| 00:02 | This is lecture nine of Neuroscience. we're going to start talking about synaptic |
|
| 00:08 | and we will talk about neurotransmission for next uh four lectures. And the |
|
| 00:15 | two lectures are more general. And we're also going to look into the |
|
| 00:20 | junction. So we're still going to looking at the periphery a little |
|
| 00:25 | And then subsequently, we will have on glutamic or glutamate signaling and gabba |
|
| 00:31 | gabba neurotransmission. And we will also what we call diffused neuromodulatory systems in |
|
| 00:39 | section where we will study the five like acetylcholine, dopamine, norepinephrine, |
|
| 00:47 | serotonin on the brain. And you'll how all of these different neurotransmitters have |
|
| 00:53 | own functional roles that have their areas they're being expressed. And you'll really |
|
| 01:00 | a solid understanding of neural transmission following four lectures. But it all started |
|
| 01:07 | Auto Lowy and it really is one the more colorful stories in the history |
|
| 01:15 | neuroscience. And the story is that out here by a low in the |
|
| 01:20 | of Easter Sunday, 1921 I awoke 100 and three years ago, almost |
|
| 01:28 | awoke, turned on the light and down a few notes on a tiny |
|
| 01:32 | of paper. Then I fell asleep . It occurred to me at six |
|
| 01:36 | in the morning that during the night had written down something most important, |
|
| 01:41 | I was unable to decipher the That Sunday was the most desperate day |
|
| 01:46 | my whole scientific life during the next . However, I awoke again at |
|
| 01:52 | o'clock and I remembered what it was time, I did not take any |
|
| 01:57 | . I got up, immediately went the laboratory, made the experiment of |
|
| 02:02 | frog's heart described above. And at o'clock, the chemical transmission of the |
|
| 02:10 | impulse was conclusively proven. Careful consideration daytime would undoubtedly have rejected the kind |
|
| 02:18 | experiment I performed because it would have most unlikely that if the nervous impulse |
|
| 02:25 | a transmitting agent, it would do , not just in sufficient quantity to |
|
| 02:31 | the factor organ in my case, heart, but indeed, in such |
|
| 02:35 | excess that it could partly escape into fluid which filled the heart and could |
|
| 02:43 | be detected and collected. Yet, whole nocturnal concept of the experiment was |
|
| 02:49 | on this eventuality and the result proved be positive contrary to expectation. So |
|
| 02:57 | he did is he runs into the , he had a dream, he |
|
| 03:04 | into the lab and in his he saw what he did in the |
|
| 03:10 | . He thought that if I stimulate vagus nerve, which is cranial |
|
| 03:16 | 10, you'll also learn about cranial in this section, vagus nerve, |
|
| 03:21 | nerve. 10. It has projections the brain stem all throughout different organs |
|
| 03:28 | significant projections into the heart. It's most vastly innervating cranial nerve throughout the |
|
| 03:34 | and the whole body. And when stimulate the vagus nerve, the contraction |
|
| 03:44 | the heart slows down. And what did is he stimulated the vagus nerve |
|
| 03:51 | this vagus nerve was hooked up to fluid here that is bathing the |
|
| 03:58 | And he collected this fluid from the into another vessel and exposed this fluid |
|
| 04:07 | he collected to a heart. It has the ova nerve attached, but |
|
| 04:12 | heart is not being stimulated at But instead, what he saw, |
|
| 04:18 | saw the equivalent effect. He saw when he applied this fluid onto this |
|
| 04:26 | heart, the heart rate slowed So what he understood is that by |
|
| 04:35 | vagus nerve, there was some chemical was released in the fluid. And |
|
| 04:41 | he speaks about it, the amount that chemical was significant enough that when |
|
| 04:47 | onto the other heart and in the of any stimulation, when applied without |
|
| 04:53 | heart, it had the same It essentially re reproduced the fluid reproduced |
|
| 05:01 | stimulation of the vagus nerve. Because you stimulate the vagus nerve, you |
|
| 05:08 | a neurotransmitter. Oh Acey co and already learned about acetylcholine and uh motor |
|
| 05:22 | . Those were one of the cells you have to know for the |
|
| 05:25 | And motor neuron is a multipolar cell releases acetylcholine on the skeletal muscle. |
|
| 05:34 | we talked about the simple reflex arch we said that this causes contractions of |
|
| 05:40 | skeletal muscle. But in the the same substance, acetylcholine reduces the |
|
| 05:49 | slows down the heartbeat, essentially slows the heart rate. So it's a |
|
| 05:56 | muscle, it's cardiac muscle versus the muscles that we discussed. And then |
|
| 06:02 | muscles we learned today, you have specific type of acetylcholine receptor called nicotinic |
|
| 06:10 | receptor. And you will see that the heart, you have a different |
|
| 06:16 | of this receptor. So there is and there's also muscarinic acetylcholine receptors and |
|
| 06:22 | have different effects on either the cardiac or the skeletal muscle dependent, not |
|
| 06:29 | the substances, the same substance But one situation is an excitatory |
|
| 06:35 | promoting contractions. In another situation, slowing down the heart rate and the |
|
| 06:40 | acting through a different receptor. Do have a question? Oh OK. |
|
| 06:47 | now why is this story really famous neuroscience? Because sometimes you dream of |
|
| 06:57 | and what he did is he wrote down. He didn't act on his |
|
| 07:04 | . One of my postdoctoral mentors used say that sleep is for the |
|
| 07:09 | And what he meant by that is that you shouldn't sleep and have a |
|
| 07:15 | good sleep cycle. But sometimes when need something done, you just need |
|
| 07:20 | get it done. And if it's p.m. and you have to get it |
|
| 07:25 | , you have to get it So that's what he did. He |
|
| 07:30 | up and went to the lab and discovered this chemical girl transmission. So |
|
| 07:37 | to this point, think about what know, we know about staining of |
|
| 07:41 | . We know about a lot of morphology. We know the cyto architectural |
|
| 07:45 | of the brain. We don't know 19 twenties that there are action potentials |
|
| 07:52 | we really can't record them yet. we start recording them in the |
|
| 07:55 | forties and really capturing the recordings in in the late forties and fifties. |
|
| 08:02 | now we understand that there's a chemical is being released and that nerves release |
|
| 08:09 | and this is the basis of neural . This is a typical chemical |
|
| 08:17 | And when this action potential that we about that gets generated at the axon |
|
