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00:00 | maybe this is Lecture 12 of neuroscience transmission three, we will continue with |
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00:08 | transmission and then we will finish no on thursday october 13th 2022 we talked |
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00:23 | two uh types of communication in the , excitatory and inhibitory E. |
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00:30 | S. P. S. And PS PS. And we also contrasted |
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00:36 | types of the synopsis. We contrasted synapse and neuro muscular junction and we |
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00:42 | that the level of the neuro muscular , the signaling there is pretty simple |
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00:49 | you produce very large amplitude amplitude potentials E. P. P. |
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00:56 | That are always in one synapse, 70 million volts in amplitude. And |
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01:04 | is not the case in the N. S. And the |
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01:07 | N. S. When we talked E. P. S. |
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01:10 | S. Is that a single ep activation of a single synapse will produce |
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01:19 | Synapse approximately 0.5 mil. A ball polarization. And so if you're addressing |
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01:27 | potential of about -65 million balls and need to reach the threshold for action |
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01:38 | Which if you recall is about -45 volts. That means you have to |
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01:45 | and engage a lot of excitatory synapses you have to either engage them all |
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01:51 | plans. And this is going to . Each synapse is going to contribute |
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01:58 | a mil, evolved half a Well half a mil evolve until eventually |
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02:03 | have a map of the excitatory They also may have to be activated |
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02:07 | the same time. If they're activated time it may increase to reach this |
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02:14 | . It may take longer time period increase this this threshold, this is |
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02:21 | T. In time. So these E. P. S. |
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02:25 | S. And P P. P. S. Are small and |
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02:29 | very reliable. And E P. . P. S. Are produced |
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02:34 | neurons will release glutamate, okay, synaptic glutamate and this glutamate will bind |
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02:45 | the post synaptic glutamate receptors and this what's depicted there and there's going to |
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02:51 | an influx first of all of sodium positive current. So influx of positive |
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02:58 | is gonna cause deep militarization in this synaptic cell. This is pre synaptic |
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03:04 | and this is post synaptic cell. there's going to be a default realization |
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03:09 | this post synaptic cell here. So . P. S. P. |
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03:14 | . A small I. P. . P. S. That are |
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03:17 | by Gabba. Gabba binding to gabba channels. The inhibitory amino acid neurotransmitter |
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03:25 | allowing for the flocks of chloride and flux of chloride produces hyper polarization. |
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03:32 | again these hyper polarization can submit And larger or a single synapse activation of |
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03:43 | synapses. Also going to cause a small change in the membrane potential of |
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03:50 | 0.5 million balls but in the opposite hyper polarizing potentials. This is excitation |
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03:59 | inhibition that we have in the We also have ion a tropic versus |
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04:04 | tropics. So these types of receptor . Ion a tropic receptor channels this |
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04:11 | metabolic tropic receptor channel. We'll talk more about metabolic tropic receptor channels but |
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04:19 | is no flocks of ions. These not channels. So I constantly same |
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04:24 | tropic receptor channels and I misspeak because metal but tropic G protein coupled receptors |
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04:31 | these Joubert in couple of receptors are channels. So binding to the neurotransmitter |
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04:36 | activate G protein complex. And that complex can have downstream effects on the |
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04:43 | membrane channels or downstream effects on the and the production of the secondary |
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04:49 | So we'll talk about this in in little bit. Okay, well we'll |
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04:55 | more about the systems that we've But uh let's look at this slide |
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05:03 | . We can we can jump to slide here because some of the slides |
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05:07 | repeat in the next section in the lecture, immuno history chemistry and in |
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05:13 | hybridization of the two most common ways studying neurotransmitter, the neurotransmitter systems remember |
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05:20 | as we have synthesized and degrading enzymes receptors you have neurotransmitters themselves. So |
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05:25 | you want to study neurotransmitters, immuno chemistry relies on the produce of the |
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05:31 | and you would isolate for example a neurotransmitter from an animal like a |
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05:38 | And then you would inject that neurotransmitter into an animal like a rabbit rabbit |
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05:45 | rabbit as a foreign substance. So is going to start generating immune response |
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05:52 | generating antibodies to this injected substance. these are these black. why like |
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05:58 | uh molecules here. These are the . And those antibodies can be tagged |
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06:08 | the visible markers, those visible Certificate li like fluorescent markers. And |
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06:14 | antibodies will bind to the neurotransmitters. during immune artistic chemistry is that it's |
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06:20 | it's a many steps the reaction can sometimes two or three days. You |
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06:25 | also use multiple antibodies. One let's targeting acetylcholine and other targeting God another |
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06:33 | some kind of receptor or something And what you do is you basically |
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06:39 | the Santee body on the brain tissue that you're interested in studying. Typically |
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06:45 | thin about 350 to 500 micro And you penetrate the Santee body with |
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06:52 | detergents through the membranes and the cells contained manure transmitter. The antibody will |
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07:00 | to that nerd transmitter and then you're go through the steps of some |
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07:06 | And if it is bound up to , the antibody will stay inside the |
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07:10 | . And if it is not and another south will get washed away. |
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07:14 | only the south that expresses candidate neurotransmitter show up and blow on your on |
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07:20 | on your on your slice uh in part of the brain or slice or |
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07:26 | that you're studying in situ hybridization. advantage of M. R. |
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07:33 | A. So we know certain sequences code for neurotransmitters and different aspects of |
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07:42 | systems. So you have a strand M. RNA which will be in |
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07:45 | neuron. And you prepare radio actively probe which contains the proper sequence of |
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07:53 | nucleic acids. So you are the that designed the sequence of nucleic acids |
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07:57 | you know is gonna have to find complimentary messenger RNA, which codes in |
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08:03 | case for neurotransmitter. And if they each other they bind up to each |
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08:08 | like really sophisticated two pieces of al and they'll stick together. And the |
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08:13 | that express this neurotransmitter. M. . N. A. Will then |
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08:18 | up on your on your slides on slices in the south that don't contain |
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08:23 | neurotransmitter obviously will not show up will give you any optical signal. The |
