| 00:01 | This lecture 12 of Neuroscience. And we discussed neurotransmission, we talked about |
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| 00:06 | fact that there are excitatory and inhibitory . So the cry synopsis, we |
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| 00:13 | discussing the use of glutamate li binding . So, glutamate is like and |
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| 00:20 | app. And a after a possible early P, the EPSP A is |
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| 00:27 | for the limit phase of the The reason for that is that as |
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| 00:32 | as glutamate binds to a receptor, starts flexing positive sodium ion which is |
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| 00:39 | this initial depolarization. However, an A receptor is blocked with magnesium. |
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| 00:46 | for this magnet to be essentially kicked of the channel from blocking it, |
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| 00:52 | has to be a depolarization that takes . So when you have this |
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| 00:57 | magnesium leaves an MD A receptor And now an MD A receptor is |
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| 01:03 | for the late portion of this And as you can see these channels |
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| 01:09 | conduct ions inside sodium and potassium And in case in an MD |
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| 01:15 | it's also a significant source of calcium and MD A receptors reverse at zero |
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| 01:22 | as we discussed. And in m plate pools which are created by |
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| 01:29 | . And it's a flux of sodium potassium through nicotinic acetylcholine receptors and MD |
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| 01:35 | receptors, amper receptors, which are mostly by sodium potassium foxes. All |
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| 01:42 | these excited for potentials that we've discussed far. Ample potential and epsp which |
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| 01:48 | be broken down to either an MD currents or ample currents. Because in |
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| 01:51 | example, we talked about isolating an A current and demonstrating how magnesium is |
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| 01:58 | that an MD A receptor current. So, understanding these three different |
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| 02:05 | essentially how they flux the uh the ions that they flux ion, sodium |
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| 02:11 | potassium. And the fact that all of these potentials will reverse at zero |
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| 02:18 | lay potential A EPSP and, and A PSP, they will all reverse |
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| 02:25 | zero millivolts. Glutamate again, is the only thing that needs to happen |
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| 02:30 | order to cause activation of an MD receptor. It's also glycine co factor |
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| 02:35 | is important. So, glutamate binding glycine binding and of course depolarization which |
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| 02:41 | magnesium block, which allows for influx sodium and calcium and deflux of |
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| 02:47 | Magnesium will have its own or maybe two binding sides within the channel where |
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| 02:52 | blocking the channel. Zinc will have binding side. Also as well as |
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| 02:57 | MD A receptor is a target for pharmaceutical uh drugs as well as illicit |
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| 03:04 | such as PC P, which uh some of these drugs, we talked |
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| 03:10 | how most of the LNS that we are reversible agonists or reversible antagonists. |
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| 03:16 | some of the illicit drugs, the , these stops where they have much |
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| 03:21 | binding, what we call binding is these receptor channels and they can stick |
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| 03:26 | these channels for much, much longer . So, sometimes illicit use of |
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| 03:31 | uh uh intoxicating in this case, P uh kind of illicit drugs can |
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| 03:38 | to severe damage to an MD A signaling. And so there are things |
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| 03:44 | can impair the whole system just with single use. So, and that |
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| 03:48 | is because of an MD A an MD A receptor again is important |
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| 03:53 | synaptic plasticity and in strengthening the And so, if you have a |
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| 03:58 | effect on an MD A receptor through drugs or drugs of abuse, it |
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| 04:04 | impact or impair or improve if it's drug, potentially. Um all of |
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| 04:11 | aspects of an MD A receptor participates such as snap with plasticity and a |
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| 04:16 | part of learning and memory as well calcium influx inside the cells. We |
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| 04:21 | started discussing this concept that once glutamate released, it will also in the |
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| 04:28 | will monitor tropic receptors. So we've just discussed how tropic kind with |
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| 04:33 | ND A but also metro receptors. are different subtypes of metro glutamate receptors |
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| 04:39 | is G couple of receptors glutamate. it gets released in the synoptic |
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| 04:45 | it gets transported back through the glutamate into the presynaptic terminal and it gets |
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| 04:53 | into the vesicle. So, glutamate synoptic terminal will have to have a |
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| 04:59 | for glutamate. And we will also to have a transporter or glutamate vesicular |
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| 05:07 | . So now that glutamate is re here, it can be re-released, |
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| 05:12 | we also spoke what an intricate role especially asides play in this whole |
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| 05:19 | And the way that they interact with is they have their own glutamate |
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| 05:28 | And they will essentially transport glutamate from synapsis inside the glia and will transform |
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| 05:36 | into glutamine ase in into glutamine with synthese. OK. So they will |
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| 05:43 | glutamate, uh glue and make glutamine and then they will release this glutamine |
