| 00:01 | This is lecture nine of Neuroscience. we begin talking about neurotransmission. And |
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| 00:07 | , we start talking about one of favorite of many of the people's neuroscience |
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| 00:12 | neurochemistry favorite stories. It's Uncle Lowy discovered chemical neurotransmission. And Uncle Lowe |
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| 00:22 | himself in this account in 1953 that 1921 the ow turned on the light |
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| 00:30 | jotted down a few notes on the slip of paper. Then I fell |
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| 00:34 | again. It occurred to me at o'clock in the morning that during the |
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| 00:37 | I had written down something most but I was unable to decipher the |
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| 00:43 | that Sunday was the most desperate day my whole scientific life during the next |
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| 00:48 | . However, I awoke again at o'clock and I remembered what it was |
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| 00:53 | time. I did not take any . I got up, immediately went |
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| 00:56 | the laboratory made the experiment on the heart described above. And at five |
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| 01:03 | , the chemical transmission of nervous impulse conclusively proved careful consideration in daytime, |
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| 01:10 | have undoubtedly have re acted the kind experiment at the form because it would |
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| 01:15 | seemed most unlikely that if a nervous released a transmitting agent that would do |
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| 01:21 | , not just in sufficient quantity to detector organ in my case, the |
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| 01:27 | , but indeed, in such an that it could partly escape into the |
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| 01:32 | which filled the heart and could therefore detected. Yet, the whole nocturnal |
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| 01:37 | of experiment was based on this eventuality the result proved to be positive contrary |
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| 01:44 | expectation. So what experiment he what dream he had, he had |
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| 01:50 | dream that he needed to go to lab. And he was already working |
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| 01:56 | frog hearts and muscles. And there's nerve, the cranial nerve, 10 |
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| 02:04 | nerve. So later in this we will study the cranial nerves, |
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| 02:08 | nerve very extensively runs out of the stem area and innervates a lot of |
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| 02:14 | viscera, a lot of organs, also amongst those organs, the cardiac |
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| 02:19 | or the heart. So when you the vagus nerve, the known effect |
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| 02:24 | vagus nerve stimulation is that the heart will slow down, which is equivalent |
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| 02:32 | reducing the number of contractions in the . So what he thought, |
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| 02:40 | let me put this fluid and superfuse heart with physiological fluid. And while |
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| 02:48 | doing that, I'm going to stimulate nerve, this vagus nerve projects on |
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| 02:55 | the cardiac muscle. And as this runs through the heart, and I'm |
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| 03:01 | the vagus nerve, I'm going to this fluid from the stimulated heart. |
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| 03:08 | I'm going to collect it into a that is now attached to what you |
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| 03:13 | call it a naive heart, meaning it has vagus nerve, but there's |
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| 03:18 | stimulation here of vagus nerve. And can actually even sever vagus nerve off |
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| 03:23 | it all completely all together. But this solution from the stimulated are dripped |
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| 03:30 | this vessel, the contractions and the rate of this naive heart versus the |
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| 03:38 | heart showed the same effect. It slowed down. And that was a |
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| 03:43 | proof that when you stimulate vagus it releases something in the fluids that |
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| 03:50 | bathing the stimulated or the donor And as he wrote, it was |
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| 03:56 | enough of that fluid that chemical in fluid following the stimulation to now exert |
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| 04:03 | same effect on the uns stimulated And it's a great story because one |
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| 04:12 | my mentors who was a MD phd is neurosurgeon. He used to say |
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| 04:19 | sleep is for the week and uh know, sleep is very important and |
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| 04:25 | should sleep, have a really good cycle. But sometimes things need to |
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| 04:31 | done and you just need to get in the middle of the night at |
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| 04:36 | o'clock and go straight to the And the other cool thing about this |
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| 04:41 | that his vision, he's so involved his work that he is dreaming the |
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| 04:50 | . So that, that shows you the amount of dedication, not just |
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| 04:54 | up at three o'clock, but the of dedication in his brain and his |
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| 05:00 | life that he spends thinking about how prove or see how there is a |
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| 05:06 | uh in this neurotransmission pathway. And chemical that he discovered, they called |
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| 05:13 | the begu stuff, begu stuff begu in Germany. And it's acetylcholine, |
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| 05:20 | turned out to be acetylcholine. So will say, wait a second, |
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| 05:25 | , we talked about a Pseudy Colline the neuromuscular junction because we talked about |
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| 05:32 | you have the motor neurons that project the skeletal muscles and they release |
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| 05:41 | right. This is one of the that you learned about motor neurons versus |
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| 05:46 | gaba interneurons. And in the skeletal , when we talked about the reflex |
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| 05:52 | , we said that when the motor activates a muscle and releases the pseudocode |
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| 05:57 | skeletal muscle contracts. But here it the opposite effect here in the cardiac |
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| 06:04 | is not like skeletal muscle. You today, the skeletal muscle expresses only |
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| 06:10 | subtype of a pseudo receptor and the expresses a different type of uh acetylcholine |
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| 06:18 | . Uh and you'll learn that there's , I am atropic acetylcholine signaling and |
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| 06:25 | metabotropic acetyl coal signaling that will have effects on the cellular physiology, membrane |
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| 06:33 | as well as uh molecular physiology inside cell. Ok. So that's why |