| 08:23 | segment in the axon hill up when reaches the exon terminal is going to |
|
| 08:30 | the exon terminal cause the release of neurotransmitter, neurotransmitter. This chemical is |
|
| 08:37 | to cross through the physical space of we refer as synaptic fo is the |
|
| 08:42 | distance of about 20 nanometers between the terminal and the postsynaptic membrane. And |
|
| 08:49 | postsynaptic membrane will contain postsynaptic densities. are areas that has dense collections and |
|
| 08:57 | of the postsynaptic receptors. If the is excitatory and releases glutamate binding the |
|
| 09:04 | . In this case to Ln it channels. So when we spoke about |
|
| 09:10 | action potentials, we spoke about voltage sodium and voltage gated potassium channels. |
|
| 09:15 | this case, these are Ln gated channels. And when glutamate exciter neuro |
|
| 09:24 | binds to these psyop receptors. it allows the influx of sodium. |
|
| 09:31 | will also learn that there's going to also an EFX of potassium through the |
|
| 09:34 | channels, eventually causing the depolarization that can record postsynaptic that we refer to |
|
| 09:43 | EPSP, which stands for ex excited posy tic potential. Epsp. So |
|
| 09:51 | synopsis will produce excitatory synopsis potentials E OK. OK. And we also |
|
| 10:14 | an inhibitory synopsis. The response is to be IP SP which is an |
|
| 10:25 | or active potential. Now, if epsp, what we learned, if |
|
| 10:32 | epsp po synoptic is strong enough to the threshold for action potential that will |
|
| 10:39 | fasten app itself will generate its own potential in response to this epsp excitatory |
|
| 10:47 | . In addition to chemical synopsis in brain, we also have electrical synopsis |
|
| 10:56 | electrical synopsis are different. If for example, produce an action potential |
|
| 11:04 | this electrode, you depolarize the cell produce this action potential, which as |
|
| 11:09 | know, is about 100 millivolts in and you have a second cell from |
|
| 11:16 | you're recording and that second cell is to the first cell through gab |
|
| 11:22 | those are called gab junctions or connection or electrical synopsis electrical junctions. There's |
|
| 11:31 | be a small fraction of that current is going to be immediately recorded in |
|
| 11:39 | second song. Now, when the gets released from the chemical synapse, |
|
| 11:45 | has to cross the cleft the bond the receptors and cause the CPSB. |
|
| 11:50 | from the time of the stimulus, this is the time of the stimulus |
|
| 11:55 | this stick right here, this is time of the stimulus to the time |
|
| 12:00 | the epsb response, epsp response. going to be a delay and that |
|
| 12:12 | can be anywhere 5 to 15 for example. And that is referred |
|
| 12:19 | synaptic belief. So from release of neurotransmitter to one that this is a |
|
| 12:26 | that's equivalent to action potential in the terminal and some milliseconds later, 5 |
|
| 12:32 | 15 milliseconds later, you'll see this synoptic response. OK. So this |
|
| 12:37 | the stimulus is the pre synoptic OK. This is presynaptic stimulus and |
|
| 12:44 | is the post synaptic response. Now, in electrical junctions, there |
|
| 12:51 | no delay, there's no delay as as you have this action potential |
|
| 13:00 | that action potential is reflected in the cell. However, as you can |
|
| 13:05 | , it's a very small depolarization has same shade as the action potential in |
|
| 13:11 | one, but it's only a fraction its size only about a millivolt |
|
| 13:16 | So in amplitude. So PSPs, synaptic potentials are also as we call |
|
| 13:29 | potentials. PSVS come in different sizes the smaller ESPS can be larger ESPS |
|
| 13:44 | they're graded. And that's not the with action potentials. Once the action |
|
| 13:50 | reaches the threshold, it's always the amplitude 100 millimeters now. So this |
|
| 13:56 | the excitatory synopsis. This is the synopsis here in the inhibitory synopsis. |
|
| 14:04 | neurotransmitter that gets released as Gaba Gaba bind to Gaba receptor channels that will |
|
| 14:14 | chlorine the binding of this neurotransmitter. Ln to Gaba receptor channel, in |
|
| 14:21 | Gaba, a receptor channel will cause of fluoride. So sodium going in |
|
| 14:28 | charge going in causes depolarization, epsp going in negative charge going in, |
|
| 14:37 | causes hyper polarization which is IPs P those also can come in different |
|
| 14:45 | They're graded potentials. So you have and inhibitory potentials. And so what |
|
| 14:52 | learned is a single neuron may have of thousands of synapses and maybe 60,000 |
|
| 14:59 | them are excited and 40,000 of them inhibitory and each one of them is |
|
| 15:05 | of producing an epsp or excited or one of them are capable for inhibitory |
|
| 15:12 | an IP sp. So neurons will this depolarizing and hyper polarizing information and |
|
| 15:20 | if there's enough input or input to with its own action potential to transmit |
|
| 15:26 | information further down the network down then connect the chain of neurons. So |
|
| 15:38 | chemical neurotransmitters and this is an overview we will delve into it with, |
|
| 15:45 | more and more details. We will about uh some very interesting neurotransmitters in |
|
| 15:53 | course. And you'll start forming an of where they're expressed and what function |
|
| 16:00 | served. So if you look at major neurotransmitter, so the lot you |
|
| 16:08 | amino acids and we already discussed and discussing gaba glutamate and glycine is the |
|
| 16:16 | amino acids. And then next year have amines, which is acetylcholine |
|
| 16:26 | if we're not for antihistamine, nor from serotonin. And we actually study |
|
| 16:35 | studying them pretty well with the exception histamine. Although we, we'll talk |
|
| 16:38 | histamine when we talk about the injury gain mediation and when they, it's |
|
| 16:44 | matter of sensory system, but there's image here that shows acetylcholine system and |
|
| 16:54 | shows that acetyl COVID system has this we call nucleus. So, nucleus |
|
| 17:01 | the brain is a collection of cells are responsible for the same or very |
|
| 17:06 | functions. And there is this new that is called Ponto Meena holo tal |
|
| 17:14 | here. And there's another nucleus that called basal nucleus of manar here. |
|
| 17:23 | there is a third one that is medial septal Lyle located here. What |
|
| 17:29 | this mean? That means that all the cells in the brain in the |
|
| 17:37 | , the express acetyl code are located these. So, in some instances |
|
| 17:45 | these immune systems such as acetylcholine or . In some instances, there are |
|