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| 05:53 | that glutamine will get transported into the and neurons excited to neurons will have |
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| 06:04 | and they will produce out of glutamine and with the help of glutamate and |
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| 06:11 | glutamate will be uploaded into the vesicles released again. And so this is |
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| 06:18 | the unique thing we also discussed just glial cells. And I mentioned that |
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| 06:24 | will have a slide. So I'll the slide, you know, for |
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| 06:28 | students, I will also upload this . So for your quiz, the |
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| 06:32 | students who will have two articles. you'll be have to be familiar with |
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| 06:37 | . Um uncaging. OK. On of uh of neurotransmitter and caging in |
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| 06:46 | dimensions. That's one of the articles you'll find in your folder later this |
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| 06:51 | if it's not there already. And second one is on this metabolism uh |
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| 06:57 | the uh interactions with L A and . So you graduate students, I'll |
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| 07:02 | you to know a little bit more when answering uh the questions from the |
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| 07:08 | you'll have the link to that article well. But this very clearly demonstrates |
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| 07:15 | complex palings here. But so glutamate reuptake not only by uh glutamatergic |
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| 07:24 | it also gets reuptake by astrocytes and gets released by astrocytes. OK. |
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| 07:33 | this is glutamine, it gets released astrocytes and then you have a separate |
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| 07:39 | uh snack transporter that will transport glutamine these neurons. So, glutamic neurons |
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| 07:47 | have glutamate transporter and glutamine transporter. . Now notice on this side, |
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| 07:54 | have Gaba. So these are gabba neurons and we'll talk about galic neurotransmitter |
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| 08:01 | and phos effects in a few But the point being here is that |
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| 08:06 | Gaba gets released Gaba also gets not only by neurons back into the |
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| 08:17 | terminal, Gabo also gets reuptake by . So, astrocytes will take Gaba |
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| 08:26 | we'll plug it into this cycle, sustain this TC A cycle and al |
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| 08:34 | come out glutamate inside astro sites, . So if you can make glutamate |
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| 08:43 | Gaba ostracizes, make glutamate from Gaba they just transport glutamate in and then |
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| 08:51 | convert that same glutamate, whether it's from glutamate, they converted into glutamine |
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| 08:56 | from Gaba, they convert it into . Also. Now that glutamine we |
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| 09:03 | talked, we will go back into neurons. But that glutamine will also |
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| 09:07 | into the inhibitor neurons when it goes the inhibitor and neurons. This uh |
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| 09:16 | gag glutamine cycle right here, glutamate that gets reuptake and gag glutamine. |
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| 09:25 | essentially glutamate is produced and you have that out of glutamate converts it into |
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| 09:35 | , uploads it into vesicles and releases the synapse. So now you have |
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| 09:44 | slurping up glutamate, slurping up What astrocytes are doing is they can |
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| 09:51 | convert glutamate into glutamine or they can gamma through TC A cycle into |
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| 09:58 | And both excitatory cells, glutamic cells inhibitory gabba erin cells will have transporters |
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| 10:05 | glutamine and excited to sal will make out of glutamine. And Gaba sauce |
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| 10:13 | have to work a little bit harder glutamate and then make gaba out of |
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| 10:17 | glutamate. And so I'll conclude this for everybody to have in an article |
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| 10:23 | the graduate students. But that's sort the principle of this tropic arrangement |
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| 10:30 | And again, it is not unique to glutamate signaling, but also |
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| 10:36 | And what that tells you is that ostracizes, regulate the total available amount |
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| 10:46 | gate. Therefore, oocytes regulate the available amount of excitatory activity or excited |
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| 10:53 | synoptic activity in neurons. So, are neurological disorders and they can be |
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| 10:59 | problems if lit a transporters and wea impaired. And that means that there's |
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| 11:06 | much glutamate. Now, that means there's too much excitability and that has |
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| 11:11 | to do with neurons. Neurons are that they have over abundance of, |
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| 11:16 | glutamate glutamate. It's always transported back glutamate to the piece of false and |
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| 11:24 | available because astrocytes are not taking up level of that glutamate into themselves. |
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| 11:32 | , when we look again at the A receptors, those are ionotropic uh |
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| 11:39 | receptors. But in addition to ionotropic , we also have metabotropic receptors. |
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| 11:47 | glutamate receptors are subdivided into metabotropic One metabotropic group two and three. |
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| 11:56 | most of the metabotropic gluttons that occurs one are located poop and group two |
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| 12:05 | three are located recently and therefore their where it's possy will determine their cellular |
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| 12:17 | . So, posy, we have of calcium and metabotropic glutamate receptors can |
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| 12:28 | neuronal excitability through the secondary messenger And they also can modulate excitability of |