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| 06:40 | a very important story and that's why important to understand that the same |
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| 06:45 | While it can cause contractions of the muscles, the same chemical can cause |
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| 06:52 | contractions of the cardiac muscle. this clearly illustrates that the response of |
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| 07:02 | cells or the types of the cells the types of the muscles does not |
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| 07:07 | on the chemical that stimulates it, depends on the receptors to which that |
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| 07:13 | bonds and that those receptors have distinct and sometimes opposing roles even stimulated by |
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| 07:19 | same chemical. Most of the things we talk about and so far have |
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| 07:27 | is we talked about how there are synopsis and then excitatory synopsis you'll have |
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| 07:35 | chemical synopsis, you'll have release of a presyn ically that glutamate will bind |
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| 07:41 | glutamate receptor channels. So, in first section of the course, we |
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| 07:47 | we focused on voltage gated sodium channels voltage-gated potassium channels. And these are |
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| 07:55 | receptor channels and so binding the glutamate cause influx of sodium which will cause |
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| 08:02 | . This hyper polarization will come from fact that you'll learn in a couple |
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| 08:06 | electrics that these channels are also permeable potassium monophysite direction, creating what we |
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| 08:12 | excitatory poop potential or epsp. In to chemical transmission and chemical synopsis, |
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| 08:21 | have also electrical synopsis. And it discovered, I believe in the sixties |
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| 08:27 | if you have two electrodes and two cells and two distinct neurons and you |
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| 08:35 | an action potential in cell. this action potential, this potential that |
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| 08:39 | learned about which will be about 100 or so in amplitude immediately. Without |
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| 08:46 | time delay. Without any time you see a very small electrical o |
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| 08:53 | response that gets recorded in the second , which is only a fraction about |
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| 08:58 | millivolt in size. But it's an replica of this action potential. And |
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| 09:04 | important because if you release neurotransmitter. at this stage, here you release |
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| 09:14 | . OK, you can call this the stimulus that neurotransmitter is going to |
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| 09:21 | across the synaptic cleft. It's going bind to postsynaptic receptors here and then |
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| 09:30 | membrane potential, sodium coming in the potential is going to change. And |
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| 09:36 | there's going to be a delay from there was a stimulus which this would |
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| 09:40 | an action potential arriving in the pre terminal. This is that stimulus right |
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| 09:47 | . It's the same. OK. would be about 5 to 15 millisecond |
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| 09:54 | . Here. In this delay, call synaptic delay and that synoptic delay |
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| 10:05 | be observed. In chemical synopsis. takes time for the neurotransmitter to cross |
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| 10:10 | space of 20 nanometers to bind to postsynaptic receptors to evoke this epsp response |
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| 10:18 | we're looking at on the left But in electrical synopsis, there's no |
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| 10:26 | . So if I put a dashed through here or if I held up |
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| 10:30 | a yardstick, something like that, is not our steps is that thing |
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| 10:39 | doesn't work. So if I held up here, you would see that |
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| 10:44 | all occurs within about the same It might be a tiny little delay |
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| 10:50 | not really. OK. So this in milliseconds. So it might be |
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| 10:54 | fraction of millisecond delay, but it not be as in the chemical synopsis |
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| 11:00 | 5 to 15 mill uh milliseconds. SPS and IP sp. So ep |
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| 11:09 | are exci possy tic potentials, they generated when glutamate binds to glutamate |
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| 11:16 | In this case, channels that generate EPSD IP SPS are inhibitory fo synoptic |
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| 11:25 | . They cause the hyper polarization. ep SPS are depolarizations. So EP |
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| 11:32 | will try to drive the membrane potential its threshold value. If this is |
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| 11:39 | resting membrane potential, the cell will receiving some very small EP SPS, |
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| 11:46 | small IP sp, some stronger and EP SPS, very larger, maybe |
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| 11:54 | SPS sometimes until it reaches this value the threshold for action potential. And |
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| 12:03 | the EPSP is large enough to reach value, it will then subsequently generate |
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| 12:10 | action potential and the EPSP are longer duration. So I should actually draw |
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| 12:16 | a little bit differently. Once it here, it almost looks like a |
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| 12:21 | line like that. And this is actual potential that we've learned about. |
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| 12:28 | hyper polarization come when gamma gets we said now because it will |
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| 12:33 | In this case, these are troop that we're talking about. In both |
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| 12:37 | , they're called ionotropic receptor channels because the lien binds to this receptor, |
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| 12:43 | channel conducts ions. So it's OK. So this is ionotropic glutamate |
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| 12:50 | Gaba receptor and binding of Gaba to ionotropic Gabba A receptor will cause influx |
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| 12:57 | fluoride and negative charge flexing inside the will cause hyper polarization in the form |
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| 13:04 | IP SP. When we talk about neurotransmission, there's some very interesting things |
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| 13:12 | we have to first place kind of a on a gross anatomical scale. |
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| 13:21 | This is gonna be my cartoon of of the brain. Forgive me and |
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| 13:28 | brain migraine. The major neurotransmitters here shown in different classes. You have |
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| 13:41 | acids, you have amines, dopamine serotonin and you have peptides. |
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| 13:48 | we already mentioned peptides. Remember we about cholic system CCK. We said |
