for seconds things have lost four Uh And long term processes. Obviously
18:16 take more like minutes and hours and days. And if most of the
18:22 term processes will be taken place here the actual synapse this excellent terminal interacting
18:30 the state and very spine. And have the secular post synaptic receptor dynamics
18:36 you're regulating. But long term changes long term plasticity often can evolve the
18:44 mechanisms secondary messenger transcription factor mechanisms affecting the way to the cell nucleus of
18:55 of neurons determining what things that they be expressing or not. So what
19:07 lTp long blasting? You can have relation of existing with separate channels with
19:16 is you can have insertion of new inside of the cell from the extra
19:22 number of locations production synthesis of neuro and transcription factor activation. The person
19:30 if you do that your changes are to be long term and in order
19:36 see long term changes it's typically not to produce one train of stimulus.
19:41 during this train of stimulus this is hertz train of stimulus. Okay and
19:49 repeating it every 6 17 seconds if were to measure the E.
19:54 S. P. S during the of stimulus, maybe you would see
20:00 term depression during the actual train of . So you have something sp sp
20:12 . Well and then you repeat these . But guess what happens five minutes
20:22 , five minutes later. This is . This is time. Yes this
20:33 when your stimulus repeated stimulus took place . Okay This is amplitude of
20:41 p. s. p. and sampling it and it's 100% baseline before
20:48 stimulus before the conditioning. And then the conditioning you actually may have short
20:56 depression During those 15 seconds or one of stimulated. You're repeating every 15
21:03 or you have a different protocol. then what you'll see gradually Let's say
21:10 is 15 minutes gradually. You will an increase in this E.
21:17 S. Be causing long term potential or long term plasticity. It's a
21:25 term facilitation and depression are very quick dynamics and their encoding doesn't last very
21:31 time. But if you repeat this term bows, if you repeat that
21:37 phone number now instead of once or , just dial it, you repeated
21:42 20 times in a row, that is gonna be sustained and it's going
21:49 be increased. Its gonna be retained a longer period of time. This
21:54 this is really an important thing to . A lot of times when people
22:01 understanding what is being recorded. GPS amplitude of slopes. Short term plasticity
22:07 versus long term plasticity. There is one explanation. There's no one correct
22:14 to this is an emerging developing story what's happening in the brain and how
22:19 interpret it to. So this is pathway of course that we're talking
22:26 This is our famous pathway the stimulation schaffer collaterals. And that's why I
22:33 that most of the cases it would excitatory because you're really stimulating the excitatory
22:39 outputs onto the C. One parameter . And when you record the
22:44 P. S. P. You're recording from a single CIA want
22:47 cell or if you're recording field, PS PS. You will collect recording
22:52 a collection of the parameter all the network of the criminal sauce and
22:56 sea A one. And so there's normal synaptic transmission. You can have
23:04 synaptic transmission. You can have retrograde clearly increase. And there's also this
23:13 long term plasticity that you can actually a repeated long stimulus of activity.
23:19 the LDP may last for an hour two. Like in this case.
23:24 there's also if you repeat these jaws activity like the same exercise over and
23:30 . You're just taking a little break between and then you do the same
23:33 and you take a little break in and you do it. Multiple bombs
23:37 that activity becomes sustained. Maybe it's of the stimulation instead of one or
23:44 trains to produce 20 trains of That maybe that activity is going to
23:47 more sustained and not always in the ation. Not always in the
23:53 This is E. P. E . P. S. P.
23:55 . So amplitude or slope. This E. P. S.
24:00 So you will measure the amplitude or slope. Um Obviously the slope will
24:06 also will not have to do mechanisms late L. D. P.