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| 12:35 | MD A receptor. So it's po effects on the cell. You're not |
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| 12:40 | get into the details of the secondary or pacs and things much or uh |
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| 12:48 | little. We'll talk about that pre . So if fossil optically, you |
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| 12:54 | neuronal excitability, you modulate fossil topic , what are you doing presyn |
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| 13:00 | So, pre synoptic, we saw gaba order receptors can block exocytosis. |
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| 13:13 | looked at this example of the auto in the previous lecture that we'll look |
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| 13:18 | again. But when we talked about Gaba auto receptors, right, we |
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| 13:25 | that when you activate auto receptor that Gaba B, it will block calcium |
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| 13:31 | and it will block exocytosis. That in the previous uh lecture slides. |
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| 13:38 | we have a similar mechanism here and it's the same target, the same |
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| 13:44 | gated calcium channels or potassium channels But the effect is also blocking excitatory |
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| 13:52 | movies. That's another way pre we we have metabotropic glutamate receptors. |
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| 13:59 | of on the inhibitory synopsis, we metabotropic Gaba receptors that, that will |
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| 14:05 | in greater detail in a minute. also it can regulate essentially neurotransmitter cycling |
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| 14:12 | neurotransmitter exocytosis. So, depending on they're located, their effect on the |
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| 14:21 | is going to be different. All , now, let's talk about galic |
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| 14:26 | inhibitory uh signaling. So when Gma to Gaba receptor channel, we have |
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| 14:36 | of chloride. So we'll talk about Gaba channels. The first Gabu channel |
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| 14:45 | G A and another one is a G protein coupled GMA B receptor. |
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| 14:58 | , and we'll see that it is linked to another ion channel on the |
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| 15:04 | . So when Gaba, this is to be our Gaba channel. |
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| 15:11 | This is our Gabba A. When molecules bind to Gabba channel, you'll |
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| 15:19 | influx of chloride. So you will negative charge coming in and Gabba A |
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| 15:27 | going to be responsible for the early of IP sp inhibitory po synoptic |
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| 15:35 | So when Gaba binds, you have of fluoride. OK. When that |
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| 15:43 | Gaba molecule binds to Gaba B it initiates as is shown here, |
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| 15:51 | initiates g protein complex and catalytic sub of this G protein complex will target |
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| 16:03 | synoptic, they will target potassium channel in particular, they will open that |
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| 16:12 | channel and they will cause the efflux potassium. Yeah, equal of potassium |
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| 16:22 | gonna result in further hyper polarization. this portion here is Gaba a this |
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| 16:32 | here is Gaba be again, if have a substance that binds to inotropic |
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| 16:42 | . So this is your stimulation, have a few milliseconds delay, let's |
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| 16:47 | five millisecond delay. That's a synaptic , chemical synaptic delay. You'll see |
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| 16:52 | early E IP SP because you have of fluoride and then through activation of |
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| 17:00 | protein coupled cascade, you can see this is some uh delay of, |
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| 17:07 | say 20 to 50 millisecond. It varies. Uh But let's just put |
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| 17:14 | to 30 millisecond delay here from from the signal. Now you have |
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| 17:21 | the potassium channel. So this is happening post synoptic. But what we |
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| 17:29 | saw pre synoptic is that pre synoptic B activation and Gaba synopsis blocked calcium |
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| 17:45 | . OK. So it has an effect on potassium channels. So, |
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| 17:54 | B, if we're talking about potassium they post synaptic, ok. And |
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| 18:08 | going to open these channels through the in cascade. And the calcium channels |
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| 18:20 | presynaptic and Gaba B is inhibitory to calcium channels, which it's going to |
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| 18:39 | these channels pre synoptic which is going impede with exocytosis. That so and |
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| 18:59 | why you have also a delay here you have the G protein activation for |
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| 19:05 | psyop particularly, but pre cynically you be controlling the neurotransmitter release. |
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| 19:11 | Gaba in the CNS media is most synaptic inhibition. Uh Glycine mediates, |
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| 19:18 | of the non Gaba synoptic inhibition, particular, in the spinal cord and |
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| 19:25 | receptor is aside to many molecules uh sides for many molecules. So today |
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| 19:36 | Wednesday, we used to in college call it over the hump uh parties |
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| 19:43 | Wednesday evening. Uh or next time at the happy hour, you consume |
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| 19:49 | , ethanol binds to gamma receptors and increases inhibition. So, and you'll |
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| 19:59 | really, yeah, well, if have one or two drink, it |
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| 20:04 | inhibition because they're all agonous. All these molecules are agonous. So they |
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| 20:08 | promote influx of fluoride. So they basically dampen the brain activity and people |
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| 20:14 | are pretty chilled out with a glass wine or two. But if you |
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| 20:18 | a person dancing on the bar and off their clothing, that's typically like |