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| 13:54 | some of the parameter cells in the are CCK positive versus CCK negative. |
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| 13:59 | also saw that you can have vesicles with neuropeptide vesicles co expressed in the |
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| 14:08 | . So petal cells that release glutamate produce CCK and neuropeptide. It means |
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| 14:15 | can co express glutamate and CCK and a release mechanism and recovery biosynthesis mechanism |
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| 14:24 | glutamate and CCK. So now one that in which these systems differ, |
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| 14:34 | is really important to understand from the beginning is that if we stain the |
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| 14:41 | and this is just a very sparse , but if we stain the |
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| 14:48 | And we asked this question, where glutamate expressed? Where are the cells |
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| 14:56 | that express glutamate? The question where glutamate expressing themselves? And the answer |
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| 15:06 | that it will be everywhere. You that you had them in, in |
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| 15:11 | cord, you have them in the , you have them in the |
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| 15:17 | you have them in different regions of brain. It's very broadly distributed. |
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| 15:22 | there are billions of these glutamic And typically in cortical circuits, rhy |
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| 15:32 | meic neurons account for about 80 to percent of the of the cells. |
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| 15:40 | that sort of thing. What about , the major inhibitor neurotransmitter? Is |
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| 15:47 | the same case? Yeah. So you ask the question, where is |
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| 15:53 | expressed? And you do a stain inhibitory gaba producing neurons, let's say |
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| 16:01 | is called G but there aren't as of the inhibitory cells and most of |
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| 16:06 | special cortical circuits in the cortical you have about 10 to 20%. |
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| 16:14 | we're talking about the cortex here and cortex, you have 10 to 20% |
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| 16:21 | the inhibitory GVA producing cells versus excited glutamate, producing and so on. |
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| 16:29 | their expression amino acid expression is wide different parts of the brain and different |
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| 16:39 | when it's billions of cells in the disproportion, especially when it concerns the |
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| 16:46 | . The cerebral cortex. What about means it means the same way. |
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| 16:51 | if you ask the same question where acetylcholine producing neurons located? And you |
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| 17:00 | the brain just like you took the brain there as they drew and they |
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| 17:05 | it throughout. And you saw gag all over the answer would be |
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| 17:12 | the cells that synthesize and produce acetylcholine confined to what we call these |
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| 17:21 | which are collections of cells responsible for same very similar functions on me that |
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| 17:27 | to complex basal nucleus of main art medial septal nuclei. And that's |
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| 17:37 | So these are very small nucleon in brain that are responsible for producing all |
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| 17:44 | the acetylcholine. That's all of the acetylcholine has. And we, when |
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| 17:50 | talk about the means we talk about and even in your class notes and |
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| 17:57 | , it's called diffuse modulatory systems. you'll understand what modulatory means to the |
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| 18:05 | of the second lecture and diffuses the is that these nuclei will have axons |
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| 18:13 | project very diffusely and it's very difficult delineate their precise synoptic endings and |
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| 18:22 | but sometimes they're referred to as the systems. So we sort of like |
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| 18:27 | , almost like para crime, like . And then of course, the |
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| 18:32 | to these neurotransmitters like acetylcholine will be on the type of the receptors that |
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| 18:37 | binds in different areas of the And so now we have these nuclei |
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| 18:45 | project into, you know, the and into the spinal cords of cortically |
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| 18:51 | thalamus and cortical all throughout the Uh But there are far and few |
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| 19:00 | between compared to the excitatory gabba who make the film. So in some |
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| 19:06 | , there is tens of thousands or hundreds of thousands of those neurons. |
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| 19:12 | the question is if you a blade if you surgically remove this nucleus, |
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| 19:19 | and this nucleus, does that mean is no acetyl toin in the |
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| 19:25 | And the answer is yes, there's sign. So it's very kind of |
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| 19:30 | select number. If you may, special, there's a few of |
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| 19:35 | they project very broadly. And if look at other means, this is |
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| 19:39 | dopamine system. You have me tal and substantial migraine that will be providing |
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| 19:45 | to the brain here at these two equally so that there is significant damage |
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| 19:50 | this part of the brain to substantial and BT A. You will compromise |
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| 19:56 | dopamine system. Yeah. Is it acetylcholine or very low acetylcholine in the |
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| 20:04 | ? It, it, it's um a small number of cells. So |
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| 20:10 | to the amount and metabolism of glutamate gaba, obviously, yes, |
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| 20:16 | accordingly, you have so many more processing amino acids, it's gonna be |
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| 20:22 | of the uh metabolic turnover and uh lesser amount of those molecules. |
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| 20:31 | What does CCTD? I mean for CTX cortex? That's an abbreviation for |
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| 20:40 | . Sorry. Um Use my bad anatomy habits. I should put CCK |
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| 20:47 | to him and ask you what is ? What is CTX? So, |
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| 20:50 | know, this is all beli you Gaba, you know, we'll be |
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| 20:54 | around saying G A Gaba, everybody is gonna be either G or |
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| 21:00 | an ND A or am a, know, like you play Tetris |
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| 21:06 | That's interesting. It's like this ancient , computer game. It's like things |
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| 21:13 | and you have to stack them Then you start seeing like stacking |