| 17:52 | tens of thousands of neurons that express molecule, a pseudopod or dopamine molecule |
|
| 18:00 | some instances is hundreds of thousands of . And from those nuclei, the |
|
| 18:07 | means of being supplied here going into brain stem. If, if |
|
| 18:11 | we're in the spinal cord here supplying front cortex. These nuclei are supplying |
|
| 18:19 | of the parietal cortex and also the cortex. So their expression of these |
|
| 18:27 | is very confined and very limited. in contrast to amino acid systems. |
|
| 18:38 | , if we have an expression, let's say glutamate or Gaba and we |
|
| 18:48 | stain the brain for glutamate. And said, well, where are all |
|
| 18:52 | the glutamate expressing itself from? And will not be found everywhere, but |
|
| 18:58 | would be very, very broadly expressed throughout the brain. So they are |
|
| 19:07 | , they are not confined to one nuclei or two or three specific nuclei |
|
| 19:12 | the brain. But rather, let's this is glutamate, they're expressed throughout |
|
| 19:20 | entire set, the nervous system. the same is the case when |
|
| 19:27 | So you can intersperse Gava everywhere. just put the dots for glutamate. |
|
| 19:33 | are all of the cells and glycine the same way all of the amines |
|
| 19:40 | very confined to expression. All of amino acids have very broad, very |
|
| 19:47 | distributed expression. So there's a much larger number of these uh amino |
|
| 19:55 | producing cells as compared to a mean cells. And what is shown |
|
| 20:01 | for example is that uh this is in the TUI nuclei v segmental area |
|
| 20:10 | a substantial micro that supply the entire with dopamine. The substantial library of |
|
| 20:18 | these stratum area that you will learn uh sub cortical areas in this local |
|
| 20:25 | areas, supplying the the they're usually into the frontal cortex. So these |
|
| 20:34 | systems quite often are referred to as sprinkler systems. So you sort of |
|
| 20:39 | uh the water supply, right? is the central water supply and then |
|
| 20:45 | have lines, sprinkler lines running all the cortex into the periphery from this |
|
| 20:51 | supply and very long axions in some in some instances, shorter axons that |
|
| 20:58 | essentially release this anine molecules from different of the brain. But that is |
|
| 21:04 | contrast to very broad expression of amina . We also have already mentioned some |
|
| 21:14 | the peptides and we will not talk about peptides, but we'll look at |
|
| 21:19 | differences between neurotransmitter and peptide synthesis and . But we've discussed some of the |
|
| 21:27 | somatostatin came up. Uh when we about hippocampal cells, CCK or cholecystokinin |
|
| 21:36 | up and we said like look some cells are CCK positive and others are |
|
| 21:43 | . So parameter cells, you also release glutamate. So what does it |
|
| 21:50 | that a cell is also CCK positive means that it also has the ability |
|
| 21:57 | synthesize CCK and has a mechanism for release and neuropeptide release. But it |
|
| 22:03 | a different mechanism but it is by same cell. So these molecules we |
|
| 22:11 | about per volin for example also, that AAT also is in the gaba |
|
| 22:17 | cells. So a cell can be oric or glutamic and it also can |
|
| 22:23 | express and core release these peppo But there's immune cells a fairly uh |
|
| 22:34 | spatially small number. So your question be. So professor, we took |
|
| 22:40 | essential tal and substantial n area. that mean the brain would not have |
|
| 22:47 | ? And the answer is yes, brain would not have dopamine. But |
|
| 22:52 | I took a big chunk or even parietal cortex with this brain still have |
|
| 22:59 | and gama, we'll have plenty of and gamma must all have a different |
|
| 23:03 | of sense. Do you do areas the clo have receptors or um do |
|
| 23:10 | and whatnot or? Yes. So is a very good question. We |
|
| 23:14 | not talk much about it. We'll some of the receptors in the immune |
|
| 23:19 | . But yes, we will have specific receptors in the CNS. We |
|
| 23:23 | nicotinic and muscarinic. We'll have dopamine . D one D two different subtypes |
|
| 23:29 | dopamine receptors. And the only other that you'll also learn is that acetylcholine |
|
| 23:35 | signal through ionotropic and metabotropic channels and rest of them means dopamine Norine serotonin |
|
| 23:45 | will study it all work through a G protein coupled receptor system only. |
|
| 23:50 | , they're, they're, they're not channel. Uh They don't activate channel |
|
| 23:56 | directly. Are those receptors like specific the areas where the channels run or |
|
| 24:03 | they just throughout? No, uh are different. So when we talk |
|
| 24:09 | norepinephrine, we'll talk about norepinephrine norepinephrine beta receptors and they can be |
|
| 24:16 | expressed on the same side or they be expressed. Alpha is dominant in |
|
| 24:21 | structure. Beta is dominant in another . Sometimes they can be equally co |
|
| 24:26 | in different structures. So yeah, you have different receptors and you'll also |
|
| 24:31 | that alpha and beta will actually have . They will work in the antagonistic |
|
| 24:37 | against each other. Uh And as as activating cyclic K MP production inside |
|
| 24:43 | cell. So good questions. The thing that I want you to take |
|
| 24:50 | is that when we looked at the for neurological disorders, for example, |
|
| 24:57 | was a definition of Parkinson's disease as motor disorder. And quite often, |
|
| 25:05 | you'll see what we talked about the of tremors and Parkinson's inability to control |
|
| 25:12 | motor commands. And it's a dysfunction dopamine. When we talk about Alzheimer's |
|
| 25:23 | , we talk about different symptomology, talk about memory loss, anxiety, |
|
| 25:28 | navigation, all these other things. related to acetylcholine loss, serotonin and |
|
| 25:38 | treatments. You may have heard. I serotonin specific re reuptake inhibitors are |
|
| 25:48 | and serotonin dysfunction is correlated with uh and anxiety. So what does that |
|
| 25:59 | you? It tells you that these systems? So you can think of |
|
| 26:04 | switch on positive G A switch But what these neuromodulators do is they |
|
| 26:14 | color, they get activated for specific so that switch stays on longer, |
|
| 26:21 | flips on easier or switches off faster turns on back again. So it |
|
| 26:29 | a whole different functional, how to uh really a functional range of activities |
|
| 26:42 | controlling this on and off switch. specific loss in these neurotransmitter systems is |
|
| 26:50 | with not only specific behaviors, motor , but also with specific neurological disorders |