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| 20:23 | shots into it. And now it's completely different rule. So now there's |
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| 20:28 | complete disinhibition actually. Uh there's no inhibition often. So it depends on |
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| 20:36 | levels of how these molecules stimulate different receptive channels and their respon benzodiazepines. |
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| 20:46 | you will, you will hear about . So I was just listening to |
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| 20:51 | , something about Benzos. Benzos. rap songs about Benzos. Benzodiazepines are |
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| 20:58 | seizure drugs or epileptic drugs. they're sedative, they are used in |
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| 21:05 | conditions. Also. Um barbiturates are sedatives uh as well as neuro |
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| 21:14 | they all have binding sides on this channel and all of them are |
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| 21:20 | which means that they will increase the of fluoride and it will increase the |
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| 21:26 | of in condition. And benzodiazepine is one of the most effective drugs for |
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| 21:32 | types of severe seizures and epilepsy. um the way it works is it |
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| 21:40 | inhibition, essentially uh seizures and uh conditions a lot of times have too |
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| 21:47 | excitation. So when we talk about excited or inhibitory inputs and circuits, |
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| 21:52 | a certain dynamic balance. It's not they're always staying, you know, |
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| 21:58 | there's always fluxes of less or more or excitation, but it is within |
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| 22:03 | certain dynamic range. And if it outside that dynamic range with AOL is |
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| 22:08 | blow off with Benzodiazepines, the anti drugs that they actually will make people |
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| 22:14 | like they're drunk too. Uh So have similar effects. Um OK. |
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| 22:24 | this is Gaba B which we already And if you want to read about |
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| 22:29 | , you can click on this link to current opinion of neuro uh uh |
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| 22:33 | neurobiology just like and, and MD receptor channels, Gaba A has its |
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| 22:39 | agonist musim all and its own antagonist Kulon and Gabba B has its own |
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| 22:46 | bac with and antagonist flo. And , we already talked about how when |
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| 22:55 | have activity along the pathways, when stimulating some pathway, quite often, |
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| 23:03 | will have both responses. So in case, we were stimulating the axons |
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| 23:09 | were coming out of the eye and were going into the thalamus, the |
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| 23:16 | that you will learn a lot about in particular, the lateral geniculate nucleus |
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| 23:21 | the thalamus. And so we were the set of fibers and in these |
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| 23:27 | , we have a mix of excitatory we also in there have some inhibitory |
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| 23:35 | and then see if I have a color plan here, they're all running |
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| 23:41 | slowly. So in the next you're gonna also have some inhibitory |
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| 23:49 | So it's called this blue are gonna our ex excited and these green are |
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| 23:57 | to be our inhibitor synopsis. So you stimulate across these fibers, you're |
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| 24:02 | cause release of litigate and gobble. in these experiments, what we saw |
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| 24:09 | if you, this is the stimulation here and with a little bit of |
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| 24:14 | , we saw an EPSP. So is that Epsp right here, you |
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| 24:20 | that after the stimulation, you have EPSP and that EPSP was followed immediately |
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| 24:29 | an IP SP, which was Gaba IP SP and that was followed by |
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| 24:37 | B IP SP. So what we is we evoke stimulation. And as |
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| 24:42 | mentioned, a lot of synopsis, lot of the cells that you're recording |
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| 24:48 | , if they're being stimulated from these from these tracks and the cell you're |
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| 24:54 | from is, is, is here the thalamus and this is your |
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| 24:57 | This is the trace coming from the . So if you're recording this electrical |
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| 25:03 | here, OK, you're gonna see first, you actually excite excited through |
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| 25:10 | synopsis, you get EP SBS but that EPSB gets controlled and shaped by |
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| 25:18 | . Gabba A and Gabba B. the reason why we say it gets |
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| 25:21 | and shaped by Gabba A and Gabba is, if you apply by |
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| 25:28 | bi kulin is a Gaba, a . So it blocks Gaba A. |
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| 25:36 | you block Gaba A, there's no of chloride, there's no hyper |
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| 25:44 | So if you block Gabba A with , you now have this giant giant |
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| 25:54 | . So in control conditions where you excitation and inhibition, you will see |
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| 26:00 | excitatory response followed by inhibitory response. you block out a now all of |
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| 26:08 | sudden, your response can become That's why we say that inhibition is |
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| 26:15 | draw the insult and how much excitation produced. If you walk this inhibitory |
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| 26:22 | , here you get this massive So that is abnormal and that is |
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| 26:28 | excitability. And I'm not gonna get details of two hydroxy Sacco film because |
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| 26:34 | G but the antagonist and it's different what is stated in your book, |
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| 26:40 | actual substance of. Uh So this my work from graduate school. I |