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| 21:18 | start seeing the neurotransmitters and thinking who more like dopamine, who is more |
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| 21:24 | serotonin? And that's important thing to about because when we talk, for |
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| 21:32 | , at the very beginning about different disorders, I asked you to know |
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| 21:37 | disorders. Um dopamine uh disorders are disorders such as Parkinson's disease. And |
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| 21:45 | because there's significant dopamine input into the here that is involved in initiation and |
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| 21:55 | of some of the motor commands that recall of some of the complex motor |
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| 22:01 | that then get sent to the motor . They have this acetylcholine system. |
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| 22:12 | have this dopamine system, you have serotonin system have rapha nuclei that supplies |
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| 22:20 | to the whole brain and norepinephrine So this is just to give you |
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| 22:24 | general understanding of these different systems and expression where they are, how limited |
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| 22:32 | are compared to amino AIS. And start forming this uh view that maybe |
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| 22:40 | and gabble can be viewed as a and off switch. So G's excitation |
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| 22:46 | to fire actions, glutamate is excitation fire action potentials. Glo's inhibition inhibit |
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| 22:55 | cell activity. But then these what we call these dopamine. Uh |
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| 23:03 | I mean, like uh modulators, can imagine they add a lot of |
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| 23:08 | . So some of them will be necessarily turning on and off the light |
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| 23:13 | maybe just dimming part of the lights the room. Ok. And that's |
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| 23:19 | it's modulation. So it's not all on all off, but it's a |
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| 23:23 | amount of light and different amount of in different parts of the classroom with |
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| 23:29 | parts of the brain as they projected different parts of the brain. All |
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| 23:36 | . So gab junctions are the electrical and you can see where two cells |
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| 23:42 | you have an image uh of two and you see they've come very close |
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| 23:48 | and almost fused together. There's actually small distance of about 3.5, 4 |
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| 23:54 | . And this would be what a junction is electrical get junction. The |
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| 24:00 | that they are formed is that you a connection channel and each neuron. |
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| 24:08 | this is neuron. One usually the is about 20 nanometers for the chemical |
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| 24:14 | . But here the membranes can close in physical space about 3.5 nanometers apart |
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| 24:21 | each other and one side of one will contain a Kaon and |
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| 24:28 | Two will also contain an Exxon and connections are comprised of six connect |
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| 24:36 | So the sub units are connect six of them make a connect |
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| 24:42 | And when two connect songs come they form a gob junction or an |
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| 24:49 | junction. So we call, we refer to neurons that have gab junctions |
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| 24:56 | electrically coupled. And that's because ions flow from one cell into the other |
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| 25:03 | through these gap junctions to a certain , uh they can flow in both |
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| 25:10 | . So what we learned, for , about voltage gated sodium channels versus |
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| 25:14 | and sodium was influx and potassium was in here is movement from one cell |
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| 25:21 | the other and vice versa. Apart uh fluxes of ions in both |
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| 25:30 | those gap junctions also allow for the of small molecules such as secondary messengers |
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| 25:36 | as cycle MP. And that's So it's not just a source of |
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| 25:41 | conductance of ions, but it's also a way for cells to exchange certain |
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| 25:50 | . Uh they are always open. they're not gated by voltage, they're |
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| 25:56 | gated by livens, they are always except sometimes they're open more and sometimes |
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| 26:02 | open less. But for the most , they're always open. The way |
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| 26:07 | think that they open more or less that there might be a little bit |
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| 26:12 | a torque that gets put on the sides. And with that torque, |
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| 26:17 | opening narrows a little bit. So less open and sometimes they go into |
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| 26:21 | position where the opening is basically juxtaposed without the torque and allow for more |
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| 26:29 | of violence on small substances. It's fast transmission. I already told you |
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| 26:34 | there is no delay and neurons are fast. You have to integrate P |
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| 26:42 | , excitatory personality potentials and inhibitory IP occurring simultaneously at the same time. |
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| 26:51 | these gap junctions can allow for very neurotransmission can mediate very fast neurotransmission. |
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| 27:00 | if it's only a fraction of that potential as we saw 100 millivolts on |
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| 27:04 | side. One millivolt on here that still a significant of depolarization sometimes in |
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| 27:12 | , which allows for these gap junctions synchronize neuronal networks. So these neuronal |
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| 27:20 | , these two cells are sitting in neural network that is receiving the same |
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| 27:25 | . This is cell one on top this is cell two and these two |
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| 27:29 | are interconnected through the gap junctions What will be observed is that those |
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| 27:36 | almost all of the time will fire controls at exactly the same time, |
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| 27:43 | all of them. And that means they're synchronized, that their activity is |
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| 27:49 | . And if you remove gap junctions these two cells number three and |
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| 27:56 | but you're still putting the same stimulus the neural network onto the circuit where |
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| 28:03 | two cells are located, those two will fire action potentials. But those |
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| 28:09 | potential shells will be what we call of sync, it will occur at |