|
| 26:59 | having too much, too much, much or too little. It's |
|
| 27:04 | it, it says it's never, never too much of a good |
|
| 27:08 | It can be too much of, a good thing. So it could |
|
| 27:11 | over expression. Not all neurological disorders a loss of functional loss. It |
|
| 27:17 | be a mutation in the channel. could be uh alteration in the kinetics |
|
| 27:22 | that channel, not necessarily loss of . But when we look at diseases |
|
| 27:27 | Parkinson's, there's a loss of dopamine , there's a loss of it |
|
| 27:31 | in Alzheimer's patients. So yeah, , it's more common to have a |
|
| 27:37 | and then a loss of function associated it. And the see people out |
|
| 27:49 | what the, with, with So it's uh it's a more uh |
|
| 27:59 | kind of a, I, I know if it's a recent technique, |
|
| 28:02 | for me, it sounds like something came from the 19th century actually, |
|
| 28:06 | beginning of the 20th century, but a dissociate. It's called dissociative |
|
| 28:12 | So you really just uh knocked out for about 45 minutes and when you |
|
| 28:19 | back, it's supposed to help with and anxiety and it's a little bit |
|
| 28:25 | a kind of a still on the like Kelsey C Ball doesn't do |
|
| 28:29 | but you'll have Ketamine injection clinics for depression. There's uh some of the |
|
| 28:35 | that are FDA approved otherwise they wouldn't able to do that completely. But |
|
| 28:40 | not as widely accepted by all of health care institutions as of yet. |
|
| 28:45 | is a specific um intranasal uh product specifically for suicidal. It's at the |
|
| 28:53 | specific purpose. That's very interesting to here. The uh so yeah, |
|
| 29:02 | not FDA W for depression. Yeah. Ketamine is. Yeah. |
|
| 29:12 | . So I didn't know that, obviously it has a, you |
|
| 29:16 | an inhibiting function, almost like anesthetizing a little bit in the case |
|
| 29:20 | I guess suicide to um cases It's supposed to be, it's actually |
|
| 29:25 | only treatment out there that's supposed to like we can take away suicidal radiation |
|
| 29:33 | a matter of minutes and, and does that in the amount of minutes |
|
| 29:38 | it's a nasal spray because of what talked already in the past that if |
|
| 29:43 | swallow a pill and we will learn , especially for, for controlling some |
|
| 29:49 | these systems like uh depression, suicidal thoughts, things like that when |
|
| 29:54 | use the serotonin system is not on . But when people um have uh |
|
| 30:01 | for those pharmaceuticals, they often take to three weeks to see a significant |
|
| 30:07 | . And that's not uh that's not to fix the situation of, you |
|
| 30:13 | , urgent situation where the person is in crisis and the suicidal. |
|
| 30:18 | And that's why nasal spray uh gets there faster. Uh In this |
|
| 30:23 | I'm not talking about the K ketamine have a fast effect. But what |
|
| 30:27 | talk about the antidepressants, they take to build up too. So, |
|
| 30:32 | right, very good questions and maybe of them will get answered even further |
|
| 30:36 | we go and we'll spend the whole on these uh mono iun systems. |
|
| 30:41 | this is the norepinephrine system and this serotonin system here. And as you |
|
| 30:48 | see the, the the projections, some of these projections are throughout the |
|
| 30:55 | cortex. Others are confined in this , dopamine system more to the frontal |
|
| 31:00 | of the cortex as well as the area. But they all have their |
|
| 31:05 | respective nuclei or serotonin. That's RAA . So you have 1234, I |
|
| 31:12 | there were five, maybe I'm not them all. And then you have |
|
| 31:17 | Aurelius uh for norepinephrine. So locus location Crius, it's blue and, |
|
| 31:28 | in Latin, because when this tissue cut, norepinephrine will oxidize and turn |
|
| 31:35 | . So that's why when they first it, they call it sort of |
|
| 31:38 | the blue location, the blue locus locus civil. So gap junctions, |
|
| 31:44 | we already talked about, there's an of having these gap junctions. As |
|
| 31:49 | can see the distance between these cells they have gap junctions is much, |
|
| 31:54 | smaller as opposed to what you see the chemical synopsis. And what happens |
|
| 32:00 | that typically the distance between the pre and possy side and about 20 |
|
| 32:06 | But in some instances, the cell cell membranes will come closer to each |
|
| 32:13 | in the vicinity of about 3.5, nanometers or so. And they will |
|
| 32:18 | on both sides, what we call channels that are formed by having a |
|
| 32:26 | on each number on a piece of itself. So those are referred to |
|
| 32:32 | job junction channels. The sub units called connections. When these subunits come |
|
| 32:42 | on one side, they form a called connect song and then two connect |
|
| 32:48 | , one on the presynaptic and one the postsynaptic cell membrane form what we |
|
| 32:54 | gob junction. So six connections will a connection and two connections will form |
|
| 33:01 | gap junction. And this case cells referred to as electrically coupled because |
|
| 33:09 | as we saw already with actions with , both C inhibitors. So sodium |
|
| 33:15 | potassium because that was, that was piece of A I also really cross |
|
| 33:21 | these G but in addition to the is also small molecules. So for |
|
| 33:29 | , secondary messengers uh such as cyclic P can cross their gab junctures. |
|
| 33:38 | it's not just electrical conductance and the of the electrical activity from C one |
|
| 33:43 | C two, but it's also flux small molecules and secondary messengers. In |
|
| 33:50 | case, these job junctions are almost open, they're not closed. They |
|
| 33:57 | , they don't have a gate lien bind to them. So do they |
|
| 34:07 | close or they're always open? So thought in three dimensional understanding of these |
|
| 34:14 | is that there's maybe a little bit a torque that gets put between the |
|
| 34:19 | sides and makes the opening a little smaller. And then it goes into |
|
| 34:23 | little different confirmational shape and makes the a little bit larger. But gap |
|
| 34:29 | are always open. So they're not because there was a flux and voltage |
|
| 34:35 | because some substance bound here, unlike chemical synopsis, they are bidirectional. |
|
| 34:42 | you learn that there is a lot bidirectional even in chemical synopsis where pre |
|
| 34:47 | neurotransmitter will bind on the posy membrane it will also bind to its own |
|
| 34:53 | on the presynaptic side as well. very fast transmission, there's no delay |
|
| 35:00 | electrical synopsis and it's very important for that information. So if the cells |
|