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08:30 | way of studying neurotransmitter of facts is we know classically is we stimulate the |
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08:38 | . So let's say you stimulate excitatory pre synaptic terminal here and you get |
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08:43 | new PSP response here and it's pretty . So if you stimulate certain fibers |
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08:48 | can get a single synapse activation that's localized and you can study this input |
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08:54 | response from the south because you're recording here. Member and potential of the |
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09:01 | . And in some instances if you the original experiment by Otto Loewy was |
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09:07 | he drew the fluid from outside the heart. And then he applied that |
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09:13 | to a heart that was not stimulated it also slowed its heart rate |
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09:18 | So here you would then isolate And because we have microfiber pads and |
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09:23 | electrodes you can bring those two very proximity of the synapses that you want |
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09:28 | stimulate. For example in this done and you can apply this fluid containing |
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09:34 | and this should also produce an equivalent . If it is glutamate should also |
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09:40 | this is lieutenant ergic pre synaptic terminal show up as an E. |
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09:44 | S. P. And with this and the fluid and automated you should |
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09:49 | be able to record an ep However uh this is not a very |
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09:56 | method. It's an older method and still being used quite a bit. |
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10:03 | you can imagine what can happen actually you do these kinds of experiments is |
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10:14 | say you're targeting specific aspect of the and dendritic spine and the synapse that |
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10:23 | connected to this neuron here. And you apply this fluid through the |
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10:32 | a lot of that fluid is going diffuse around and cover a certain |
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10:40 | And so you'll have the highest concentration those molecules somewhere around here. But |
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10:47 | you'll also be defusing a lot of and this is quite large volume and |
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10:54 | your experiments are not as specific as to stimulate a single fiber or trying |
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11:01 | stimulate a single synapse. And so that case what what can be done |
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11:09 | what is done is neurotransmitter caging and caging and this is a very interesting |
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11:17 | where you can literally caged neurotransmitter like in little cages, their chemical cages |
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11:28 | you can use photo license. So glutamate when it's caged it's inactive. |
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11:33 | cannot bind to glutamate receptors so it cause any fast synaptic response. But |
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11:40 | lasers using light, you can break cages and release glutamate molecules and you |
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11:50 | do it in very localized fashions and that cloud of diffusion from uncaged molecules |
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11:59 | potentially gonna be much, much smaller much more spatially spatially temporally precise. |
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12:07 | the other advantage of using optical engaging photo license with lasers is that lasers |
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12:14 | very fast these days, the speed lasers are about them two seconds. |
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12:23 | within the middle a second you can many synapses using these super fast |
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12:30 | And that's something you cannot do with electrode because you have to position the |
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12:35 | near the cell, release. that means you have to again reposition |
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12:41 | electrode somewhere else. It's a lot mechanical disturbance. It's a lot of |
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12:48 | in here. You can have glutamate everywhere in the slice and around other |
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12:56 | . They're all be caged and you have other neurons located close to this |
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13:02 | caged glutamate. And so you can quickly uncaged and activate other neurons with |
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13:09 | glutamate here and and uh class lecture materials. I have this article which |
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13:36 | how uncaged ng works. So this for if you're interested in microscopy, |
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13:41 | you're interested in the science of uh engaging and total ISIS. It explains |
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13:50 | you can do it, how you do it in the fast fashion. |
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13:52 | you can see that each one of dots, it's like a little laser |
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13:58 | can engage compounds very precisely and target a single synapse. So it's a |
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14:05 | really nice method of combining microscopy. using this laser and caging chemistry, |
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14:14 | chemistry where you have cages around neurotransmitters electrophysiology because you're responding, you're recording |
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14:21 | certain response from the south electro Uh The other advantage of this technique |
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14:28 | that you can uncaged in multiple focal fast speed, which means you are |
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14:38 | four dimensional map of activation of the X. Y. Z. |
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14:47 | Okay. Before dimensions. So you the Z dimension because you can go |
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14:53 | different focal planes as a stack through slice that will contain different neurons or |
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14:59 | synapses of the same neuron and activated four dimensions and see how that changes |
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15:04 | dynamics of the response in that Okay, so it's there for aficionados |
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15:12 | and for non aficionados, you need know that there is this technique of |
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15:18 | aging your transmitters and that this technique done with photo license and be more |
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15:25 | and activating spatially uh specific areas or synopsis even. Okay. Uh this |
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15:33 | you know, it's the chemistry showing you can actually do Minister chemistry. |
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15:37 | can do um other method of labeling situ hybridization on entire embryos. And |
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15:48 | is an interesting image because a lot molecules neurotransmitters receptors, the ratios of |
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15:54 | receptors the amounts of the receptors and changes were mature as the age |
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16:01 | So sometimes when you look at the embryo you will see whether a dark |
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16:05 | in this case it's uh harassing chinese two receptor staining and everybody see it's |
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16:12 | an abdominal cavity for example but it's heavily expressed in the spine. Is |
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16:16 | expressed here in the brain stem and areas. So you can track sort |
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16:21 | a whole view of how these molecules neurotransmitters change over the development as I |
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16:30 | earlier. Cns synopses are unreliable and produce small E. P. |
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16:37 | P. S. The single synapse small I. P. S. |
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16:40 | . S. And so one way which the brain strategizes to go around |
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16:46 | make sure that it has an effect the synoptic capsules has an effect on |
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16:50 | post synaptic neuron post synaptic neuron produces active potential is spatial summation And temporal |
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16:58 | . So in special summation you can 35% at the same time in three |
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17:05 | spaces and you will get a very response. So you can see that |
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17:10 | over space that will summit and this is going to be three times of |
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17:15 | single synapse activation because you're activating three . The other way in which you |
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17:21 | sum it is over time in which same axon produces a certain frequency of |
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17:29 | potentials. And you can see that you sum it over time the cps |