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| 28:14 | time points. So you will lose synchrony. And that's important because quite |
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| 28:22 | in order for neural circuits to be , large populations of neurons need to |
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| 28:28 | synchronized. And they some of the , some of the activities that we |
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| 28:32 | in the brain are very fast in order of 100 plus cycles per |
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| 28:38 | And G allow neurons to use the between the cells to have these neurons |
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| 28:47 | and fire at the same time so they can make more impact on neurons |
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| 28:52 | . Now, with gaps, do have uh always have the same dialect |
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| 28:58 | do different categories of neurons have That's a good point uh to different |
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| 29:05 | of neurons will express gab junctions. here we're talking about neurons but gab |
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| 29:11 | are also present in gluteal cells. a very good point. And uh |
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| 29:16 | we look at the dialects, we stimulate individual cells, we don't stimulate |
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| 29:22 | networks while the interconnectivity of these different cells and the objections may affect how |
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| 29:30 | whole network activity happens. So, right, chemical synopsis are everywhere on |
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| 29:38 | but mostly on dendrites and mostly on . So if there are dendrites that |
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| 29:44 | oxo, if they're so are a already uh discussed. And I think |
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| 29:50 | is another example of where you can a pre synaptic active zone here loaded |
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| 29:55 | vesicles and then another presynaptic active zone loaded with synaptic vesicles that will store |
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| 30:02 | such as amino acids and the means also down score vesicles. Also what |
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| 30:08 | call them. A you lies a or Granules and those secret or Granules |
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| 30:13 | contain neuropeptides. So again, a cell can pop neuropeptide and an amino |
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| 30:21 | and can co express it and core it. There will be different rules |
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| 30:25 | the synthesis of this molecules and release we'll discuss a little bit later. |
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| 30:30 | , all of the uh axons that onto the cmos and onto the dendrites |
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| 30:37 | play into the integrated properties of the that they're targeting. In other |
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| 30:42 | they will influence whether the target cell find action potential or not. Because |
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| 30:48 | it is a very strong excitatory input there's hundreds of them close to the |
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| 30:53 | , then the cell will integrate the information and we'll fire the action |
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| 30:58 | We'll have a lot of ep depolarizations of fire action potentials. If |
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| 31:04 | on the SOMA, it's the same , also quite a lot of |
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| 31:08 | So it will influence how the cell respond to all of the inputs, |
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| 31:14 | the cell will integrate that information. the cell will have to integrate excitatory |
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| 31:20 | inhibitor information, excitatory and inhibitory In this situation, you have ason |
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| 31:29 | and that's a little bit different because these axons will help the cell or |
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| 31:38 | influence the cell, whether it's going fire an action potential or not. |
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| 31:45 | , the C has made that decision by other inputs on dendrites. And |
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| 31:52 | this guy here is conflicting its axon it can no longer this this axonic |
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| 31:59 | , it doesn't influence integrate properties of cells. It just modulates the |
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| 32:06 | So if it's an inhibitor neuron onto action potentials, maybe there's a train |
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| 32:12 | 10 action potentials and this inhibitor neuron this excitatory Axion will reduce that number |
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| 32:19 | 10 action potentials by inhibiting to let's seven action potentials that will finally be |
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| 32:25 | to break through and arrive at the terminal. And so there's a modulatory |
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| 32:32 | . So it really controls the output the integrated properties, how it's being |
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| 32:38 | by the cell uh by accumulation and of all of the exci inhibitory |
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| 32:43 | Then you also have dendrodendritic synopsis. like wait a second, that's the |
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| 32:49 | , sir and uh axon terminal. for the most part, that's what |
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| 32:53 | study. There are always exceptions to rules and these are rare, but |
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| 32:57 | are dendrodendritic Synopsis uh that can be in the as well. Some of |
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| 33:04 | synopsis, if you visualize them, will be a symmetrical, that means |
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| 33:08 | they will contain pretty narrow, pretty , spatially presynaptic active zones and pretty |
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| 33:16 | p synaptic densities and they'll also contain rounded vesicles. And there are other |
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| 33:24 | that if you visualize them you will that there are flattened vesicles and that |
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| 33:30 | both sides, the presynaptic and the synoptic sides are symmetrical, refer to |
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| 33:37 | as symmetrical differentiations, membrane differentiations. are about equal sides. So one |
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| 33:43 | these sy synopsis is inside to one them is inhibitory and you'll have to |
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| 33:49 | it out as your whole impression. , you also see that there are |
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| 33:54 | sizes of synopsis and different numbers within individual axon. So this is a |
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| 34:00 | classical axon onto dendritic spine. That's we study most of the time. |
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| 34:06 | . And then you have the cell , but you can also have axons |
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| 34:09 | bifurcate around five, they split basically two endings. So we'll have two |
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| 34:16 | terminals and one of them may be large and they have three active zones |
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| 34:21 | exposed to three posy densities and one them may be small. So there's |
|
| 34:26 | , some of them will wrap So this is axon wrapping around. |
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| 34:30 | axon will have 123456789, 10 re terminals. 10 synopsis essentially around this |
|
| 34:42 | that form. And then other you'll have six or seven, some |
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| 34:48 | them will have three release sides, will have one release sides. So |