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| 26:46 | my phd at LSU. It was to be LSU Medical Center, it |
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| 26:53 | uh LSU Health Sciences Center. Uh uh it was published in 2009, |
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| 27:00 | journal of Neurophysiology. So this was of my first articles in neurophysiology and |
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| 27:06 | physiology. And in that case, were studying the surface from the eye |
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| 27:11 | the retina into the thalamus and stimulating tracks that are running into the thalamus |
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| 27:17 | recording from thalamic cells and trying to what happens during early development along these |
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| 27:26 | and how excitation inhibition shapes the development the structures in the thalamus and also |
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| 27:33 | excitation and inhibition uh influence plasticity and rules in the early developing visual |
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| 27:42 | OK. So let's put it all because that's a slide that puts it |
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| 27:46 | together. We have these inhibitory synopsis already discussed. And pho synical, |
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| 27:53 | have gabba a influx of fluoride pho . You also have these little winged |
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| 27:59 | B receptors and pho synoptic they will potassium channels. So they will cause |
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| 28:05 | hyper polarization right. This is gabba hyper polarization, you open potassium |
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| 28:11 | more hyper polarization, potassium is Now, we also talked about how |
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| 28:17 | Gaba the auto receptors in this case regulate calcium and can basically block or |
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| 28:26 | exocytosis. And so this is the sims. Now, this is the |
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| 28:34 | sys, this is glutamate and glutamate released fop A activates, this is |
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| 28:43 | MD A receptor and MD A receptor lots of influx of calcium activates downstream |
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| 28:49 | cascades activates kinase such as calcium calmodulin . And what happens then then through |
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| 28:59 | kind signaling and through either Gaba B which are also poop. Like |
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| 29:06 | So yes, this is an ex for snap because glutamate gets released through |
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| 29:12 | and you have glutamate receptors, but same synapse will have Gaba receptors |
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| 29:17 | So, so what, what what are we doing there? So |
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| 29:21 | can be modulated by cellular mechanisms. B receptor here, there's no Gaba |
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| 29:27 | the synapse here, there's no Gaba released. So they get modulated through |
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| 29:33 | cellular mechanisms and they can still open potassium channel po synoptic. When they |
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| 29:39 | potassium channel posy, they cause hyper when they cause hyper polarization. And |
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| 29:45 | A receptors can no longer open because need depolarization and, and, and |
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| 29:52 | polarization, they're blocked with magnesium So the other thing that happens is |
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| 29:58 | if there's a lot of Gaba, lot of inhibitory signaling, it can |
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| 30:02 | over in the nearby synapses. let's say ostracized, it didn't slurp |
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| 30:07 | all of that gaba, excessive that's kind of a traveling outside the |
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| 30:13 | synapse and it spills over into the synapse. So the excitatory synopsis will |
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| 30:21 | have Gaba view receptors pre synoptic and they will block influx of calcium just |
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| 30:28 | they did in the inhibitory synopsis and regulate the release of glutamate. So |
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| 30:35 | , that's pretty brutal. You can like inhibitory takeover of the excitatory synapses |
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| 30:41 | it can have so much inhibition so much synaptic inhibition, so much |
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| 30:46 | release that it also actually even in , blocks glutamate release. Now, |
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| 30:54 | course, there will be other other channels in this whole looks |
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| 31:01 | But it's a pretty simple representation of happening. Now, is there cases |
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| 31:07 | a neuron will well like a neural , would it like fire X ray |
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| 31:15 | uh around a ex excited to, inhibit it if it's not responding to |
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| 31:23 | a specific signal where they intentionally release extra gas that is missed by the |
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| 31:29 | to inhibit an exacto or is it , it's just if it spills over |
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| 31:36 | the nearby excitatory symptoms? Yeah. that what you're asking me? I |
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| 31:41 | just wondering if like there, there's intentional firing of the Gaba uh inhibitory |
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| 31:49 | . So that more is in the is missed by the astrocyte. So |
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| 31:54 | can inhibit other excitatory symbol uh signals is it always just accidental? Um |
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| 32:04 | , I don't know if they're like acting in disguise, but I think |
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| 32:11 | is happening is the transporters and le only have a certain rate of |
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| 32:18 | And if you release more and more more you over on that system, |
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| 32:23 | not gonna, all of a you know, there is gonna be |
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| 32:26 | in the transport because part of it driven by gradient too, but it's |
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| 32:32 | gonna like, you know, speed 10 times more. If there's 10 |
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| 32:35 | more release, it works in a steady amount that it can transport |
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| 32:41 | So you will have in those instances much uh gab accumulated potentially and in |
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| 32:47 | case, uh it's not acting in , it's just too much of land |