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17:34 | response all those three synapses but it's the same south, it doesn't quite |
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17:39 | the same peak as three synapses activated spatial summation at the same time. |
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17:46 | the reason for it is because the start decaying and then you activate another |
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17:52 | sp on top of it starts So the closer and frequency the faster |
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17:57 | frequency of uh stimulation, the larger going to be a response. So |
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18:04 | slower frequency of stimulation each action potential synaptic alie will evoke E. |
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18:11 | E. P. S. Post synaptic li like this for |
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18:16 | Okay this will be the sum mated . P. S. B. |
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18:20 | time and then you can repeat the . But now you're gonna increase the |
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18:28 | of stimulation. So this is the . P. S. P. |
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18:33 | this is the action potentials. And you increase the frequency of stimulation now |
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18:39 | cell is not gonna have time to . You see here you already gonna |
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18:47 | it up and then here you're gonna it up again. So if you |
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18:53 | the frequency you're likely to get a response. Okay that makes sense. |
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19:01 | the closer in time the larger is to be the post synaptic response. |
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19:08 | as we talked about axons and action we said that action potentials are producing |
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19:14 | initial segment and then each note of there has a set of voltage gated |
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19:19 | and potassium channels that will will regenerate action potential. And in done drives |
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19:26 | don't have Myelin. So that means whenever you generate an E. |
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19:31 | S. P. Whenever there is current change like a deep polarization over |
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19:37 | this current is going to leak It's called the dendritic cable which is |
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19:42 | insulated. Unlike that zonal cable that talked about which is insulated and produces |
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19:49 | action potentials. So that means that you have some stimulation here or current |
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19:55 | which is pretty large at this area distance away along the dendrite. If |
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20:01 | place another electorate and you record that in potential, only a fraction of |
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20:07 | number of potential is going to be is going to be a lot of |
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20:12 | . It's going to leak out. leads us to this concept of the |
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20:19 | and lambda in general as the length length constant of the dendritic cable and |
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20:28 | length constant is measured where V. the origin or initial change in voltage |
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20:37 | . O. Which you can also 100%. This is the maximum 100% |
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20:43 | here And over distance along them. that it takes for that maximal signal |
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20:52 | decay to 37% of its value. V. O. Is the voltage |
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21:06 | . And the distance that it takes travel along the den ride is the |
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21:12 | . So the cells that have long constance This is the 37%. This |
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21:28 | 100 the cells that have a long constant. This lambda value is going |
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21:38 | be long. The cells that have length constance the land of value is |
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21:44 | to be short. So if you a long length constant you're good at |
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21:54 | some mating. That means that the from this synapse will not die down |
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21:59 | much. It will reach this. will summit with this will summit with |
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22:03 | and will effectively activate the neuronal Okay so this is the deal's long |
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22:12 | constant. It takes long distance to . Long travel space to decay and |
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22:19 | is short lambda. These are the constants in the cables and the summation |
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22:29 | . So now so the nature build brain and many instances where neuronal circuits |
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22:36 | have excited turning inputs coming into the parts of the democrats and inhibitory |
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22:46 | Gabba inputs targeting proximal dendrites and somatic just like you saw on the hippocampal |
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22:56 | . The same as present in the circuit. A lot of inhibitory cells |
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23:00 | subject their synopsis around what we call paris. Somatic regions of neurons And |
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23:07 | you have an excited for synapse that's on this done dr remember most of |
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23:12 | inputs coming in from dendrites and spines so almost two there's other inputs that |
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23:18 | talked about this in african action. you produce this ep sp here and |
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23:25 | of that current will leak out. of that current will reach the south |
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23:31 | . And you will record uh smaller still noticeable E. P. |
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23:36 | P. At the level of the all the way from the distal den |
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23:40 | . And that is only if there excitation. And if the inhibitors synopses |
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23:46 | . But what happens if the inhibitor is active at the same time? |
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23:51 | means that first of all it's excited recurrent is leaking out over distance depending |
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23:56 | the life constant is leaking out of den ride. And now you also |
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24:00 | inhibition here and there's two things. active release of inhibition will hyper polarize |
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24:06 | cells that will further reduce this excitatory . P. S. P. |
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24:13 | the response that you will see at level of the cell is gonna be |
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24:18 | . So inhibition can cancel out excitation cancel out by hyper polarizing themselves. |
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24:23 | also through this method of shunting more the current out through the nearby open |
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24:32 | . Yeah. So if you basically just excitation you get nice C. |
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24:37 | . S. P. If you the same amount of excitation as you |
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24:42 | inhibition you get no responsible level of south. If you have more inhibition |
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24:47 | excitation you will actually get an P. S. P. |
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24:51 | And if you have way more excitation just a little bit of inhibition then |
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24:56 | will still be able to record a synaptic response there. Okay. At |
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25:01 | level of the summer. Okay so is a interesting tactfully for Nora and |
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25:14 | friend and I think I'm gonna it's little bit out of place. Maybe |
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25:20 | story responses is the last slide and gonna come back to the slide. |
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25:26 | following lecture. Just remind ourselves about systems that we're talking about how we |
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25:41 | these systems and these are the systems interest for us. So what do |
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25:54 | have to know for the exam or the quiz? You would have to |
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26:00 | that the major amino acids are Gaba and also glycerin which is not |
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26:07 | here. You have to know that and the spinal cord is an inhibitory |
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26:11 | today you'll learn that glycerine in the . N. S. Is a |
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26:15 | factor. So it's not a classical mean acid neurotransmitter it's more of a |
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26:20 | co factor and maybe that's what it's listed on here. Okay you have |
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26:25 | know that glutamine through blue dominates. glutamate will study this pathway in |