|
| 34:53 | vary in size and in shape and size and the shape and the number |
|
| 34:59 | contacts that it makes in the but which it communicates is important. |
|
| 35:04 | important to synaptic plasticity. So the is the synoptic communication is the larger |
|
| 35:10 | the synapse. The more of the synaptic contacts it can be making and |
|
| 35:17 | released more of the release zones and neurons that don't communicate with each other |
|
| 35:22 | well during early development. And even adulthood, uh they don't sync up |
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| 35:29 | activity and their synopsis may become smaller small release sites and sometimes may be |
|
| 35:36 | driven away. Not just the dendritic . We learned about dendritic spine pruning |
|
| 35:41 | early development, but also the axons innervate those dendritic spines equally. |
|
| 35:48 | during synaptogenesis and during the upkeep of synaptic plasticity in in adults, and |
|
| 35:56 | do have uh neurogenesis and synaptogenesis in brains. We just don't have as |
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| 36:02 | of the stem cells in adult brains we have when we are newborns. |
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| 36:10 | we're much more stemming when we're born the older we grow, the less |
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| 36:16 | we get. Uh and I will in the semester, I will post |
|
| 36:22 | TED talks for everyone to have in kind of a cachet neuroscience, TED |
|
| 36:28 | , cachet. And one of those will be uh you can grow new |
|
| 36:33 | cells in adults. And uh the tells you how to do that. |
|
| 36:40 | there are certain activities and certain elements actually promote a healthy state of the |
|
| 36:46 | cells in the brain and certain activities certain habits that decrease the availability of |
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| 36:52 | stem cells uh and, and aging or imbalanced uh uh uh imbalanced |
|
| 37:03 | brains of human. So we also about the dendritic spines. We |
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| 37:08 | oh, they have the spine apparatus have mitochondria right next to the |
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| 37:13 | So you need energy for this postsynaptic . We also said that they have |
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| 37:19 | complexes in the postsynaptic dendritic spines. we said that that makes them somewhat |
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| 37:27 | and biochemically independent from at least the . They don't have to communicate through |
|
| 37:31 | SOMA of the cell. Uh The thing to notice is that you have |
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| 37:36 | presynaptic neuron with neurotransmitter vesicles, you the pos synaptic density here and in |
|
| 37:45 | or what color is the cyan actually cyan color wrapped around the synapse, |
|
| 37:51 | have glial cell. And so that's we refer to neuronal signaling uh as |
|
| 37:59 | tripartite synapse where neuron, one is part, neuron two is the second |
|
| 38:07 | and neuron glia is the third sorry neuron, one, neuron two |
|
| 38:13 | glia is the third part. And it's tripartite synapse and they'll say, |
|
| 38:19 | , is it just insulation? In case, we're talking about Astros? |
|
| 38:25 | you will notice uh as you learn the next two lectures, I ostracizes |
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| 38:31 | the amount of glutamate and the amount gaba that is available for signaling between |
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| 38:38 | two neurons. So it's very much involved in metabolic control of the major |
|
| 38:46 | or inhibitory neurotransmitters in the brain. If you recall from the very early |
|
| 38:54 | of uh Ramona Cajal with Golgi Ramona Cajal was able to reveal the |
|
| 39:02 | already. However, as the microscopes more and more with greater and |
|
| 39:10 | better, better with greater and greater resolution, we could see more and |
|
| 39:15 | of the dendritic spines. When we to electron microscopy, we could really |
|
| 39:20 | the three dimensional structures of these But in the early days, the |
|
| 39:27 | or electron microscopy imaging was just done two dimensions. And this is another |
|
| 39:34 | of type of discovery in your book The Love of dendritic spines that describes |
|
| 39:39 | by Doctor Kristen Harris who not only but was extremely persistent and just probably |
|
| 39:49 | Otto Lowy dreaming the dendritic spines at and rushing into the bob that she |
|
| 39:56 | a part of the era that ushered understanding of the three dimensional structures of |
|
| 40:03 | and deri spines, not just on external morphology, but also what is |
|
| 40:11 | composition of these dendrites and dendritic So what you can do in a |
|
| 40:19 | dimensional electron microscopy is you can use tags or stains uh or markers, |
|
| 40:28 | example, for cyto skeletal elements versus markers that specifically label postsynaptic densities in |
|
| 40:38 | lytic spines. And now, instead just having a simple two dimensional way |
|
| 40:45 | describing Ridic spines and saying, remember we talked how important the shape |
|
| 40:50 | the number and the densities are uh spines during early development. And we |
|
| 40:56 | about this disease of Fragile X which is uh intellectual uh recordation and |
|
| 41:05 | uh in the in in impairments. what we see now is that it's |
|
| 41:12 | just external shape of these spines. important when we spoke about the cyto |
|
| 41:18 | elements. We said, well, a second, the cytoskeleton elements support |
|
| 41:21 | shape of the spots. And we that they can polymerize into longer chains |
|
| 41:26 | depolymerize. And that means that if understand the structure, the internal structure |
|
| 41:33 | how that shapes the outside boundaries of synopsis and dendritic spines in three |
|
| 41:41 | inside and out, you have gained lot more knowledge on how these independent |
|
| 41:48 | units function and what is the actual ? So the skeletal support structure in |
|
| 41:53 | finds overlaid with other elements that indicate um profiles uh of and spatial maps |
|
| 42:06 | the cells. So, neurotransmitter, transmission principles of chemical transmission, you |
|
| 42:15 | to have neurotransmitter synthesized, you have load this neurotransmitter into the vesicles. |
|
| 42:21 | vesicles have to fuse with the possible neuro transmitter has to be released, |
|
| 42:27 | released into the synoptic clu. It to be bind to the phos |
|
| 42:32 | Once it binds to the phos there has to be a biochemical or |
|
| 42:38 | electrical is an EP SP. When talk about metabotropic transmission, we'll talk |
|
| 42:43 | bio chemical response. And as far secondary messengers, uh porl depos |
|
| 42:49 | What happens inside the cell. And finally, these uh uh neurotransmitters. |
|
| 42:56 | when we talk about glutamate or they are agonists because they open glutamate |
|
| 43:04 | glutamate receptor channels. So the we already talked about agonist and antagonist |
|
| 43:10 | they bind to glutamate receptor channels. later, we'll talk about acetylcholine receptor |
|
| 43:16 | . Once they bind to glutamate receptor , they don't stay there forever. |
|
| 43:22 | bind to the channels. Remember we about um uh how in voltage gated |
|
| 43:29 | channels. Once you had a confirmational of opening the channel. Following that |
|
| 43:34 | change, there was also an activation that channel. So things are tied |
|
| 43:38 | . So once you initiate a confirmational with this Ln binding site, |
|
| 43:44 | eventually, with some time these molecules , they don't form covalent bonds. |
|
| 43:52 | they dissociate from the protein receptors and either get broken down in the synoptic |
|
| 44:01 | class here or they get r are back and transported back into the three |
|
| 44:07 | termin. So they don't bind to receptors and, and, and stay |
|
| 44:12 | for us. So they are, reversible, they can bind and un |
|
| 44:18 | and they can get cleared out of synapse. And in contrast to some |
|
| 44:23 | the substances that can irreversibly bind um receptor channels. OK. So let's |
|
| 44:32 | back a little bit since I see Colline was discovered by OTA Lowy. |
|
| 44:40 | uh this is what Luigi Galvani also uh releasing when he was stimulating the |
|
| 44:46 | , nerves and frogs, uh nerves onto the muscles. So to the |
|
| 44:51 | muscles in the frog at that he just didn't know it was acetyl |
|
| 44:56 | um that was discovered a couple of years later. But we go back |
|