| 35:08 | we talked about relevant time scales for or milliseconds for humans of seconds in |
|
| 35:16 | to minutes for neurons and some And if you have enough of these |
|
| 35:23 | SPS and these EP SPS can summary of the gap junctions that are interconnecting |
|
| 35:31 | different neurons, they can cause enough the depolarization to encourage an action potential |
|
| 35:39 | the postsynaptic neuron. So, presynaptic might be excited. Po synoptic cell |
|
| 35:44 | be receiving some inputs but also gets from pre synoptic cell. And now |
|
| 35:51 | summ its very quickly this information and an action function. So it is |
|
| 35:58 | , very useful for a fast synaptic in this diagram. What is shown |
|
| 36:06 | two cells that are connected through gab and these two cells are receiving excitatory |
|
| 36:16 | . And as they're receiving excitatory their membrane potential is changing, it |
|
| 36:21 | the threshold, produces an action potential another action potential, another action |
|
| 36:27 | another action potential. And you can most of these action potentials between the |
|
| 36:32 | cells that are connected with gab junctions synchronized. That means that they're occurring |
|
| 36:38 | the same time during the depolarization hyper cycle and they're producing action potential at |
|
| 36:45 | same time. So they're synchronized and means that they will send that information |
|
| 36:51 | synchrony down the line to the interconnected . If you have no gap junctions |
|
| 36:58 | if you block out junctions, there chemicals that can block out junctions, |
|
| 37:03 | can now have the same equivalent input into those two cells or into that |
|
| 37:08 | network. But cell one will produce own pattern of action potential. So |
|
| 37:14 | three rather, and cell four will its own distinct pattern of action |
|
| 37:21 | So now the synchronization between action potential lost between the South and Don gods |
|
| 37:31 | not only important for fast communication, also for synchronizing neurons for synchronizing neuronal |
|
| 37:39 | and doing it in a very fast chemical synopsis. There's a variety of |
|
| 37:47 | . We already looked at the pre terminals that have a lot of mitochondria |
|
| 37:54 | a lot of these vesicles that are with neurotransmitters as a presyn pre synoptic |
|
| 38:00 | zone. It's juxtaposed to these postsynaptic on the postsynaptic side can zoom into |
|
| 38:08 | uh area even closer. And you see that there's a collection of synaptic |
|
| 38:15 | and also dense four vesicles and dense vesicles will contain peptide. So as |
|
| 38:21 | mentioned before, the cell may be expressing like a parameter. Cell, |
|
| 38:27 | glutamate neurotransmitter which will be in this Vesico and also a peptide like CCK |
|
| 38:39 | . And that will be housed in dense core bicycles. OK. Both |
|
| 38:45 | by the same self when axons project to other cells, most of the |
|
| 38:52 | in the CNS are formed of dendrites solos with other neurons. So if |
|
| 38:59 | a dendrite, it's actually driven, a soma, it's an ax. |
|
| 39:06 | synapsis, sometimes the synopsis also form other axions. And those are reported |
|
| 39:14 | axial exon and even more rare. it's also possible when two dendrites have |
|
| 39:21 | between each other. Some rare dendrodendritic synapse. What's uh important to |
|
| 39:30 | is that the synopsis that contact the or the SOMA of these neurons will |
|
| 39:39 | how this neuron produces actions. So will influence the integrative properties of this |
|
| 39:47 | . In other words, the cell receive 1000 exotic inputs. 50 |
|
| 39:53 | This SOMA is going to integrate all the excitatory synopsis, all the other |
|
| 39:58 | synopsis that may be formed here. these synopsis will influence the integrated properties |
|
| 40:06 | the cell, the decision making, that cell is going to fire an |
|
| 40:10 | potential or not. But axonic they will modulate the output because this |
|
| 40:22 | has already made a decision whether it's to fire an action potential or |
|
| 40:27 | that happens at the level of And so if the cell made a |
|
| 40:33 | that is going to fire an action and says that action potential down its |
|
| 40:39 | axonic synapse, the only thing it do, it can modulate that action |
|
| 40:46 | output. And so it has more a modulatory rather than integration cell integration |
|
| 40:53 | . So it can affect maybe the of these action professionals, but it |
|
| 40:58 | affect whether the cell will produce an potential or not, not the integrated |
|
| 41:08 | . So also what's interesting is that are, if you look at these |
|
| 41:14 | , some of these synopsis have asymmetrical differentiations and others have symmetrical membrane |
|
| 41:23 | What does that mean? If you in the situation here in a, |
|
| 41:28 | have very large poop density and you fairly small active zone. That feature |
|
| 41:36 | the synopsis, you have round the . If you look on the synoptic |
|
| 41:42 | , the pre synoptic octave zone and po synoptic densities are about equal or |
|
| 41:49 | in size. And also you'll notice the vesicles are flattened. So they |
|
| 41:56 | this flattened shape. So this will on the quiz. One of these |
|
| 42:02 | excitatory, one of these is inhibitory you can find out for yourselves. |
|
| 42:09 | this is another display of kind of different synaptic connections, chemical synaptic |
|
| 42:18 | neurons can have axon dendrite, but can also collateralize, you can see |
|
| 42:27 | larger synapses. So maybe this is really active synapse that established during early |
|
| 42:34 | . It has three presyn optic active and there's other small synapse coming off |
|
| 42:41 | same axon onto the same cell only one. Which one do you think |
|
| 42:47 | going to have more impact on the ? The one that has larger synapse |
|
| 42:52 | has three points of release and communication presynaptic and postsynaptic areas versus just one |
|
| 43:01 | of communication. That means that EP or IP SPS, whichever the synapse |
|
| 43:06 | responsible for the EP SPS. In one are going to be larger versus |
|
| 43:14 | synapse that is smaller and has only docking station, but one po not |
|
| 43:19 | descent, you can have situations where will wrap themselves around another axon. |
|
| 43:28 | these are axonic as we talked about only one large synapse. And you |
|
| 43:36 | see 123456789 communication zones, very powerful of doing it. Or you can |
|
| 43:45 | nine inputs with one communication zone or this case, six or five |
|
| 43:51 | some will have one communication zones and will be larger, others will have |
|