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26:32 | And we'll see how glia involved in pamphlet you have to know that glutamate |
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26:40 | God becomes Gaba. So all of inhibit ourselves will actually convert glutamate into |
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26:49 | through the enzyme God G. D. Now on the amine systems |
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26:56 | there's a lot of amines and there obviously precursors that we're talking about. |
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27:04 | Trip to fan is a precursor to hydroxy. Trip to Fan which is |
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27:09 | precursor to five hydroxy. Trip to which is serotonin. This is sort |
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27:15 | the serotonin ergic system of humane and enzymes that are here there's a lot |
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27:21 | information. So the question is do need to know the enzymes? No |
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27:25 | do you need to know what are means to recognize the tryptophan five Htp |
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27:33 | and and that means they're all the . I see the choline. |
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27:40 | And that they're different from amino They're different from past times. Remember |
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27:46 | peptide synthesis is different, it's closer the soma. The transport is different |
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27:51 | the release is not specially specific Now means and I mean acid neurotransmitters will |
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27:57 | released from the synaptic terminals. So we'll focus in our class a lot |
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28:08 | Gaba glutamate acetylcholine. So you have know the synthesis by chat to breakdown |
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28:14 | cyclical industries the entire city locally in cycling of that and how alzheimer's medications |
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28:22 | uh for serotonin will study some aspects serotonin that relate to what function serotonin |
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28:31 | . But we will not look into signaling of serotonin when concerns signaling for |
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28:38 | . We're gonna look into nicotine acetylcholine which already did a neuro muscular |
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28:44 | They are also in the C. . S. And N C. |
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28:46 | . S. You also have metabolic masculinity. Acetylcholine receptors. So that's |
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28:51 | signaling that we'll talk about the How about the functions of signaling further |
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28:58 | . I think knowing that dopamine is to reward the motor functions that have |
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29:03 | epa norepinephrine are like stimulants, the of the brain, the fi and |
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29:08 | response. Those basic things I think important to know. And as far |
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29:13 | signaling of these molecules, we're really going to look at norepinephrine. Norepinephrine |
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29:20 | and generates metabolic tropic signaling cascades. this is what what I would study |
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29:29 | every section. I have these good kind of a slides that have everything |
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29:34 | there. There may not be from book like they all all the glia |
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29:39 | except for one radio glia here. have all of the neurotransmitter. So |
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29:43 | is a good slide to take and take your own notes and listen to |
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29:49 | part of the lecture and video and your notes on what I'm saying might |
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29:54 | important for you to remember for the the quiz and exam. Okay so |
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30:02 | go back to the acetylcholine system that know pretty well. Just remind ourselves |
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30:09 | through chat released can target nicotine acetylcholine channels, masculinity. Medical tropic g |
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30:17 | coupled receptors. It gets broken down Seattle Colin Colin transporters will transport it |
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30:24 | , we synthesize reloaded alzheimer's medications block and necessaries. The reason why is |
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30:32 | ergic neurons energy producing neurons are susceptible Alzheimer's disease and the neuro degenerate or |
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30:41 | and die early in early stages of disease. So that's why Colin ergic |
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30:50 | here. Drug modulator pharmaceutical drugs the at the local investors by blocking and |
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30:56 | restoration along the availability of the succinylcholine the synapses. And we talked about |
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31:03 | the strategy may not be best because you lose collin ergic neurons, I |
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31:09 | to look up how many acetylcholine producing in the brain you have Yesterday somebody |
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31:15 | class looked it up and don't quote because I haven't cross checked it. |
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31:19 | said I don't even know how many neurons there on the brain. And |
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31:23 | looked it up and said 300,000. how many neurons do you have in |
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31:28 | brain? Billions. So let's say the population of the whole earth, |
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31:37 | , what is 300,000 small town but massive function that it performs dopamine for |
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31:47 | for motor and so on. I'm gonna look it up, how |
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31:51 | cells produce acetylcholine. So if you're acetylcholine cells, what you may have |
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31:56 | do, you may have to increase medications and then once you lose all |
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31:59 | the acetylcholine producing neurons if that really and it does because you have an |
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32:05 | stages massive growth neuro degeneration of the tissue then it's really not effective medication |
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32:13 | . Uh and this is another thing that medications will target all parts of |
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32:19 | system. It's quite common that they target the synaptic components like here, |
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32:24 | industries. It's quite common that they target the transporters. You can block |
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32:28 | transporters and prolong availability of molecules It's quite possible that medications also, |
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32:36 | lot of medications will target post synaptic , make these receptors more open or |
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32:44 | closed as it may be depending on condition or or or or pathology. |
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32:51 | acetylcholine is a natural endogenous agonist to IQ and IQ satyrs nicotine, which |
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33:01 | exogenous substance which is found in tobacco and some other plants, bon receptor |
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33:10 | corinne, which is also an exogenous in this case. Uh It can |
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33:18 | not only necessarily found in nature, also synthesizes must corinne antagonist for the |
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33:26 | will block nicotine, acetylcholine receptor mascara, nick receptor blocking the protein |
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33:34 | activation as atropine. These are both ergic neuro pharmacology. Both types of |
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33:41 | receptors receptors that will be functioning in brain and acetylcholine medical, tropical low |
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33:54 | receptor activation opens potassium channel. So mentioned earlier when we started talking about |
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34:04 | transmission, as we said, that same neurotransmitter molecule acetylcholine combined to |
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34:13 | acetylcholine receptor. And when advanced the acetylcholine receptor, sodium can flux in |
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34:22 | cause deep polarization to nicotine, acetylcholine and that same molecule can bind to |
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34:31 | carry nick receptor and masculine IQ receptor activate G protein complex and G protein |
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34:42 | can open potassium channel an opening of potassium channel positive charges, leaving making |
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34:50 | inside of the membrane more negative. the same neurotransmitter binds the nicotine IQ |
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35:04 | causes a small deep polarization and the . N. S. It causes |
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35:08 | deep polarization of the neuromuscular junctions cause deep realizations in the cns on the |
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35:15 | that have those nicotine IQ to go the suckers and muscular local in the |