24:14 can see that there is calcium Do you have activation of the secondary
24:22 ? These are just examples. I'm not going to ask you. Is
24:25 crab of psychedelic mp cycling mp of is very important. So is my
24:31 . So you should know everything Just joking. But the point here
24:34 that you then essentially go all the down to the transcription factors of
24:40 That's when these changes are not only lasting but they could be quite
24:45 They could be structural to it. other thing to remember on the post
24:49 side is that you have side of elements and you can rearrange the side
24:54 skeletal elements and you can rearrange the number of anatomy and isn't really
25:01 You can make them larger, smaller you can maybe collapse the whole synapse
25:07 it's inactive and that's how pruning would in part is also through the changes
25:13 the side of skeletal elements. Post aly and then you we would turn
25:18 certain factors inside the cells like brain neurotrophic factor and others. The details
25:25 not as important. But what is is that it's not just the biochemical
25:31 , it's not just the insertion but actually structural changes. It's the growth
25:37 the synopsis, it's innovation of its development of new external terminals and
25:43 such. Yes. Question regarding the and studies skeletal could the reason why
25:54 looked that way in for instance with those developmental disorders could be attributed to
26:01 side of skeletal elements. And that's we kind of see some deformities and
26:06 . Please don't make long. Yeah will disrupt the side of skeletal on
26:12 some part two. But if you're about fragile likes then it's a
26:16 M. R. P pro And it's not necessarily with the side
26:20 scalable all amounts but there might be little different function at the level of
26:25 spine but also dem island nation. is also emerging autism and and fragile
26:34 to. So when we talk about hallmark feature so to speak of fragile
26:40 being or autism spectrum disorders in some in severe cases of mental recommendation having
26:47 great experiment abnormalities. Were now also to see scientists starting to see some
26:54 Allan nation issues also. You know very good question. There's no very
26:59 answer for for this this is an of imaging. And you have this
27:07 boston optic receptors And what is being is that basically this before lTP stimulation
27:18 after the LTP stimulation you induced LTP here. This is glutamate response.
27:26 what you're doing basically is now instead stimulating the fibers you can apply
27:33 apply glutamate and you can image the and this is imaging of the activity
27:40 this is before stimulus and this is stimulus. So this is one of
27:44 ways in which you can actually see activation or glutamate activation of the
27:53 So we'll talk about that a little more when we talk about um
27:59 And so this is the silent synapses we've mentioned already actually. But this
28:07 uh an M. D. Posting up the spine that has an
28:12 . A receptors. And the synopsis silent. And then the synapses become
28:19 when you have ample receptors. So is just a reminder of this.
28:25 this is an electro physiological evidence of synapses where you are stimulating here.
28:30 stimulating axon and you fail produce an post synaptic responses stimulating these axons.
28:39 have an electric boston optically there's no . And then when you de polarize
28:47 cell to positive 55 million million balls robust response can be seen here.
28:57 is that? So in this case are an experimenter in your vault using
29:07 cloud And you do polarize member of to -55 that alleviates magnesium blog from
29:17 M. D. A. And now you can see post synaptic
29:24 . So if it was just ample you would see a response at -65
29:31 volts. But here it's actually not -55. So it's positive 55.
29:40 very positive potentials holding potentials in voltage . And now you see this massive
29:45 because an MD A channels are So this is a great way to
29:51 a review this and ample receptor stain red and M. D. A
29:56 stain and green and putting them did where they overlap is yellow. This
30:04 you how boston optically their co localized overlap and space. So how can
30:15 same synapse generate Lt P. And . T. D. Using the
30:21 an M. D. And calcium . And maybe at this point I
30:28 see how many slides I have Maybe we'll go into the another
30:44 No, it's here. Yeah. think from here these slides overlap.
30:59 repeat. Whoops. Sorry. All , feisty. Okay so we learned
31:17 the rate code. Okay, we about ample an M. D.
31:27 . We talked about the synaptic So if you stimulate or if you
31:31 glutamate into the synopsis you will have synaptic delay. This is sort of
31:39 drawing for you guys that that that can use off. You have this
31:48 code same synopsis same pathways. But you annoy and stimulate that synapse once
31:56 one second. And that's what I'm be very happy. That's gonna decrease
32:02 activity. But if you stimulate that's very high frequency trains and all of
32:10 sudden boom you can have this 120% from the baseline. 100% baseline before
32:19 stimulus. So this is your You're stimulating these fire just boom record
32:25 . P. S. P. 15 seconds later boom recording PSP
32:31 And then you deliver the conditioning That conditioning stimulus can be boom boom
32:38 boom every one second. Or that stimulus here can be very fast frequency
32:45 train and then you repeat that training the same sin house instead of being
32:53 . Now shows this potentially ation that ation can persist. So you can
32:58 long term depression. Long term potential where potentially ation will be strengthening increasing
33:04 activity efficacy or a number of synapses depression will be weakening driving that
33:11 And it's not always again linked to depression. Depression is a mechanism of
33:17 things too which is very important if want to learn and memorize and move
33:23 with new things. So there's something with this uh image here I
33:34 Yeah this is better. So how the same synapse generate L.