| 43:56 | communication zones, some larger, some , there's different iterations and variations of |
|
| 44:02 | uh contacts and the synopsis. So we talked about Roderick mckinnon as somebody |
|
| 44:09 | was chasing the structure of local G potassium channel and used all of those |
|
| 44:15 | techniques uh very forward thinking at the . And your book talks about Doctor |
|
| 44:23 | Harris who has spent a lot of life and trying to visualize and trying |
|
| 44:30 | study the anatomy of the dendrites. , a really cool thing that we |
|
| 44:35 | discussed is dendritic spines. And we how dendritic spines actually can be detected |
|
| 44:42 | BGE stain. So you can visualize . But still in those days in |
|
| 44:48 | 19 early 19 hundreds, the resolution the quality of the microscopes was not |
|
| 44:54 | great. And even if you did something for many, many years, |
|
| 45:00 | visualized it in two dimensions. What that mean? That means that you |
|
| 45:07 | at the picture, you know, took a camera image of the |
|
| 45:12 | you're looking through the microscope and then can go down two micrometers and take |
|
| 45:19 | picture and go down another two micrometers microscope, take another picture and you |
|
| 45:25 | do this stack. In this it's a stack of images. And |
|
| 45:32 | is that Stagg going to allow you do? It's going to allow you |
|
| 45:35 | produce three dimensional picture because two dimensions not going to show you three |
|
| 45:43 | So one picture is not going to you three dimensions. And that is |
|
| 45:48 | uh Houston Harris was after and got really, really complicated electron microscopy |
|
| 45:59 | As we talked about already, you see the spine apparatus and postsynaptic density |
|
| 46:07 | . OK. So this is dendrite dendritic spine, spine apparatus, |
|
| 46:12 | We also mentioned that it will have the Russ Soal conflict system, the |
|
| 46:17 | spine. And we talked about how dendritic spines are somewhat biochemically independent of |
|
| 46:22 | cell. They are capable of doing post translational modifications in particular on their |
|
| 46:30 | . You can also see that from electron microscope pictures, you have the |
|
| 46:35 | synoptic terminal with vesicles in green and the synapse in blue is glia. |
|
| 46:43 | these are oocytes and this is what call tripartite synapse or synapses consists of |
|
| 46:49 | parts neuron, one presynaptic neuron, past synoptic and glial cells surrounding that |
|
| 46:57 | . A tripartite synapse and glial cells regulate a lot of what happens to |
|
| 47:02 | and gaba neurotransmission between neurons because they're in the metabolic cycle of the amino |
|
| 47:10 | . In particular of interest to us glutamate and Gaba. And of |
|
| 47:16 | once you get into electron microscopy, you also you can do three dimensional |
|
| 47:24 | microscopy imaging and you can do it only just with taking uh images of |
|
| 47:29 | focal planes and making a sort of three dimensional stack of what you can |
|
| 47:36 | uh also labeling different aspects of the and the synapses with different markers. |
|
| 47:45 | when you ask, for example, the specific channels, there are specific |
|
| 47:50 | that are going to be expressed in presynaptic side versus postsynaptic side. There's |
|
| 47:58 | of these protein channels that will be , there will be dyes that are |
|
| 48:03 | to cyto skeletal elements that we discuss as microtubules, for example. Uh |
|
| 48:10 | this is what some of the original of three dimensional dendrites look like. |
|
| 48:18 | that is really, really important because we talked about dendritic spine anatomy, |
|
| 48:24 | alluded to this disorder, Fragile X . And I said that if you |
|
| 48:31 | abnormal formation of these spines the the densities and their shapes is correlated |
|
| 48:41 | intellectual and and mental retardation. But is only in two dimensions and number |
|
| 48:50 | density. These types of studies allow to address things in three dimensions. |
|
| 48:56 | not only because you're interested in the structure of the building in three |
|
| 49:02 | You're actually interested in the inner structure all of these different elements, |
|
| 49:08 | neurotransmitters, uh Kines, micro tal elements to really understand how these dendritic |
|
| 49:18 | and dendrites are structured and what is beyond the number or shape or densities |
|
| 49:26 | these spines. The product which is molecularly in dendritic spines. And we |
|
| 49:32 | that for example, fragile axis correlated uh a, a specific protein uh |
|
| 49:41 | . And so this kind of the three dimensional 3D em or electron |
|
| 49:48 | imaging is something that uh took people , decades and careers to develop and |
|
| 49:55 | visualize and produce images like this. it's still quite rare to have a |
|
| 50:01 | dimensional em specialist to be able to that. And II I don't even |
|
| 50:07 | if we have one here at this actually. So it's a very, |
|
| 50:13 | um tedious uh committed work to in to do that. But this will |
|
| 50:20 | a lot more to us about diseases structures internally, not just externally and |
|
| 50:25 | they relate to external structures also. , some of the principles of chemical |
|
| 50:31 | transmission is the cell that releases neurotransmitter has to synthesize that neurotransmitter. So |
|
| 50:37 | a glutamate, releasing solid has to glutamate. If it's gabba releasing solid |
|
| 50:43 | to synthesize Gava pyo in releasing solid to synthesize the PSEO it has to |
|
| 50:49 | neurotransmitters into synaptic vesicles. So there's that will load these neurotransmitters into the |
|
| 50:57 | , those vesicles, those vesicles, have to fuse to the plasma membrane |
|
| 51:08 | release the neurotransmitter into the synaptic, vesicle membranes. They don't get wasted |
|
| 51:16 | during exocytosis. But after the neurotransmitter , they get endocytosis back into the |
|
| 51:24 | optic terminal and reload it with Neurotransmitter doesn't stay in synaptic clo |
|
| 51:33 | It binds to the receptors of interest as glutamate receptors and glutamate synapse. |
|
| 51:39 | then it doesn't stay bound to it . Either different substances will bind, |
|
| 51:47 | call reversibly for a certain amount of and then they will diffuse or dissociate |
|
| 51:54 | the protein that they bound. And they will either be enzymatic, broken |
|
| 52:01 | these neurotransmitters or they will be transported with the neurotransmitter transport or something. |
|
| 52:10 | pre synoptic terminal again. So we'll this in greater detail. In a |
|
| 52:15 | slides. Po synoptic, this molecule to bind to the receptor and there |
|