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35:22 | will open up potassium channel and it be a small inhibition on the sound |
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35:29 | that there is a one acetylcholine bonds's year, this channel opens. This |
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35:38 | channel opens but once the seal Colin to the muscular muscular acetylcholine receptor, |
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35:46 | gonna take some time to activate G G protein. It's gonna affect this |
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35:53 | . This is called called the shortcut because there's no chemical intermedia reads because |
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36:02 | are no chemical into media is between and and the substrate this podium |
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36:12 | the potassium channel. It's a shortcut . We will have an inhibitor |
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36:17 | So in some instances, cells can express nicotine IQ and masculinity receptors and |
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36:25 | different temporal scales. So think about temporal scales you already have learned about |
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36:33 | the brain, neurons are fast glia inhibitory neurons can be super fast excited |
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36:44 | the neurons a little bit slower in tropic signaling through the channel is fast |
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36:54 | tropic will come with 10 2050 millisecond between the binding of the acetylcholine and |
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37:02 | actual activation of the potassium channel So medical tropic is slower. This |
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37:14 | how it works. Now. We're come back to this but we're going |
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37:17 | continue with the means. Nicola as I mentioned, you have to |
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37:22 | about these molecules are responsible for different of being cata cola means control |
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37:30 | dopamine in particular mood, reward, , attention, visceral function, |
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37:40 | norepinephrine and difference, fight or flight . You drop everything. Your full |
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37:48 | is on a big bear coming at . So um cata cola means again |
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37:56 | have a lot of precursors. Tyrus as a precursor to L. |
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38:00 | L dopa is a precursor to Dopamine is a precursor to norepinephrine. |
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38:05 | is a precursor chip in effort. somebody likes chemistry or remember some basic |
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38:13 | , what is hydrocephalus will add the group, deco box decoder box late |
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38:20 | take the acid group. C. . H drops a legal adult age |
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38:26 | . Methyl transfer raise. We're talking CH three group here. You don't |
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38:32 | to know that but you should know cattle Cola means again will follow the |
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38:37 | kind of a pathway will be Will be re up taken and amphetamines |
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38:43 | illicit street drugs like cocaine. Block re uptake of cata cola needs. |
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38:50 | if you think about cocaine as being an upper and you release norepinephrine and |
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38:56 | and then you block the re There's going to be more of the |
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39:00 | molecules in the synopsis. Cata cola also get broken down uh inside the |
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39:11 | terminals too. But we won't get details of that. We'll come back |
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39:16 | this um maybe in but I can but there mon amine oxidase inhibitors of |
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39:24 | colonies will get broken down here in synaptic terminals and some of the mono |
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39:29 | oxidase inhibitors will will will be like medications that raise the levels of cata |
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39:36 | means or raise the levels of You can see that trip to fan |
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39:43 | to five HTP precursor to five So mood, appetite, sleep learning |
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39:52 | is all interrelated if you're in a mood, you don't sleep well, |
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39:58 | don't have appetite and you can't So it's a pretty significant molecule. |
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40:05 | don't know how many serotonin ergic neurons have in the brain but it's probably |
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40:08 | small town to uh now tryptophan when you think about tryptophan, a good |
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40:18 | to think about tryptophan is an upcoming . Thanksgiving Turkey contains quite high |
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40:25 | especially I believe in dark meat of and so maybe one of the reasons |
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40:32 | everybody wants to pass out after eating thanksgiving meal in America here is because |
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40:38 | know you also get sleepy and happy and and and full at the same |
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40:44 | full with turkey, entrance, PROzac and other mood and mental state |
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40:54 | medications will targets are down and re . So again if serotonin is mood |
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41:02 | happy molecule release of serotonin you want prolong the availability of the serotonin molecule |
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41:09 | you will hear S. S. . I. S. Serotonin re |
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41:13 | inhibitors, that's what it stands A lot of the by the process |
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41:19 | mood medications are S. S. . I. Serotonin re uptake inhibitors |
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41:24 | they inhibit re uptake just like we're about PROzac here re uptake of serotonin |
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41:30 | prolong its by availability. So we at this mechanism here where the same |
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41:39 | acetylcholine molecule can act in the cns nicotine IQ and mascara Nick acetylcholine receptors |
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41:49 | other means and the brain will interact with medical tropical suffers and if here |
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41:58 | showing that nicotine IQ and mascara nick an opposing biophysical effect. Deep polarization |
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42:07 | nicotine IQ and hyper polarization through masquerading opening of the potassium channel and having |
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42:14 | leave. Then how can medical tropic have an opposing biophysical biochemical effect in |
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42:24 | same cell and the way they do is through having different types of receptors |
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42:31 | which functions only through medical tropics signaling the brain so tone and also all |
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42:37 | other means with the exception of the code. So open that front when |
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42:43 | activate something. This is not a back away you now activate intermediaries these |
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42:50 | so this is a G protein complex this is an intermediary one such intermediary |
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42:54 | a cyclist. And when you stimulate nominal cyclists you can produce a lot |
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42:59 | cycle KMP. And that cyclic GMP produce protein time and say the protein |
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43:06 | S. A. Or P. . A. And finances in general |
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43:14 | will add a phosphate group on the they can force for relate different |
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43:22 | And you also have in the south cases And they will defense for a |
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43:35 | so they will take the p. . 4 group off and so part |
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43:41 | the cellular activity regulation and is through of protein kindnesses and phosphate asses. |
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43:52 | uh in this case we're looking at mechanism that's norepinephrine specific norepinephrine as two |
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44:00 | subtypes Alpha two and beta receptor. receptor is linked to a stimulatory podium |
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44:12 | G. S. Which is not up in the corner there and when |
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44:16 | activate norepinephrine binds to beta receptor, activate catalyze the G protein complex. |
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44:23 | on a dental cyclist activity through a can write cycling KMp and produce a |
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44:31 | of burden kindness. So the stimulatory protein complexes pushing to produce more cyclic |
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44:39 | than to produce more protein keane's The alpha two receptor for norepinephrine is |
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44:47 | to an inhibitory G. I. you have different subtypes of G protein |