| 45:03 | talk about neuromuscular junction in this case cyto skele uh skeletal muscle and the |
|
| 45:11 | that acetylcholine and the differences between action and also the po synoptic responses that |
|
| 45:19 | will see at the neuromuscular junctions versus central nervous system. Synopsis and some |
|
| 45:25 | the properties of these different potentials. let's go back to our reflex arch |
|
| 45:30 | we started early on. We started about reflex arch and we said that |
|
| 45:36 | neurons they projected to skeletal muscle. , let's zoom in on to these |
|
| 45:41 | of the skep muscles and the uh endings. We refer to it as |
|
| 45:47 | end plate. Uh uh right here the postsynaptic regions and the pore |
|
| 45:53 | you have axons that will ramify into different endings. And if you zoom |
|
| 46:00 | on to one of these endings, of these synopsis, one of these |
|
| 46:05 | will be targeting a certain nerve fibers and it's a very reliable synapse. |
|
| 46:11 | soon as there's going to be release acetylcholine, there's going to be a |
|
| 46:16 | on the muscle fiber or broadly on whole muscle, which is contraction of |
|
| 46:22 | muscle. So what happens is motor action potential is actually as short as |
|
| 46:31 | direction, as short as the action that we discussed in the first |
|
| 46:36 | So approximately two milliseconds in duration. it's really, really fast. So |
|
| 46:42 | what happens at the presynaptic terminal. action potential arrives in the presynaptic terminal |
|
| 46:49 | it causes the fusion of the vesicle the vesicle will open up, release |
|
| 46:55 | acetylcholine content. And po synoptic two molecules will bind to one receptor. |
|
| 47:06 | You have about 200 synaptic vesicles that be stacked here. And once the |
|
| 47:14 | is released, it will bind to postsynaptic receptors. And these are nicotinic |
|
| 47:22 | receptors. So we only have nicotinic receptors in the skeletal muscles. |
|
| 47:33 | abbreviated as N ACH R nicotinic acetylcholine . And they're located within these junctional |
|
| 47:47 | in the muscle, but they're located close to the presynaptic terminals within these |
|
| 47:54 | halls. And as soon as there a release of acetylcholine po synaptic. |
|
| 48:01 | is this massive depolarization that we call end plate potential. This is the |
|
| 48:07 | endplate zone that causes a change of millivolts of greater. And that's significant |
|
| 48:15 | if you recall, you just talked these post synoptic potentials, the EP |
|
| 48:27 | and I PSPs. And I said of them can be really tiny, |
|
| 48:34 | will be a few millivolts in size only if they're really large that will |
|
| 48:40 | the threshold and generate an action But that is a huge contrast to |
|
| 48:47 | we see at neuromuscular junction, you very large amount of neurotransmitter release, |
|
| 48:53 | release and you always have a massive that is caused by a pseudy |
|
| 49:02 | So when acetylcholine molecules, when acetylcholine , two of them and bind to |
|
| 49:14 | receptor and the nicotinic receptor, two these molecules will bound up and sodium |
|
| 49:23 | going to flux inside the cell. right. And then you will |
|
| 49:29 | OK, well, where does this comes from? So I understand. |
|
| 49:33 | you're going inside and depolarizing. How it depolarize? So these Ln gated |
|
| 49:39 | will also be permeable to potassium rolled and that's how we polarization will |
|
| 49:46 | So first sodium will rush in through receptor channels and then potassium will come |
|
| 49:52 | through ach receptor channels. And it always cause this massive depolarization in the |
|
| 50:01 | of lay potential that is always sufficient cross the threshold for action potential. |
|
| 50:07 | therefore will always result, as I in the switch of the muscle fiber |
|
| 50:11 | contraction of the muscle, the skeletal contraction. And how does this action |
|
| 50:17 | happen? This is the lay So, what we're looking at here |
|
| 50:22 | not the action potential, it's pos lay potential. This is epsb excitatory |
|
| 50:31 | potentials. This is an excitatory or plate potential. BPP. So how |
|
| 50:37 | the action potential happen? Right, so far we talked about this release |
|
| 50:43 | acetylcholine, advanced the nicotinic acetylcholine receptors the depolarization through nicotinic acetylcholine receptors. |
|
| 50:54 | this is nicotinic causes depolarization and deeper the junctional falls. You have voltage |
|
| 51:04 | sodium voltage gated potassium channels as well uh calcium channels that will be opened |
|
| 51:13 | do to this massive end play So a lot of times we refer |
|
| 51:21 | it as a high fidelity neuromuscular junction a high fidelity synapse. 1 to |
|
| 51:26 | , meaning that if there is an potential, pre synoptic post synaptic, |
|
| 51:31 | will see a massive Epp that will cause a contraction will always form an |
|
| 51:37 | potential always fall uh cause a contraction the muscle. And now if you |
|
| 51:42 | at the different sizes or duration, the skeletal muscle will be about five |
|
| 51:48 | in duration of the same amplitude and cardiac ventricle contraction will be much |
|
| 51:57 | uh 200 milliseconds in duration and it a different shape to it. And |
|
| 52:05 | , this hump these different shapes or hump in the cardiac uh ventricle uh |
|
| 52:12 | because of the calcium channels being That's something that we don't see in |
|
| 52:17 | neurons, we don't engage voltage gated channels in the actual potential in in |
|
| 52:23 | that we've discussed so far in motor . So, uh we had an |
|
| 52:29 | discussion on the a class. Somebody , well, why is the, |
|
| 52:35 | is the heart uh contraction is so ? So, well, maybe there's |
|
| 52:43 | know we had a discussion and now I check the sources. So |
|
| 52:50 | continue the discussion. You can check sources. But one of the suggestions |
|
| 52:54 | that, you know, neurons don't all the time. So if you |
|
| 53:00 | have an electrode in the neuron, patch clamp whole cell recording in the |
|
| 53:06 | , we'll fire a few action potentials a minute. Uh Unless it's being |
|
| 53:13 | repeatedly, then it will fire as action potentials as can fire. But |
|
| 53:19 | just linger, linger boom, just we saw in those traces, even |
|
| 53:23 | the with the constant input into network don't always respond with continuous trains of |
|
| 53:29 | potentials. So, um but the doesn't stop. So maybe it has |
|
| 53:38 | do with how many you have how many contractions over your lifetime you |
|
| 53:44 | to have to generate. So that one of the points of the |
|
| 53:48 | And then I made everybody kind of about, well, what about the |
|
| 53:55 | ? What happens? So when you action potential, motor neuron releases |
|
| 54:01 | you have the skeletal muscle causes These have to be really fast, |
|
| 54:07 | ? What is the heart muscle It pumps the fluids. So it's |
|
| 54:14 | now dependent and the speed of that is dependent on the fact that it |
|
| 54:21 | to move something uh like a fluid a chamber like, you know, |
|
| 54:29 | you have a good idea. I it was slower because there's two, |
|
| 54:35 | , like, you know how like the spinal fluid in the somatic |
|
| 54:38 | like, it goes directly to the muscle. But in that part of |
|
| 54:41 | , it's like there's two, you what I mean? There's two |
|
| 54:45 | like there's a separation because free, the somatic doesn't have that separation. |
|
| 54:52 | mean, uh norepinephrine versus acetylcholine There's like, there's like two different |
|
| 54:59 | vers versus parasympathetic or? Well, , but like in the autonomic |
|
| 55:03 | right, there's two, there's two neurons but the somatic just was directly |
|
| 55:11 | . Well, cho because you have pacemaker now and it's really just following |
|
| 55:15 | pacemaker. Um the heart itself, heart, the heart moves on its |
|
| 55:21 | , right? If you, if take the heart out, what does |
|
| 55:24 | do? You provide it with the solution? It will keep, keep |
|
| 55:30 | . So it's not really about the input it's more about and we |
|
| 55:35 | , it's a pacemaker, right? it always boo boo boo boo boo |
|
| 55:40 | boo boom. And you don't have like stimulate it like you do if |
|
| 55:45 | have problems and then you have a pacemaker, it's sort of in your |
|
| 55:49 | . So maybe I'm not catching your, you know, your |
|
| 55:54 | Yeah. Is it only one V looks like that or are they both |
|
| 56:00 | uh if you record it from the ? Yeah, you mean identical in |
|
| 56:06 | and size? I haven't, I know I actually don't have a very |
|
| 56:09 | comparison to the, yeah, uh, American pulsar, cardiac ventricle |
|
| 56:16 | too fast. There wouldn't be like room for error between the |