33:48 P. And L. T. . Using the same in M.
33:51 . A. And council channels. so it was proposed you have amount
33:58 an M. D. A. activation during titanic stimulation. If you
34:03 more of an M. D. . Receptor activation during this is what
34:07 call titanic stimulation or high frequency you're more likely to have L.
34:12 . P. But if you don't during this slow frequency stimulation once a
34:19 you don't engage in other than D. A receptors you get
34:23 T. D. The other way think about it. If you have
34:26 slow frequency stimulation it will cause low of calcium flux. Okay hello levels
34:37 phosphor relation because in little levels of protein phosphate Asus may be dominating these
34:45 the molecular substrates now. And if have high frequency stimulation you may have
34:51 concentrations of calcium and now you can those calcium from marginal napkin system.
35:00 will cause the phosphor relation of channels I mentioned before. If you force
35:04 the channel we add a. 04 group on the channel. Quite
35:09 it prolongs the opening dynamics of the . Maybe it makes it more likely
35:15 open. So phosphor related synaptic proteins LTP. So that's another way to
35:25 it. Low frequency low calcium and Asus are dominating so there's decreased levels
35:33 activity. High frequency high levels of . And then you have these protein
35:39 that are dominating for for letting and activity in the cells, it's pretty
35:46 . There's no one explanation. Arch finally brings us to spike timing dependent
35:54 And the rate code was not enough explain everything. So in the 80s
36:02 it was mentioned late 80's And really Ireland in the 90's we started understanding
36:10 concept of spy climbing dependent plasticity. is shown here is in is in
36:17 diagram here in orange, you have synaptic when you're on a pre synaptic
36:27 . This is pretty okay and this post this is our possum out business
36:37 and this is the blue responses and whole spike timing plasticity idea is also
36:48 to back propagating signal. If you this synapse is going to produce forward
36:58 spike. And then forward propagating spike going to cause neurotransmitter vesicles fusion and
37:07 transmission. So when these inputs come and they generate forward propagating spike because
37:20 now the translation it was. This propagandist spike. Yeah but remember that
37:29 same acts on initial segment will also that propagating spike. And that back
37:39 spanich will slow into the den rights have these dendritic spines where synapses take
37:55 . So the timing between when you the pre synaptic and from when you
38:02 the post synaptic response and the importance that propagating spot back propagating spike is
38:10 because if you actually blocked this back spike if you block the deep polarization
38:17 wouldn't see certain forms of plasticity. we know it's important but before we
38:24 that it is important we do the recordings to make sure it's important.
38:29 gonna see what happens with the timing . What happens with the time here
38:39 the pre synaptic stimulation and the par response, not only the timing but
38:49 the order. And so in the and a. What you're seeing is
38:57 you look here on the right actually is DELTA. T. Is more
39:04 zero. What you see is you pre synaptic action potential in orange which
39:11 be a pre synaptic stimulation here. you can see this pre synaptic action
39:17 . Mhm. And then you would those synaptic cell producing an action
39:23 This is strong enough. This is followed by blue. Right? Pre
39:29 posson optic pre synaptic possum optic. with his first stimulus here it shows
39:37 synaptic response by synaptic response. And with the second stimulus here it shows
39:45 increased response. So pre synaptic posson pre synaptic before pa synaptic causes potentially
39:56 right here. This is our 100% and B. This is our 100%
40:02 at sea. Even when you want see it's 100% baseline in d.
40:07 is the response. Okay of the of that E. P.