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| 32:51 | taking over the potential excitatory synapsis. OK. So neuromodulatory systems, diffuse |
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| 33:03 | systems. Remember our acetylcholine system hippocampus, ponto mesencephalic mental complex. |
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| 33:15 | have the basal nucleus and Menard and septal nuclei. And you can see |
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| 33:22 | of acetyl colon. We talked about acetylcholine is synthesized. We talked about |
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| 33:27 | acetylcholine has degraded. We talked about many things along this back line. |
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| 33:34 | you will be responsible for knowing the synthesis and degradation of acetylcholine this whole |
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| 33:41 | and the fact that in the unlike in the neuros junction, you |
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| 33:47 | nicotinic receptor channel and muscarinic not of tropic acetylcholine receptor, the nicotine, |
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| 33:54 | is from tobacco or synthetic nicotine is agonist, nicotinic receptor, which we |
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| 34:01 | in the brain. But also as saw in neuromuscular junctions everywhere. Muscarine |
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| 34:07 | an agonist. Muscarinic receptor. We already talk about curare and how |
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| 34:14 | blocks to the receptors and reduces the potential. And that does it through |
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| 34:20 | because you can do that in neuromuscular that only has nicotinic uh ach receptors |
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| 34:28 | atropine is an antagonist for muscular So some of these things can be |
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| 34:37 | from nature. Some of these things synthetic agonist and antagonist. But there |
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| 34:42 | two distinct modes of operation. And way that the metabotropic acetylcholine receptor acts |
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| 34:51 | the brain is that when you activate acetyl colon receptor, it will open |
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| 34:58 | nearby potassium channel. Does that sound ? So if you activate metabotropic Gaba |
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| 35:07 | , it will open potassium channel. you activate metabotropic acetylcholine receptor, it |
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| 35:15 | activate the same channel. What does mean? As as I mentioned, |
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| 35:20 | are completely two different neurotransmitters. Gaba a neurotransmitter here versus acetylcholine, that's |
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| 35:30 | neurotransmitter there. But they through the and sometimes different eup protein complexes, |
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| 35:37 | both converge on the same target, is the same possy potassium trouble. |
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| 35:45 | , if nicotinic acetylcholine receptor is gonna for the influx of sodium and then |
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| 35:54 | nervous synapsis, it doesn't cause as depolarization nearly as it does in the |
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| 35:59 | junctions, but it does cause depolarization of the influx of sodium activation by |
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| 36:06 | same molecule, acetyl Colin, a metabotropic G protein cascade causes inhibition. |
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| 36:16 | leaving is gonna hyperpolarize the cell. they act in the opposite functions of |
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| 36:22 | level of the cellular physiology. Nicotinic muscarinic. OK. Does everybody understand |
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| 36:30 | part? I can draw it But basically uh nicotinic the release of |
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| 36:46 | K from the syna ccoming poly combined nicotinic ach R. And when advised |
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| 37:00 | nin ach R sodium is going to in and it's going to cause |
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| 37:07 | And that's a a see COVID molecule like we saw with Y getting bind |
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| 37:18 | muscarinic acetyl codeine the doctor this one here and finding of this molecule the |
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| 37:28 | it will activate the G protein And this is a potassium channel, |
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| 37:33 | will hold the potassium channel, the is going to be even the cell |
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| 37:38 | the inside of the cell hyperchol or . And that can coexist in the |
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| 37:47 | patch of the number. So the neuron and co expressed possible almost. |
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| 37:57 | this is the same chemical but the that it is very different, this |
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| 38:03 | logically develop there in polo but very . Uh And here is the same |
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| 38:11 | acetyl coding molecule. So the effect depends on the poynter receptor and what |
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| 38:19 | possy tic receptor does here. It additive Gaba A hyper polarizes Gaba B |
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| 38:28 | polarizes more there. It's the opposite depolarizes muscarinic hyper polarizes the plasma. |
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| 38:40 | we'll see also later in this maybe next uh how there's also uh |
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| 38:48 | actions uh inside the cell that can activated by different subtypes of metabotropic |
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| 38:57 | And so a lot of times this is referred to shortcut pathway, it's |
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| 39:03 | a shortcut pathway. Because once the protein complex is catalyzed here, the |
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| 39:08 | subunits immediately go to the nearby So there are no other chemical enzymatic |
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| 39:16 | secondary messenger intermediaries. It's actual catalytic that opens up this potassium ch. |
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| 39:25 | right. And that concludes our lecture gamma glutamate and Gaba. And we're |
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| 39:35 | to now go into more detail on diffuse neuromodulatory system. So now |
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| 39:42 | I'm not certain, we're gonna be to get through this entire lecture |
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| 39:47 | I'll also try to finish a little earlier today. Uh But when we |
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| 39:53 | about the used neuromodulatory systems, remember that these are special because there's |