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44:53 | its inhibitory G. I. Once gets catalyzed it will inhibit the dental |
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45:00 | and it will reduce the production of we can you know it will reduce |
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45:04 | block the production of protein chinese. so alpha two receptors pulling the system |
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45:13 | from producing more protein financing. This is pushing and this one is pulling |
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45:18 | away so they will be competing against other. If they are expressed in |
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45:23 | different cells, one cell will be by norepinephrine will be producing more protein |
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45:30 | . Say. And if the cells alpha two will be producing less protein |
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45:34 | say or or or regulating the amount protein finance age that is being |
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45:40 | And in some instances you can also these receptors go expressed. So these |
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45:49 | subtypes of norepinephrine receptors could be co by the same neuron and they'll be |
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45:55 | against each other. So who Well if you look at nicotine versus |
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46:01 | , nick and speed, nicotine nick . Who wins in the change of |
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46:07 | cellular effect here through medical tropic alpha a beta, who wins? I |
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46:14 | know if there's such a thing as who wins. But you're definitely changing |
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46:18 | cellular cascades in the southern of signaling certain molecules and correlation of certain receptor |
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46:25 | and opening of certain channels and so . So this is a push pull |
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46:31 | for the g proteins. Okay remember amines are special. So this is |
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46:39 | small town for locust Sibelius that means selma's If you stay in the slice |
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46:49 | the brain. And you ask where the so Mazz of neurons that produce |
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46:57 | ? You can ask a question. are the selma's of neurons that produce |
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47:01 | tona when you stain it will show that the so Mazarin, this locust |
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47:06 | nucleus locus which is nucleus or location , is blue because if you cut |
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47:14 | the tissue and you exposed it to , the cells after the oxidized Nora |
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47:20 | blue. So they actually have this tint as they appear without any stain |
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47:26 | they're exposed to oxygen. That's where name comes from local civilians. So |
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47:32 | what are these things I call Sprinkler system. This is norman and |
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47:37 | system and what those arrows are. what these sprinklers are are the external |
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47:44 | that are coming from the nuclei and are penetrating throughout the brain. The |
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47:53 | , sub cortical structures, brain stem and into the spinal cord. A |
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48:01 | cycling again will be at the level the synapses. But these are pretty |
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48:09 | , intricate and non specific. Often to spatially non specific sprinkler systems of |
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48:19 | sprinkler system for serotonin, acetylcholine and on. Okay, so so is |
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48:25 | clear? So the neuron so much express in this case serotonin, the |
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48:31 | nuclei and purple are located here. arrows are axonal projections and the release |
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48:39 | that neurotransmitter which is again like a system for serotonin. And then you |
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48:45 | the wrapping nuclei and green here that basically project their axons into spinal |
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48:52 | Applying those molecules in the spinal When we talk about acetylcholine. Acetylcholine |
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49:00 | expressed in these two small green Magna cellular based on floor brain and |
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49:08 | killer pontin and lateral dorsal tick mental . These are the two nuclei that |
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49:17 | and produce all of the super alkaline you have in the C. |
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49:22 | S. So what makes this population vulnerable in alzheimer's disease? Good |
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49:33 | What makes dough opening new neuronal loss dopamine neurons more vulnerable in Parkinson's |
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49:42 | Also good question. So but the that I'm trying to get across is |
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49:47 | if you lose if you take and this nucleus out this small tom here |
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49:57 | is no more of nothing on the . Okay so it's not and that's |
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50:02 | the case with remember everywhere in the camp was supported really different structures but |
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50:13 | are only synthesized in these very specific hypothetically if you were like like isolated |
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50:19 | damage to one of the or the you still think able to function if |
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50:27 | were to lose just one if you if you have overlapping projections which in |
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50:34 | instances you do you will but if don't have the overlapping sprinkler systems that |
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50:43 | the same areas you will not and will then lose this circuit here and |
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50:49 | circuits will subservient different function. So it may be related more let's say |
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50:55 | memory function. Executive function with cognitive here, it's related maybe more to |
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51:02 | brainstem vital functions and things. Other that would do. It's a good |
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51:08 | . Uh and the same would be . So if you eliminated the central |
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51:14 | you don't you don't have a so the brain supply anymore to the |
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51:19 | , but you have a supply to cord still left with the green |
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51:24 | So you'll you'll have a partial loss this function. Um and that's that's |
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51:29 | interesting. You know, the other too like can't we implant something that |
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51:34 | just you know what what is neuro is actually both the stillness and the |
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51:40 | and dendrites and neurodegenerative. But if cell must die, you know, |
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51:46 | we insert something here and take advantage these sprinkler systems? Like can we |
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51:51 | connect to the networks, you know the same way that these mean uh |
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51:57 | are expressed on how they function. I think that that's part of like |
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52:03 | we don't understand very well and it's part that's interesting. I think that's |
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52:08 | makes us really individual is that endogenous , how we behave physically and mentally |
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52:16 | our own endogenous molecules and exogenous molecules we use how they shape us and |
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52:23 | us, you know, from coffee bananas, to uh whiskey, to |
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52:30 | of these other things, you know it's it's really interesting. And I |
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52:37 | that that's where individuality potentially comes from none of these sprinkler systems are going |
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52:44 | be exactly the same within these circuits the functioning isn't going to be exactly |
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|
52:49 | same. And some of us may up with Parkinson's, some of us |
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52:54 | end up with alzheimer's. Some of may end up with uh no disease |
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53:00 | you know, hopefully no disease. if you look at other organs, |
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53:05 | know, you have cancers and things that and we almost which are growing |
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|
53:09 | . We don't know the reason why cell populations are more vulnerable. Uh |
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53:16 | it's related to genetics, sometimes it's chemicals but a lot of instances we |
|
|
53:22 | . And these sprinkler systems are kind beautiful. Think about how the sprinkler |
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53:27 | works when you're looking at the it sprays the law but it doesn't |