40:12 B. And anything that deviates is change in the synaptic strength. Also
40:19 the synaptic weight here. It's not greatest snapped extremes. And so if
40:26 stimulate these fibers pre before post you this red curve here. This significant
40:35 ation. And look at the time . The closer in time you have
40:41 synaptic stimulation that is followed by fox response. If it's followed within two
40:49 you have a lot of potential it's followed by 10 milliseconds. You
40:53 have significant amount of the potentially So how does how does this protocol
41:01 ? This protocol works that you are sampling E. P. S.
41:07 . S. Sample them every 15 . And instead of just stimulating the
41:20 like we did previously you actually stimulate fibers and you do polarize post synaptic
41:26 and you do induce defeat actual So you can stimuli eyes stimulate the
41:32 verse of time zero in the genes action potential. Post synaptic li five
41:39 later. 10 milliseconds later, 100 later. So this is how you
41:46 the timing between pre synaptic and fasten and the delay at that time.
41:54 the closer in time the to happen more potentially ation, the stronger is
41:58 potentially ation. And you can see about 30 milliseconds and at 40 milliseconds
42:04 this cell fires and this cell only an action potential. 30 milliseconds
42:11 This communication is irrelevant. There's actually no change, there's no plasticity.
42:17 will respond the same way. 30 . People will respond the same way
42:23 the stimulus. Okay but now look happens if you reverse the order.
42:28 you go here the order is You first produce a spy parson optically
42:35 then pre synaptic neuron fires. So first basically stimulate produce a spike in
42:43 . A. One and only then for collateral fires which is out of
42:49 order. Schaffer collateral olympics are going this way. So it should be
42:55 . Now you're gonna say no I'm disrupt disorder. I'm gonna have C'e
43:00 post synaptic cells respond first and then gonna stimulate pre synaptic. And what
43:04 in that case you get depression and closer in time you are between this
43:11 synaptic followed by free synaptic, the depression you have and this is what
43:21 referred to a spike timing dependent plasticity you can see the classic heavy um
43:30 timing dependent plasticity windows. So you understand this whole language. Habian as
43:35 Hebb. Donald, Hebb. Spike . Classic with positive pre post spike
43:44 timing intervals induced synaptic potential creation. with post pre spike timing intervals induced
43:51 depressions. The relative, Spike timing not the only determinant governing these
44:01 How long is this curve? What going to be the shape of this
44:07 . What is going to be the of either potentially ation of the
44:12 It will depend on other factors. you have these other neurotransmitters, neuro
44:19 in the brain, you have As many things that can basically push
44:25 curve around demanding much shorter communication or communication can increase it. Both the
44:36 and the temporal requirement for spiked on elasticity can be modulated. So you
44:43 this rule without neuro modulators such as neuro modulators, this will be the
44:51 . But now you can introduce as that we talked about. So what
44:56 if you introduce a norepinephrine agonist? actually changes the rule and now post
45:04 pre will also be lTP Mhm. by this virtue you can essentially have
45:14 spike timing dependent plasticity curves in each or in each cell. No classic
45:28 this here It's T. zero filing zero 200 milliseconds or so pre post
45:42 this is those three. Right? this is our 100 baseline will
45:54 So you can have this curve and you can add a substance a
46:00 we can have this curve and then happens in the circuit and you can
46:05 this curve and have it like this have it like this and then on
46:10 other end you can have classical most of the depression. The closer
46:16 are like that would be Post three the depression. This is your classical
46:24 then you can have another direction, can have it shorter and have it
46:28 but that maybe that you can probably very different shapes. As a matter
46:35 fact this is not just like it can actually be like this.
46:39 can have a lot of plasticity close much and then more further away in
46:45 . Just like with HIV plots. told the undergraduate students, maybe I
46:52 you that too. I think we to make an N. F.
46:58 . On the south neurons and F. T. For neuron would
47:03 a visual representation of its I. . Curves for the ion channels.
47:09 is also a good N. T tim put in different colors.
47:14 imagine an N. F. Of spike timing dependent plasticity for being
47:20 . N. F. D. spike timing dependent plasticity for sleeping.