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| 39:59 | limited number of neurons that are located specialized nuclei that produce either norepinephrine or |
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| 40:09 | or Choline or dopamine. And they're far and few in between. If |
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| 40:16 | is over 80 billion of cells in in the brain of neurons in the |
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| 40:24 | , these guys number in hundreds of only. That's where they are far |
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| 40:31 | few in between. In contrast, to Gaba and glutamate cells. I |
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| 40:37 | to you that Gaba and glutamate is widely throughout C MS. There's one |
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| 40:42 | that produces gama, one nucleus that glutamate. Those cells are scattered throughout |
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| 40:48 | C MS. But for the, mean signaling to have specified nuclei with |
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| 40:55 | limited number of cells. But they these extensive what we call diffuse |
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| 41:03 | they're modulatory because they primarily with an of a PSE colon act through metabotropic |
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| 41:11 | protein complexes and downstream cascades, acetylcholine forebrain complex and ponto mesen Pallo tegmental |
|
| 41:25 | . Uh If you look at this frontal complex here, basal nucleus of |
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| 41:31 | art, this medial septal nuclei, supplying essentially a lot of outputs into |
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| 41:41 | cortex because you will see that this also supplies the brain stem and the |
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| 41:49 | cord projects down the spinal cord. these uh nuclei will have their own |
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| 41:57 | of a more or less but less specific but still distinct projections inside the |
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| 42:07 | functions. Mostly unknown, participates in and memory, mostly unknown because there's |
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| 42:12 | lot of things we still don't know how these chemicals act in the brain |
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| 42:17 | they act. And because of this almost sprinkler like system, it really |
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| 42:23 | on where the receptors are located with different chemicals participates in learning and |
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| 42:31 | Absolutely impaired in Alzheimer's disease. this is the neurotransmitter system that is |
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| 42:39 | in Alzheimer's disease. Now, pontis mental complex, the function is to |
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| 42:47 | excitability of the thalamic and the sensory that are located in THS so different |
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| 42:57 | , different parts of the brain are for different functions to show a lot |
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| 43:01 | details of the columns. As we , it's a structure comprised of many |
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| 43:07 | nuclei. One nucleus processes visual information not a nucleus auditory information itself by |
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| 43:14 | here and having the projections of the , you're influencing sensory information and sensory |
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| 43:22 | processing by being here in the basal and having your projections into the frontal |
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| 43:31 | and parietal cortex and visual cortex. functions are you influencing? Oh, |
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| 43:37 | many because different parts of cortex are for different functions. And that's why |
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| 43:42 | still difficult to pinpoint. It's a soup. Think about all of these |
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| 43:49 | that are available for certain circuits and neurons gaba glutamate and men and they |
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| 43:56 | different receptors react to just this on off switch, which is glutamate on |
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| 44:02 | off. And then you have all these complex other chemicals floating around. |
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| 44:07 | you have endogenous chemicals that fluctuate day nine others that stay at the same |
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| 44:14 | of the production. Uh It's very , right? It's like a, |
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| 44:19 | like a faux soup. It can so many different ingredients to get that |
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| 44:25 | . You know, uh acetyl codeine again, just to repeat, nicotinic |
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| 44:33 | depolarizing. Muscarinic is outward current. it's hyper polarizing muscarinic will act through |
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| 44:41 | Jurden cascade. The reason why these repeat is that I hope to finish |
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| 44:45 | lecture that we just finished today. time. Now let's move on to |
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| 44:52 | , catecholamines all have a common which is tyrosine, tyrosine hydroxylase turns |
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| 45:00 | into L dopa. Then dopa loses carboxyl group and becomes dopamine, |
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| 45:12 | With one beta hydroxy step reaction becomes and with methyl transferase, norepinephrine becomes |
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| 45:26 | and all from the common precursor tyro sometimes refer to as dre adrenaline in |
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| 45:38 | brain and they will have their own for expression of catecholamines, in |
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| 45:44 | in substantial Igra and ventral tig So when we're gonna focus on dopamine |
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| 45:51 | and in dopamine, you can see you have these two nuclei, these |
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| 45:57 | nuclei compared to the acetylcholine projections. can see how broad and why they |
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| 46:04 | , why they are throughout the brain the cortex. These are uh less |
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| 46:10 | diffused, less so spread out and targeting the frontal lobe and the |
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| 46:17 | And that's important by targeting the frontal and targeting the substratum that actually is |
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| 46:24 | the areas that are involved in motor . And when we talked about Parkinson's |
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| 46:32 | of Alzheimer's is linked to a pseudy . Parkinson's disease is linked to loss |
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| 46:38 | dopamine neurons, loss of dopamine. the typical symptom for Parkinson's disease are |
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| 46:47 | tremors. Sometimes also spasms and the come and sometimes when a person tries |