| 52:22 | to be a biochemical or an electrical for synoptic. So when we talk |
|
| 52:28 | electrical change, we were talking about Ln gated receptor channels. And when |
|
| 52:36 | talk about biochemical or cellular changes, typically refer to G protein coupled |
|
| 52:44 | And it doesn't mean that activation of signaling doesn't change a membrane potential. |
|
| 52:49 | actually has an impact on the membrane but not to the same degree and |
|
| 52:54 | with the same kinetics. So, of neurotransmitter from the synaptic cla is |
|
| 53:01 | an important function of this whole cycle neurotransmission, neurotransmitter systems are then essentially |
|
| 53:10 | entire presynaptic and postsynaptic response sides to particular chemical synthesis release and response. |
|
| 53:21 | before we look at and we already looking at these synopsis, we are |
|
| 53:26 | to remind ourselves of this very simple . We already talked about how acetylcholine |
|
| 53:35 | slow down the heart rate, We said PSEO slowed down the heart |
|
| 53:40 | . But in the skeletal muscle, talked about how it will cause a |
|
| 53:44 | of the muscle. So it will promote more of the muscle contraction, |
|
| 53:48 | pseudo and the dust cell through OK, where you have. And |
|
| 53:55 | is a very simple circuit to understand just more information to add on the |
|
| 54:01 | reflex arch that we were studying in first section. So this is the |
|
| 54:06 | motor neuron that will project its axon a portion of the spinal nerve. |
|
| 54:14 | the spinal nerve to a skeletal This axon will have what we call |
|
| 54:23 | ramifications or uh uh uh bifurcations here presynaptic terminals. Each one of these |
|
| 54:35 | synoptic terminals is a powerhouse and a efficient synapse motor neuron action potential. |
|
| 54:44 | an action potential of motor neuron is we studied approximately two milliseconds in duration |
|
| 54:49 | 100 millivolts in amplitude. When this potential arrives at the external terminal. |
|
| 54:57 | , it will cause the release of cone. So you have about 200 |
|
| 55:07 | so synaptic vesicles obviously c in each of these synopsis, they're sitting very |
|
| 55:15 | to the active zones, we call primed and ready to be released. |
|
| 55:20 | other words, primed and ready to with a membrane to release the |
|
| 55:26 | po synoptic in the muscle, you acetylcholine receptors and these are receptors showed |
|
| 55:35 | red and high densities of them are right here, very close to the |
|
| 55:42 | terminal. Because as you know, poop inside the muscle fibers will have |
|
| 55:49 | imaginations that are referred to as And uh the superior thought aspects of |
|
| 55:58 | junctional holes will have high densities of in your supra. So when the |
|
| 56:05 | gets released here, it will bind see the colon rear trans and it's |
|
| 56:12 | acetylcholine molecules will bind to each aceto receptor and activation of a single |
|
| 56:25 | So you have multiple synapses here from a activation of a single synapse and |
|
| 56:33 | of neurotransmitter vesicles from a single synapse end up in formation of plate |
|
| 56:40 | So it's not epsp, it's Epp play potential. An end play potential |
|
| 56:58 | massive. It's always 40 millivolts or in size. Why is that |
|
| 57:06 | Because these EP SPS when we talk a smallest or unitary epsp that can |
|
| 57:14 | produced or the smallest unitary IP sp can get produced here are approximately half |
|
| 57:25 | mill in size. So activation of single C MS synapse results in the |
|
| 57:35 | of about half a millivolt activation of single motor neuron and plate synapse results |
|
| 57:45 | a massive depolarization of 40 plus So we call this a very effective |
|
| 57:53 | . High fidelity. That means that action potential in this terminal will cause |
|
| 58:01 | twitch of the muscle will cause a . Why? Because remember, we |
|
| 58:07 | the threshold and the threshold is about 40 millivolts. So to reach the |
|
| 58:19 | from minus 70 to minus 40 delta milliwatts, what does neuromuscular junction |
|
| 58:31 | It gives you a delta of 40 , it guarantees the depolarization for potential |
|
| 58:37 | will cause action potential in the muscle contraction of the muscle. It doesn't |
|
| 58:45 | that in the CNS in the How do you reach delta 30 |
|
| 58:55 | If one synapse produces half a millivolt , how many synapses do you need |
|
| 59:03 | activate? In order to cause a enough change of 30 millivolts from minus |
|
| 59:09 | to minus code 60 plus side to synopsis. It's not as reliable. |
|
| 59:15 | way more graded responses. We almost this like analog coding. And you |
|
| 59:22 | want that in the muscles because if muscle command is contract, you |
|
| 59:27 | contract the cup of pen. You want it to contract on the half |
|
| 59:31 | and not deduct the pen. You to have a reliable transmission. But |
|
| 59:37 | the command is, is always execution that man. And that is because |
|
| 59:43 | this very high fidelity neuromuscular junction, action potential will get produced by sodium |
|
| 59:52 | potassium channels. So we haven't talked yet. So where are these sodium |
|
| 59:57 | channels? So the the seco molecules to clo receptors in they produce this |
|
| 60:05 | 40 plus millivolt change. With that potential. There are channels, voltage |
|
| 60:12 | sodium channels, potassium channels as well calcium channels that are involved in generating |
|
| 60:19 | in the muscle that are located deeper these geal ho So how do you |
|
| 60:24 | the vatic fated sodium channels with Where does depolarization come from acetyl receptor |
|
| 60:34 | of sodium causing this massive input opening sodium channels and initiating the actual |
|
| 60:43 | in the muscle. The duration of action potential in the muscle is uh |
|
| 60:49 | five milliseconds in skeletal muscle. So longer in duration and that is equivalent |
|
| 60:57 | a muscle contraction. Essentially there you the motor neuron and uh most of |
|
| 61:05 | cells that we'll talk about in inter cells will have the fastest action potentials |
|
| 61:13 | the order of one to few milliseconds the most, but typically less than |
|
| 61:19 | milliseconds. The skeletal muscle action potentials about five milliseconds in duration or |
|
| 61:29 | With the cardiac uh ventricle contraction and potentials that are in large part, |
|
| 61:35 | mediated by calcium conducts are hundreds of in duration to 200 milliseconds plus in |
|
| 61:49 | . This is a single vesicle, we call a unitary epsp. If |
|
| 61:56 | activate a unitary epsp, you'll get depolarization of about half a mill in |
|