47:26 those are going to change. The is that those curves change also during
47:30 day or on demand or obviously as depend on activity. So neuromodulation of
47:38 timing dependent plasticity and behavior and So if you have this spike timing
47:43 plasticity a cell to be sell pre , post synaptic or post synaptic pre
47:51 you can have these either potentially ation depression. These these these slides are
47:55 great because if you read the figure that kind of a repeat. Um
48:01 neuromodulation of spike timing dependent plasticity is is an orange occurs at all three
48:09 leading to priming of synaptic plasticity by experience perspective neuromodulation. So if you
48:15 certain substances in there, it's almost already predetermined certain rules for the spike
48:23 attendant plasticity modification or even reversal of weights based on behavioral outcomes after the
48:34 inducing event, which is retrospective neuro . So this is retrospective for feedback
48:43 before, during the active state retrospectively happens now? The bottom one altered
48:52 of spike timing dependent plasticity recall that disorders quite often are linked to chemical
49:01 and it's not necessarily just a chemical of too much of a chemical,
49:06 little, it's the whole neurotransmitter system is linked to that chemical can be
49:12 . If you're talking about the you can talk about acetylcholine bicycles a
49:17 , the amount of acetylcholine that is , precision, optical. But if
49:23 talking about acetylcholine neurotransmitter system, you're talking about post synaptic acetylcholine receptors and
49:31 can change also. And so if think about it. If you have
49:36 disruption of spike timing dependent plasticity and may have that disruption during the development
49:43 you're not expressing a certain protein and the great expanse of gun rights and
49:48 they're not responding the same way to activity levels present optic activity levels,
49:55 disorders. If you look at the diseases such as Parkinson's disease. It's
50:03 linked to dopamine in this park. disease, typically linked to alzheimer's uh
50:10 uh to acetylcholine dysfunction, depressive anxiety and linked to serotonin functions,
50:21 what happens if you have imbalances in neurotransmitter systems? You changed the curse
50:28 spike timing dependent plasticity. And as matter of fact, the truth of
50:36 lies in between the rate code and spike timing code. The rate is
50:41 important. The timing in a way the rate. If you're repeating something
50:46 10 milliseconds, what's the frequency of ? But the response tide within 10
50:51 . The frequency of that is 100 . So there is this the spike
50:57 dependent plasticity on the curves really is better representation of the learning rules and
51:03 plasticity rules in the brain. And you add this other component, neuromodulation
51:09 component. Now you can start talking about neurodegenerative disorders and these neurons and
51:16 will have different learning rules in addiction, which can change the circuits
51:22 , which can bolster certain other chemicals the reward chemicals, which is a
51:27 dopamine driven. You can change the , some of those acetylcholine nicotine,
51:34 , dennison, caffeine. So not things inside things that we intake on
51:41 daily basis. Can also change the of spike timing dependent plasticity. It's
51:48 for the love of the great I don't have time to go over
51:52 , but this is a beautiful representation um dendritic spines by dr kristen
52:02 She talks about her passion about three imaging of dendritic spines and but really
52:10 thing is that Ramona, alcohol, great exponents. The Golgi stain is
52:16 one of the really good stains to at the very expired densities and
52:23 Uh But you didn't know so much than we know now of course about
52:28 drinks, Find some of the processes remember that things that are happening
52:34 This learning rules happening at that and explains a lot of times they're happening
52:39 the synapses and recall that the spines have their own energy sources poly ribosomes
52:48 . So they're little like biochemical machines their post synaptic densities here. Three
52:56 structure and anatomy and a lot of Harris's work is what led to our
53:01 of these very distinct anatomical shapes of spines. Uh There expression levels part
53:09 me during the development and also other things that we now understand.
53:20 so we're going to talk we're going start talking about the imaging in the
53:26 and when we talk about imaging in brain we have to talk about it
53:32 several different different levels. First of , there is a macroscopic imaging and
53:39 we talk about macroscopic imaging we're talking no need for microscopy which is micro
53:49 is macro you're looking at the gross of the brain. You're potentially targeting
53:58 significant anatomical area in the brain such Samantha sensory cortex ss. One primary
54:06 cortex Or maybe primary visual Cortex one then there is a different spatial
54:16 . If you start zooming in you a Mezza Skop IQ scale. Now
54:22 can start thinking about broad months areas admin and the cider architectural uh densities
54:32 cells. You can also start talking subtypes of cells that are there.