|
| 56:21 | between the two chambers because of the of the flow of the fluid. |
|
| 56:28 | it would, it would stimulate it quickly. Like it wouldn't be able |
|
| 56:32 | get any fluid, which is a one and they start to overlap. |
|
| 56:37 | , that's fine. So we're, , we have all of these different |
|
| 56:43 | , but I, I just searched up. So I was thinking about |
|
| 56:46 | preganglionic neuron on the gang one. that's like not in the somatic |
|
| 56:51 | That's why, like I've always that's why it's slow for cardiac, |
|
| 56:56 | it also doesn't have to pump the that's between the chamber. So it's |
|
| 57:01 | at least three reasons maybe or If you search more, you'll probably |
|
| 57:08 | more. But anyway, it's very discussion. Uh And the point of |
|
| 57:13 | is neurons are the fastest and we really fast brains and a little bit |
|
| 57:19 | muscles, um uh action potentials and in the brain it's even uh in |
|
| 57:26 | , in the, in the it's even the slowest. All |
|
| 57:30 | there's quite a few slides that we to cover. And we already started |
|
| 57:34 | about these different chemicals and these different and we'll continue talking about them. |
|
| 57:40 | want you to look at their So, glutamate versus Gama, I |
|
| 57:44 | want you to look at the singularity glutamate and gamma. It's almost the |
|
| 57:50 | molecule. It's just that glutamate is it has this carboxyl group and it |
|
| 57:58 | decarboxylate and becomes gabba. And you understand that these astrocytes that are surrounding |
|
| 58:09 | cells and this tripartite synapse, they also have their transporters for glutamate and |
|
| 58:17 | . So it's not only the neurons are going to return that substance back |
|
| 58:21 | the pre synoptic terminal glutamate. And is also gonna get slurped up by |
|
| 58:28 | and it's gonna get given back to and gabba producing sauce and we'll learn |
|
| 58:34 | this in the next couple of Uh Glycine you can see is |
|
| 58:40 | Some of these are 123412345 carbon dopamine, uh norepinephrine or acetylcholine is |
|
| 58:55 | that have much longer carbon chains. you look at these peptides, they're |
|
| 59:00 | large molecules. Uh and uh they obviously carbons, hydrogens and oxygens and |
|
| 59:15 | nitrogen and you have a lot of nitrogen and also sulfur in the in |
|
| 59:23 | peptides. So when we talk about neurotransmitters, the traditional neurotransmitters, we |
|
| 59:30 | about amino acids, amines, we talk about peptides that are stored in |
|
| 59:36 | or Granules. So, peptides are from the neurotransmitter vesicles. This is |
|
| 59:42 | example of where neurotransmitter vesicles are shown much uh spatially confined to the synoptic |
|
| 59:50 | here and most of its refilling exocytosis , endocytosis reuptake, refilling will be |
|
| 59:59 | place with the synoptic terminal here and action potential, an influx of calcium |
|
| 60:06 | enough to cause a fusion of the and the neurotransmitter release in the papic |
|
| 60:13 | . But the neuropeptides are stored in Granules and typically one action potential or |
|
| 60:20 | stimulus, sparse activity in these neurons not enough to release neuropeptides, neuropeptides |
|
| 60:28 | synthesized neo selma. Of course, peptide goes through the g goop forus |
|
| 60:35 | it becomes filled with the secret Granules the peptide neuros liters right here from |
|
| 60:43 | golgi. So it's not at the of the synapse and then they actually |
|
| 60:48 | produced or synthesized and released when there heightened levels activity. If there's very |
|
| 60:54 | stimulus, continuous repetitive stimulus, that is very active, multiple action |
|
| 61:00 | it will start releasing secretory Granules and . We saw that they can be |
|
| 61:05 | localized in external terminals. But the interesting thing is that in high levels |
|
| 61:10 | activity, these secretory gran animals can fuse along the extent of the axon |
|
| 61:16 | they reach the external terminal. So isn't as much of the spatial specificity |
|
| 61:22 | the signaling from the secret to And therefore, these are the differences |
|
| 61:27 | synaptic vesicles are. Uh although you see they can co localize here with |
|
| 61:33 | core vesicles are also secret Granules dense core secret Granules. You cannot |
|
| 61:40 | they have like a dense core, core of it is dense. |
|
| 61:44 | And this is vesicles that the synoptic and these are neuropeptides that require a |
|
| 61:50 | more activation, sustained levels of activity can get released along the external |
|
| 61:58 | not just uh uh uh along the extent, not just in the |
|
| 62:03 | So we have all of these molecules we'll be discussing. We'll also be |
|
| 62:08 | about some of the molecules like a and A TP. And that's important |
|
| 62:15 | we talked about a TP as a energy source in the brain and the |
|
| 62:20 | produced by mitochondria. But A TP also a neurotransmitter. A TP combined |
|
| 62:28 | glee ourselves on receptors that are called 22 Y receptors. So it's also |
|
| 62:34 | neurotransmitter and the core of A TP adenosine and adenosine. This is another |
|
| 62:42 | example to understand about these molecules. is a molecule that makes you |
|
| 62:48 | It is naturally produced in your So these are all endogenous substances. |
|
| 62:53 | , naturally endogenously produced within your body in this case. So you have |
|
| 62:59 | demain and ademas levels would go up the evening and it will bind the |
|
| 63:05 | with sus on neurons and it will glutamate release and it will make you |
|
| 63:12 | . And then in the morning, levels, the synthesis of adenosine by |
|
| 63:18 | will decrease and the signaling of a will decrease and this is morning |
|
| 63:26 | So in the morning. Now, decreasing adenosine levels, you'll have more |
|
| 63:31 | . Glutamate is the nature excited for neuro transmitter. So you will be |
|
| 63:35 | energized. Your brain will be awaken and a deist and receptors are |
|
| 63:45 | targets of caffeine. You know how are, all, most of us |
|
| 63:51 | addicted to coffee and right. Some like, don't talk to me before |
|
| 63:54 | have my coffee or my tea or bubble tea or something. And uh |
|
| 64:01 | , and that's because it interacts with denison signaling. Caffeine promotes glutamate release |
|
| 64:08 | it's a fairly addictive substance. And have like often intersections. We have |
|
| 64:13 | caffeine dealers in one intersection. Two them were Starbucks. The third one |
|
| 64:18 | like Dunkin Donuts or something like So, uh and it's, and |
|
| 64:24 | , it's like a lot of people it like almost everybody. I |
|
| 64:28 | I don't know anybody that doesn't use in one form or another shape or |
|
| 64:33 | , you know, uh different cultural variations of caffeine supply in South |
|
| 64:41 | It's the, the tea uh and like Middle, middle East |
|
| 64:48 | It's also the, then you go Africa, it's a coffee and also |
|
| 64:53 | nut, which was used to be basis of caffeine and Coca Cola. |
|
| 64:57 | comes from a cola nut with pure of caffeine. And now a lot |
|
| 65:01 | stuff that we have that we consume potentially synthetic caffeine uh in the drink |
|
| 65:08 | . Now some other interesting neurotransmitters worth that will come up during the |
|
| 65:14 | And the reason for them coming up nitrous oxide, carbon monoxide and |
|
| 65:20 | And the endo cannabis, these are because gasses and endocannabinoid are lipid |
|
| 65:29 | And that means that they're not stored vesicles because vesicles are phospholipid bilayer and |
|
| 65:35 | just cross freely. So that means there is a different way, just |
|
| 65:39 | we saw a different way with neuropeptides synthesized and released. There are different |
|
| 65:44 | , different ways by which these molecules synthesized based on the levels of activity |
|
| 65:50 | how they get released. In this , without vesicles. Once they get |
|
| 65:54 | synthesized inside the cells, they truly through plasma membranes and target their respective |
|
| 66:01 | , ni nitrous oxide receptors and endocannabinoid . So these are endogenous cannabinoids that |
|
| 66:08 | produce inside our bodies. And cannabinoids from cannabis plants because phyto cannabinoids found |
|
| 66:15 | cannabis plants interact with our endocannabinoid system , and other receptors that we'll be |
|
| 66:22 | in this class also. But these endogenous molecules that are produced. So |
|
| 66:27 | , the rules for them are going be different no vesicles and we'll learn |
|
| 66:31 | these rules and functions of these different as we continue the next three lectures |
|
| 66:37 | neurotransmission. Thank you very much for here. Uh And I'll see everyone |
|
| 66:43 | on |
|