|
|
53:32 | exactly the same way every time it distributes. And larger droplets form of |
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|
53:38 | droplets form. So this is almost of para crime like function that you |
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|
53:44 | see in in hormones and other parts the body. And the cannabinoids are |
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|
53:49 | . We're talking about all of these that are released pre synaptic aly they |
|
|
53:54 | to the post synaptic receptors to exert synaptic effect. And the cannabinoids are |
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54:00 | . First of all in the cannabinoids not stored in the vesicles and the |
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54:04 | are produced on demand When there is lot of pre synaptic activity and a |
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54:10 | of synaptic response. And it can either excitatory or inhibitor. There's going |
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54:16 | be an increased production of under They are a little bit soluble so |
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|
54:20 | will cross through plasma membranes. They're released prison optically but they will actually |
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54:27 | three synoptic neurons. They will bind to CB one receptor and ceo receptors |
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|
54:36 | the brain are the most abundantly expressed protein coupled receptors and see if you |
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|
54:43 | to receptors to link to g protein activation of g protein conflicts here will |
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|
54:50 | voltage gated calcium channels and by closing regulating with opening and closure of this |
|
|
54:57 | gated calcium channel. When there are high levels of activity it can regulate |
|
|
55:04 | tame the release of either excited for or inhibitory neurotransmitters. So in the |
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|
55:11 | function in retrograde boston. After pre on terra greatest typical pre synaptic release |
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|
55:20 | . This is integrated eliminator Galba interrogated . This is retrograde control and it's |
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|
55:29 | the three synoptic side and pre synaptic gasses as we mentioned nitrous oxide. |
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|
55:36 | monoxide will act in a similar No vesicles number insoluble retrograde signaling will |
|
|
55:43 | pre synaptic G. Protein coupled And uh and and the cannabinoids |
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|
55:51 | S. I. Stands for deep induced suppression of inhibition. And there's |
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55:58 | . Sc which stands for deep polarization suppression of excitation which basically when there's |
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56:04 | lot of de politization typically there's going be production of the and they will |
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56:10 | either excitatory synapses or inhibitors synapses. have the ability to do both. |
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|
56:16 | the cannabinoids that are produced in our . Endogenous cannabinoids are anandamide and to |
|
|
56:24 | record, donald to a g. know these two under cannabinoids is a |
|
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56:33 | cannabinoids in the body and maybe there's 5 to 7 molecules that kind of |
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|
56:41 | and may fit in the near future may be accepted as more or less |
|
|
56:46 | underground avenue molecules too. So there's of new chemicals in the brain that |
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|
56:52 | stopped. And the endocannabinoid system, when this was discovered Sixties seventies, |
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57:02 | , nineties two thousands 2010, 90s 90s it was shown that there is |
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|
57:11 | thing as cannabinoid receptors and under cannabinoid that bind to cannabinoid receptors. So |
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57:18 | discovery is only about 30 years old so. Are there certain characteristics of |
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57:27 | to determine whether it will be DsC that known as a, It's not |
|
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57:34 | very well actually. It was first in the inhibitory synapses and it was |
|
|
57:38 | but it only does D. I. But it actually then was |
|
|
57:42 | and it also does DsC and I well how does it do that? |
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57:47 | controls several levels of both excitation and and it's still abundantly expressed in the |
|
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57:53 | and it must play this kind of global balance of global regulator regulator function |
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58:00 | there's too much activity or where there's sustained levels of activity, high sustained |
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58:07 | of activity. Uh So DELTA nine . Steptoe hydrocele nominal is a phyto |
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58:17 | . So any phytochemicals, plant This is exogenous chemical. Delta nine |
|
|
58:25 | is produced in cannabis plants. And are two major types of cannabis plants |
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|
58:31 | this country and around the world. a type of cannabis plant that is |
|
|
58:37 | referred to as industrial hemp and it contain very low levels of delta nine |
|
|
58:43 | naturally. And then there is marijuana medical and recreational Canada's type plants and |
|
|
58:52 | can contain up to 30 plus percent delta nine THC and mass total mass |
|
|
59:01 | the cannabis planet. So delta nine a natural phyto cannabinoid. And if |
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|
59:08 | drive around town and you stop in gas station and then you're going to |
|
|
59:13 | up pizza and the pizza stores right to the smoke shop and you see |
|
|
59:18 | , you know, delta eight THC sold here. So delta eight is |
|
|
59:24 | variant of delta nine THC. This bond is actually located in a different |
|
|
59:31 | here and a different carbon, but eight THC does not come from the |
|
|
59:36 | that synthesized from another cannabinoid called CBD we'll talk about it more. So |
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|
59:42 | don't want you to know these Now, I want you to know |
|
|
59:45 | details because I want you to be . Uh but delta eight THC synthesized |
|
|
59:52 | CBD, oh delta nine THC. we don't know very good and reliable |
|
|
59:59 | of standardized methods for producing those delta molecules. And there's quite a bit |
|
|
60:05 | debate on the health and regulatory aspects for consumers that don't understand all of |
|
|
60:12 | details. It's quite confusing. We one regulatory system, federal regulatory |
|
|
60:18 | we have another state regulatory system for . And how uh and this in |
|
|
60:27 | is changing. Uh There was a news last week when President biden pardoned |
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|
60:37 | 8500 incarcerated uh people that simply had of cannabis and marijuana. So he |
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|
60:49 | that because in over 30 states or medical Canada's is actually a substance that |
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|
60:57 | can consult your doctor on and including texas uh and obtain it on recommendation |
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|
61:06 | in texas is prescription. So it make sense. And cannabis is kept |
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|
61:14 | schedule one. Schedule one is called substances act and controlled substances. Schedule |
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|
61:21 | One is the most addictive, the dangerous drugs that have no medicinal |
|
|
61:27 | It's on the same schedule as a , marijuana or cannabis Stone, that |
|
|
61:32 | make sense. State of texas. cannabis as medicine for over 100 and |
|
|
61:36 | conditions. And so how can it a medicine for over 100 40 |
|
|
61:44 | How can it be FDA approved medications about four conditions, vomiting, |
|
|
61:50 | epilepsy and multiple sclerosis in europe, different agency that has it approved and |
|
|
61:56 | still be on the most dangerous list has no medicinal values. So the |
|
|
62:02 | aspect of what biden did is he the regulatory agencies which is D. |
|
|
62:09 | . And F. D. To potentially remove marijuana from Schedule |
|
|
62:16 | And hemp is not on Schedule one the hemp doesn't have uh delta nine |
|
|
62:23 | . So it's really the molecule delta THC. Why people talk about it |
|
|
62:27 | much is because it causes the high . It's what is called a psychotropic |
|
|
62:32 | psycho active molecule and binding of receptors the high or the euphoria that people |
|
|
62:40 | when they consume that molecule uh naturally you release endocannabinoid, guess what |
|
|
62:49 | You feel really good too. And I mentioned uh the release of endocannabinoid |
|
|
62:56 | production can be stimulated by for example distance running. And so the runners |
|
|
63:02 | or the runner's high that people call people that work out and they just |
|
|
63:06 | really much, it seems like they much better than just you know the |
|
|
63:11 | reasons where their mental state is so greater. It's activation of the endocannabinoid |
|
|
63:17 | of the CB receptors. Alright so sort of a concludes our Armenians and |
|
|
63:24 | our little bit knowledge of endocannabinoid, come back and have another lecture of |
|
|
63:29 | endocannabinoid system which is a whole system when we talk about cannabinoid receptor CB |
|
|
63:36 | receptors on neurons symmetrically CB two receptors mostly on glia. What are they |
|
|
63:43 | on glia. So we learn about later in the course. We'll also |
|
|
63:46 | a little bit about medical cannabis so everybody gets glued in of what is |
|
|
63:51 | around them. Okay, amino acid , glutamate. Glycerin. Gaba licensing |
|
|
64:00 | a co factor in the cNS signal glycerin is the major inhibitory neurotransmitter in |
|
|