54:40 versus inhibitory Colin ergic neurons versus other builds. Gabble, allergic of course
54:48 versus and industry versus glue dramaturgy. you zoom in even closer now you
54:56 down to the circuit level and the level. You want to know just
55:02 we drew that engram. You want know who the players are. Just
55:07 on a on a on a sports who the players are who is connected
55:12 who how they're going to communicate the . So it's circuit center. And
55:20 rules of that circuit potentially ation depression rules the rules for that circuit.
55:27 as far as feed forward inhibition feedback , lateral inhibition uh on the cellular
55:38 . Then you start looking at things are happening in a single south
55:43 P. S. P. Is a response from a single south
55:47 . The bsp. A field potential be a response from a circuit like
55:52 would see and see and if you're you're placing your electorate an excitatory circuit
55:59 you're placing your stimulating electorate in the outputs of another circuit so that you
56:05 get an excitatory possible potential and then regularly what is happening at these external
56:17 at the den dries and will expire . What are the levels of calcium
56:23 are flexing. What are the changes the receptor compositions and such? Mm
56:30 . Okay. This is a really figure. And that kind of a
56:35 that you know what we need to the activity of these nerds and so
56:42 can you can take all of your in the world of trying to stab
56:46 many cells in the lobby as you , you know, to publish one
56:51 as a postdoc on the interplay of and excitatory selves doing seizures. I
56:59 I stabbed about 200 cells for And each one of those is equal
57:05 about 10 hours of experimental work Plus hours of analytical work Plus 10 hours
57:15 fighting with the reviewers proving that you everything what they asked for that.
57:21 there. It's really there. It's Photoshop you know. So uh you
57:27 think about 200 times 30. That's hours of work. So it's it's
57:36 it's half a year of just doing one thing nonstop, you know,
57:43 work wise, you know. Um it takes a lot of skill to
57:49 that. What if you want to from 10 cells. How many electrodes
57:54 you stick under a microscope plans? think the record is eight. Some
58:01 in Harvard someplace like eight cells under microscope. I've only stuck four.
58:08 was my max. I've recorded seizures three cells which was tremendous because there
58:13 different types of cells in the hippocampus cells and excited to our cells.
58:20 that's still not enough. Right. you look at the circuit, if
58:23 look at these mesozoic opic images, have hundreds of neurons, thousands of
58:31 and ultimately you want to know what of cells are doing, not just
58:36 , not just eight. And to that, you have to start imaging
58:41 activity in themselves. And there are different ways and many different things that
58:47 can image. But in this case not talking about imaging the anatomy of
58:51 south. We're talking about imaging we're talking about emerging activity of the
59:01 , electro physiological recordings of action potentials E. P. S.
59:05 S. Or electro physiological recordings that electrode. They require an amplifier.
59:13 require an oscilloscope imaging of brain When you go and you look at
59:20 F. M. R. Centers which is non invasive brain
59:24 imaging, functional magnetic resonance imaging or emission tomography. Pet imaging, there's
59:32 electrodes, nobody's stabbing any sauce in brain. It's not an invasive but
59:38 also does not give us a great . So when you're talking about understanding
59:45 or thousands of selves, you have find the means to have enough resolution
59:51 your macro micro or somewhere in between or the ability to go between macro
59:58 and micro levels all at very fast and imaging activity and many, many
60:07 at great spatial resolution. And that's you need experimental techniques. That's when
60:13 need experimental uh neuronal activity imaging. these traces here that you see,
60:21 can see they look like sort of little action potentials that are produced by
60:25 blue traces. But the imaging world gotten so good and so fast that
60:32 same action potentials can be imaged without recorded with the electrodes and now with
60:40 imaging of neuronal activity. Now you to say, well, what are
60:44 going to imagine neurons? So neurons a lot of energy. When you
60:49 at the clinical noninvasive imaging techniques as . M. R. I.