| 62:02 | CNS versus neuromuscular junction where you have potentials throughout acetylcholine. So, channels |
|
| 62:11 | the massive depolarization of 40 millivolts, will always reach this threshold for action |
|
| 62:18 | generation in the muscle. Yeah. I was wondering in the last |
|
| 62:21 | why the cardiac was so long in compared to the uh skeletal and the |
|
| 62:29 | . It it depends on the kinetics the channels that are involved and some |
|
| 62:34 | the channels that are involved in cardiac activation or prolonged activation and prolonged uh |
|
| 62:41 | channels, um sodium and also calcium . So different different channels, different |
|
| 62:48 | kinetics. So um now why is like slower? I don't know that's |
|
| 62:55 | nature build it, right? Uh we need the fastest, I guess |
|
| 63:00 | in the brain then followed by muscle and uh cardiac is is is the |
|
| 63:07 | . Yeah, it's constantly regenerating itself it's gone. So it's like a |
|
| 63:12 | . So that's a good point. And if it goes too fast, |
|
| 63:17 | we will have a shorter lifespan. there's some, some evolutionary reason for |
|
| 63:25 | too. But very good question. you. OK. So major |
|
| 63:34 | we keep coming back to them, talking about them, keep mentioning them |
|
| 63:42 | we are going to be discussing, are pop THS but I also added |
|
| 63:47 | other things. So this is our molecule. You can see that uh |
|
| 63:53 | , the major inhibitory neurotransmitter is just decarboxylate version of glutamate. So you |
|
| 64:00 | lose the carboxyl group coo H here it turns into Gaba, uh this |
|
| 64:07 | glycine is the third major amina uh . You can see that they come |
|
| 64:13 | different sizes and different shapes. Uh are 1234 carbon chains. This is |
|
| 64:25 | carbon chain shorter, this is So these are larger molecules to see |
|
| 64:33 | coline norepinephrine. It has a So it has many carbons in the |
|
| 64:40 | . And you can see for substance P those are huge, uh |
|
| 64:47 | molecules well huge compared to the uh amino acids like glycine. And um |
|
| 64:57 | influences things size, influences how things going to get packaged, how, |
|
| 65:03 | they're going to get synthesized, how they're going to get released. |
|
| 65:07 | all influences that better molecules that we'll discussing in this course are adenosine and |
|
| 65:15 | TP A denison is the core of demo triphosphate. And we learned that |
|
| 65:23 | is the major energy molecule in the and the brain that's produced by |
|
| 65:30 | But A TB is also A N there are a TP receptors uh in |
|
| 65:38 | , very active of glial cells. , it's a nontraditional if you may |
|
| 65:46 | adenosine as the core of A TP a very interesting molecule. It interacts |
|
| 65:55 | adenosine receptor. So A PP interacts this P two Y receptor. PTYR |
|
| 66:01 | glia adenosine interacts with ademas receptors of and adenosine receptor is a target for |
|
| 66:13 | . So you'll learn that uh adenosine in the evening time go up because |
|
| 66:19 | promotes sleepiness or drowsiness. And it down regulates glutamate relief and then those |
|
| 66:30 | of a demos and they cycle through day. So some of these molecules |
|
| 66:35 | not at constant levels in our brains bodies. Adenosine levels go up at |
|
| 66:42 | and they reduce in the morning time that there is a whole diurnal or |
|
| 66:48 | rhythm to, to these molecules, synthesis and even release uh in the |
|
| 66:56 | time to facilitate waking up. Most us will consume caffeine coffee, |
|
| 67:06 | bubble tea. Somebody left this Coca Cola Coca originally comes, it |
|
| 67:16 | made with cocaine. Cola comes from nut, which is uh one of |
|
| 67:23 | best natural sources of caffeine. And a, it's a very popular nuts |
|
| 67:29 | West Africa, in particular Nigerian Uh colon nuts. I don't know |
|
| 67:35 | they still make it with colon or synthetic caffeine. Now, probably, |
|
| 67:39 | those were the original uh substances in and caffeine interacts with the denison receptors |
|
| 67:46 | promotes glutamate release. So if adenosine glutamate release and makes you sleepy, |
|
| 67:55 | uh uh activation or blockade. In case, by, by caffeine wakes |
|
| 68:01 | up and some of us are so to caffeine cannot function without caffeine. |
|
| 68:07 | know, some people will say, talk to me before my coffee or |
|
| 68:11 | . And then we also have caffeine sometimes three on one intersection. |
|
| 68:17 | Starbucks and somebody else Dunkin Donuts. it's pretty addictive substance. Actually, |
|
| 68:23 | acting through a dentist and receptors. more addictive than some of the other |
|
| 68:27 | that are prohibited. Uh illegal nitrous oxide and carbon monoxide. So |
|
| 68:35 | have gasses as neurotransmitters, gasses as , they're lipid soluble, they're not |
|
| 68:41 | to be stored in muscle lipid That means that they cannot be bound |
|
| 68:46 | livid membranes. And uh always use joke when you have a Branch |
|
| 68:52 | I have too much c uh too gas in my brain. So uh |
|
| 69:00 | also interact with specific sufferers, but nontraditional. They are transmitters and they're |
|
| 69:05 | packaged in the vesicle and they're not in den for vesicles either like |
|
| 69:12 | which we will discuss in the next . Uh But at a later time |
|
| 69:17 | finally, the endocannabinoid, we will about the endocannabinoid system and the molecules |
|
| 69:24 | we produce inside our bodies like a like molecules, the same cannabis like |
|
| 69:30 | that define the cannabis plant that we endocannabinoid. The molecules in cannabis plants |
|
| 69:36 | called phyto cannabinoids or clod produced The endocannabinoid and phyto cannabinoids. They |
|
| 69:43 | with the endocannabinoid system and it's a neurotransmission, both glutamatergic and Gabor ergic |
|
| 69:51 | regulated system. They are also lipid just like gasses. So there's going |
|
| 69:57 | be different rules about how neurotransmitters packaged vesicles versus dense four vesicles versus the |
|
| 70:06 | that are not packaged. How do get synthesized? How do they get |
|
| 70:10 | ? Uh and their effects on the and the body. And from the |
|
| 70:16 | perspective, cannabinoid receptors, CB one CB two, the G protein coupled |
|
| 70:23 | in the brain are the most abundant codeine coupled receptors in the brain by |
|
| 70:27 | expression ones. So we'll learn a about in the cannabinoid system and how |
|
| 70:32 | interact with neural transmission that are endogenous produced by us and also phyto or |
|
| 70:42 | substances that will interact within the cannabinoid as well. Thank you very |
|
| 70:47 | Thank you for your patience. I'll everyone on |
|