64:06 | spinal cord. Gabba comes from So the major excited neuro transmitter glutamate |
|
|
64:15 | the precursor to the major inhibitor neurotransmitter and all of the cells that have |
|
|
64:23 | tannic acid decker box. A list God will be inhibitory cells because you |
|
|
64:28 | to have God in order to make Gaba. So part of the neurotransmitter |
|
|
64:33 | and then you can release that Gaba Gaba can bind to post synaptic gaba |
|
|
64:39 | . Gaba and glutamate will have their transporters that will bring it in. |
|
|
64:48 | load it up pre synaptic alie they'll their particular transporters that will load it |
|
|
64:52 | into the vesicles and there is one that I'm missing here which is in |
|
|
65:00 | in the previous select traction. So going to go back to that a |
|
|
65:03 | bit. Oh no it's it's in in the it's above here, I |
|
|
65:10 | . Yes, it's a little bit . So my apologies. But let's |
|
|
65:17 | at how glutamate is controlled because we're to look at the glutamate. Ergic |
|
|
65:21 | the past synaptic receptors and the production the PSP through glutamate but let's look |
|
|
65:26 | how glutamate is cycle the neurons. first of all the title of the |
|
|
65:32 | is tripartite synapse Tri partite three part synaptic neuron and post synaptic neuron. |
|
|
65:42 | by apartheid two parts. So where the third part come from Glia? |
|
|
65:47 | the synapse is really the functioning of neural transmission that we're looking at in |
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65:51 | communication between neurons. Gloria very intricately in this process and they very much |
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65:59 | this process And for excited to glutamate is how they control this process. |
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66:05 | is uploading the vessels gets released will both Iona tropic and metabolic. Tropical |
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66:11 | interceptors pass in africa and we'll learn little bit about Iona tropic receptors |
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66:16 | Then glutamate gets transported back through neuronal transporters so that those neurons can reload |
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66:25 | into the muscle and then they can . But notice what glia does here |
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66:34 | has their own glutamate transporters. Leo transporters that will take in with that |
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66:42 | turn it into glutamine. Then we'll that glutamine back to neurons and the |
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66:49 | A. T. P. Is to be turned into glutamate and uploaded |
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66:54 | the vesicles. So who can control amount of glutamate that is available to |
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67:03 | . Okay because if glee I increased glutamate transporter function there will be sucking |
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67:09 | more glutamate. If glial glutamate transporters down it could be bad news and |
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67:16 | . Too much glutamate and just clearing through neurons is not going to be |
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67:20 | enough to clear it out of the synapses right? It illuminates is working |
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67:31 | fast or too much or too It will affect the amount of glutamine |
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67:38 | is given to back to neurons. glial cells in particular astra sizes. |
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67:44 | looked at, they can control spatially ions like potassium ions then to connected |
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67:52 | gap junctions. Remember that's another two temporal scales. Gap junctions are immediate |
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67:58 | synaptic transmission is with about 5 to millisecond delay. Then I wanna tropic |
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68:05 | 5 to 10 milliseconds later and metabolic 20 to 50 milliseconds later with the |
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68:11 | protein content. So these are all temporal scales. So glia will very |
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68:16 | be involved Or not just the ionic but in a way. And the |
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68:22 | of glutamate uptake of glutamate and how of that glutamate is available to narrows |
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68:28 | that's why our synapses are really tripartite where leah plays an important role in |
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68:35 | neural transmission. Okay so yeah for first purposes especially predominantly seem to have |
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68:52 | sophisticated networks and uh yeah so glutamate a natural neurotransmitter endogenous agonist to three |
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69:05 | of glutamate ion a tropic receptor channels and India and china. Those receptor |
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69:11 | will also have their own chemical agonists antagonists. So am plays an agonist |
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69:16 | ample channel and NBA front FDA how and is for kinda channels. These |
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69:23 | the different agonists that will open up channels. And so what we talked |
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69:27 | is one the excitatory neurotransmitter glutamate is uh running out of time. Oh |
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69:45 | when they're excited during neurotransmitter glutamate is . It will bind to glutamate receptors |
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69:56 | it turns out that we have two of anna tropic receptor channels and boston |
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70:03 | we're recording activity from from this cell we have an electrode here boston ethically |
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70:09 | gonna record an ep sp as it out that when you release glutamate you |
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70:15 | activate ample receptors and as soon as binds to receptors, psyllium starts flexing |
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70:23 | and ample receptors are responsible for the phase of this E. P. |
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70:28 | . P. And and M. . A receptors are a little |
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70:33 | So when you release little made here glutamate bison and the receptors that are |
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70:38 | to open right away because an D. A receptor is have a |
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70:41 | block and that magnesium block is blocking receptor channel four. And when the |
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70:47 | of potential D polarizes through ample channels more positive potentials that alleviates the magnesium |
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70:55 | , the magnesium comes out and an . D. A receptor is responsible |
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71:01 | the late phase of the Ep sp also that ample receptors will conduct sodium |
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71:08 | potassium and then M. D. receptor some ample receptors will be also |
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71:13 | to calcium but all an NBA receptors ample receptors will be permeable to |
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71:20 | All an NBA receptors are permissible to potassium and calcium and I'm seeing that |
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71:26 | I'm running out of time here a bit. So I'm gonna pick up |
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71:30 | this slide just introduce it briefly So if you have ample time glutamate |
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71:37 | will open this channel but to open N. D. A channel you |
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71:41 | glutamate on glycerine as a co factor then opening up an M. |
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71:47 | A. Receptor channel and a lot flux of sodium potassium and calcium. |
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71:52 | review some of these things on the here but please do not confuse an |
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71:57 | . D. A receptor with metabolic with receptors which we will not study |
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72:01 | function of a tropical receptors about 12 subtypes. But an M. |
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72:06 | A receptor is not just blocked by and it is late activated because you |
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72:14 | need to activate ample receptors to de the cells and because of that an |
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72:19 | . D. A receptor is referred as coincident detector. It has to |
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72:24 | pre synaptic neurotransmitter release and Pazin optic polarization, coincidentally detect pre synaptic and |
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72:33 | optic activity in order to open and and conduct and when it conducts it |
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72:40 | 50 PICO seaman's ver versus non NMDA amper receptor channels conducting 20 P |
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72:47 | So the conductors through an M. . A receptor channels are much much |
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72:51 | . Alright that's enough information for I'm going to save the lecture. |
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72:56 | the next professor come in. I'll everyone on thursday and I'll give you |
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73:01 | the details on your quiz for next . On thursday. Okay, so |
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73:05 | in on thursday, please. It be online, as I mentioned. |
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73:09 | have a good rest of the |
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