60:53 measuring changes in hemoglobin levels, oxygenated non oxygenated. When you're looking at
61:00 positive and emission tomography, you're looking the glucose levels. So neurons consume
61:07 lot of oxygen. They consume a of energy nutrients, the neurons and
61:12 circuits that are active. They will oxygen into them and they will also
61:20 And once they're active, what other are happening? There's a lot of
61:24 flux in. There is a lot sodium flux, there's potentially ample receptors
61:32 from extra snapping into the synaptic spaces all of these things, we can
61:38 image all of them, which means have guys that are ion specific dies
61:44 they will light up and can be on a microscope whenever calcium concentration goes
61:50 and there's another die and the same where you order and it dies from
61:55 sodium and it will glow sodium and fluorescent microscope. One of these islands
62:03 grillo and green and others will grow in yellow or red. Now you
62:08 image fluxus of multiple ions. You also track activity of single channels,
62:15 receptor channels through the plasma membrane. can also image release of neurotransmitters from
62:23 vesicles using a technique called epic floor , single particular release of how the
62:31 comes out of that bicycle with the and all of these levels. In
62:36 end, they're very, very And ultimately, What I imagined as
62:43 20 second century is having the hospitals will non invasively be able to study
62:57 synopsis of the sub cellular lava um whole macroscopic or holistic activity of the
63:07 and maybe even the spinal cord. that's I think is another 100 years
63:13 now, maybe will control this with link before that. Uh if you
63:22 to go with MArs to mars with . So, but this is I
63:27 really is, well, this is in the lab now and then,
63:31 know, inevitably another a few decades , you see it in the in
63:36 clinics to so it's just like the describes our static imaging versus functional
63:43 static imaging is you wanna use Golgi , You want to use immuno history
63:49 . Um you want to use other of stain. Um but if you're
63:55 about functional imaging, do imaging blood flow metabolism flux is of ions
64:02 slow and fast flux is calcium and versus glia. Guess what? Both
64:09 the South's track calcium. So how you now going to determine which one
64:13 neuronal calcium? Which one is glial gli how much slower it turns
64:20 So if you're gonna see imaging and , these fast flashes, those are
64:24 in neuro slow calcium waves. You're it's astro sides and we ourselves but
64:31 still have to prove it. You also image membrane voltage which is the
64:38 representation of the ions of electrical potential across the whole plasma membrane and the
64:46 movement. Yes. Question kevin. , I have a question. Oh
64:59 , yeah, go ahead. Can go back to slide seven please?
65:05 . So in this image it's each step is just zooming in to
65:11 right, It's just looking in closer closer at it. So what do
65:15 just want us to learn the names what that image corresponds to or another
65:21 about it. So, first of , I want to point out that
65:28 is your reading materials in your lecture class materials And I would really encourage
65:38 because I have tried to pick and our this is from 2019, there's
65:45 new rules in place. There's something's changed with this. Great,
65:49 think, description of.com and dependent So, I would encourage you to
65:54 and look at this information and know . Um this right here when we
66:07 about voltage sensitive dye imaging will come to this article, but this is
66:12 you will find the figure that we discussed. And it's uh particularly talking
66:19 genetically expressed voltage sensitive dyes. for now, it doesn't make any
66:27 of sense to you what that But in another lecture, as we
66:30 about imaging, you'll understand what both sensitive dyes are. And it's very
66:37 , Yeah, that, you know these different levels are. And as
66:41 talk about functional imaging or voltage sensitive imaging or these genetic express voltage
66:47 you will know more. So maybe will answer your question better at that
66:51 also. But I'm urging you not forget about these extra class materials that
66:57 have in your in your supportive supporting material folder. Uh huh. Does
67:05 answer your question at least in that is definitely the levels or the
67:11 of study. And as you learn imaging, you'll understand that more detailed
67:16 may even follow from or about this studies as we talk about the more
67:22 the next couple of lectures or at the next lecture we'll talk about intrinsic
67:27 signal imaging. We'll talk about voltage dye imaging and what it means.
67:32 I think maybe it will answer some your questions and you'll also know what
67:36 going to ask you on the test and then for for that slide that
67:42 on right now. Thank you for that. Do you want us to
67:44 oxygen is m ri blood flow or is? Um yeah, we'll we'll
67:50 go through this. This is a slide and we'll delve into the details
67:53 that actually on Wednesday because we're out time today. Thank you. All
68:00 . Thank you very much. Don't to confiscate your pen
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