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| 46:53 | execute a task like pick up a of coffee and have a sip and |
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| 46:58 | cannot control it because these dopamine inputs they don't produce the motor command. |
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| 47:06 | motor command comes from motor cortex. cortex is located in the front below |
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| 47:11 | striatum, um contributes to the complex commands that we initiate. And then |
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| 47:19 | motor cortex. Once you have that command, the motor cortex sends the |
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| 47:24 | to the muscles of the spinal cord the brain stem. Uh cranial |
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| 47:31 | it's a signal to the spinal So the cranial nerves to activate the |
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| 47:35 | from the spinal nerve or the face from, from the brain stem. |
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| 47:42 | this is me cortic limbic dopamine the er projection midway substantia nigra has |
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| 47:53 | that are going into this area here is facilitating the initiation of of the |
|
| 48:01 | . So you kind of have on fact about on the frontal lobe and |
|
| 48:05 | not just going to be motor dysfunction because a lot of these neurological disorders |
|
| 48:11 | Parkinson's disease, people can also have , for example. So there's other |
|
| 48:16 | and other things and we're not entirely if this, it's just because of |
|
| 48:21 | dysfunction or maybe it's because of the dysfunction. Now, there is a |
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| 48:28 | inflammation of the frontal lobe which is a lot of different cognitive and executive |
|
| 48:33 | and, and um and and, such norepinephrine, all right, |
|
| 48:42 | you have production of norepinephrine and locus , the blue nucleus. You can |
|
| 48:48 | the axons are innervating the cerebral cortex in in innervating the thalamus, the |
|
| 48:56 | projecting into the spinal cord, the of the system. So functions of |
|
| 49:02 | system is regulation of attention arousal, also sleep wake cycles. So you'll |
|
| 49:11 | see serotonin regulate sleep wake cycles. you need something that makes you more |
|
| 49:16 | and something that makes you more It's a part of the sleep wake |
|
| 49:20 | . Also learning in memory, anxiety pain, mood, brain metabolism, |
|
| 49:27 | of norepinephrine system is with new unexpected sensory stimuli. So, painful stimuli |
|
| 49:34 | be uh somebody you know, scratch or cut themselves. That's no su |
|
| 49:40 | . We'll talk about no susceptive sensor , they'll carry that information to process |
|
| 49:45 | pain. But uh this stimuli, expected stimulator is a bear running at |
|
| 49:52 | and all of a sudden, you , you don't just back up and |
|
| 49:56 | like, hm, what should I ? It immediately kicks in your no |
|
| 50:02 | or adrenaline, the brain, it's fight of flight response. So you |
|
| 50:07 | fight the bear or you run away I don't know what's correct to |
|
| 50:11 | Don't quote me. I think maybe have to stand still and pretend it's |
|
| 50:16 | there. So, but nonetheless, will get that uh stress, almost |
|
| 50:23 | response of some unexpected stimuli. Let's about catecholamines. Again, catecholamines are |
|
| 50:30 | like dopamine. But also here we're at norepinephrine as well and let's talk |
|
| 50:39 | uh illicit substances such as cocaine or . And some of them are also |
|
| 50:47 | applied as pharma pharmaceutical medications, but and the particular targets that do immediate |
|
| 50:56 | . So this is a second When we talked about Alzheimer's disease, |
|
| 51:01 | said that medications for Alzheimer's disease the degradation, they block acetyl |
|
| 51:08 | So there's more acetyl code than the . The second strategy in pharmacological manipulation |
|
| 51:16 | mechanisms of the list of action is block the reuptake of them. Now |
|
| 51:22 | if you release dopamine and you don't a proper reuptake of that dopamine, |
|
| 51:27 | a lot more of that dopamine There's a lot more of that more |
|
| 51:32 | that on the bill. Uh So will be stimulating and increasing poop with |
|
| 51:41 | uh and increasing the availability of dopamine uh and norepinephrine alpha methyl thyroxine can |
|
| 51:57 | the synthesis of these molecules or inhibit synthesis of all dopa. So there's |
|
| 52:05 | ways you can either reduce the amount inhibiting the synthesis pre op or you |
|
| 52:11 | increase the amount by blocking the Serotonin, also abbreviated as five HD |
|
| 52:21 | derived from tryptophan. It regulates emotional behavior, sleep. So you're |
|
| 52:26 | catching on to how different chemicals. a second. You just said dopamine |
|
| 52:30 | motor motor commands. Now, serotonin mood. So that's different functions lead |
|
| 52:39 | , the pathways, you can see there are multiple nuclei, rapha nuclei |
|
| 52:45 | innovate many of the same areas as systems. So if you compare it |
|
| 52:49 | the norepinephrine nog system and see innovations are balanced spinal cord, the |
|
| 52:57 | thalamic areas, as well as broader throughout the cortex. Together with node |
|
| 53:04 | system, it comprises this ascending reticular system. And this reticular activating system |
|
| 53:12 | a part of the waves that kind a slow down your brain activity when |
|
| 53:16 | kick into the sleep cycle. So mediating your sleep cycle, sleep wake |
|
| 53:22 | mood. So it has to be , right? You need to calm |
|
| 53:26 | the uh the up and be more and then you need to change the |
|
| 53:33 | of these amines throughout the cycle of day. Also change the amount of |
|
| 53:40 | , which we also talked about is in the in the sleep cycle um |
|
| 53:45 | to change again and wake up. tryptophan will produce five hydroxy tryptophan and |
|
| 53:53 | hydroxy. Tryptophan will get decarboxylate into HD and serotonin. When you eat |
|
| 54:01 | on thanksgiving, turkey meat has a of tryptophan and that's why everybody gets |
|
| 54:07 | . I don't know. All family are so happy. Well, at |
|
| 54:12 | everybody is full and content and it's the amount of food, but maybe |
|
| 54:17 | a tryptophan and the turkey that allows to synthesize more serotonin. So when |
|
| 54:24 | talk about serotonin and we talk about uh impairment associated disorders. We were |
|
| 54:32 | about mood disorders. Uh You may heard ssrissr I is a selective serotonin |
|
| 54:40 | inhibitor. It's a very common Uh so, FLUoxetine shown here is |
|
| 54:50 | SSR I serotonin reuptake in the, terms of medication by blocking reactive of |
|
| 55:00 | increases the amount of serotonin because sir regulates the mood and uh helps with |
|
| 55:08 | and other uh anxiety and uh mental as well. Tricyclic is another group |
|
| 55:18 | medications that inhibit both La Neron and reactive. And that's kind of important |
|
| 55:28 | if those two systems regulate the sleep cycle, then you're kind of a |
|
| 55:34 | , maybe both and maybe that could your sleep wake cycle too. Which |
|
| 55:41 | when people don't sleep, well, in a bad mood. When they're |
|
| 55:45 | a bad mood, they get in worse mood and then they don't get |
|
| 55:51 | and they get in the worst mood it's like a, it's like a |
|
| 55:57 | . So ma O inhibitors, what MA O it's actually shown better in |
|
| 56:04 | next slide. But if you're looking MA L, MA L breaks down |
|
| 56:14 | , ok. So when serotonin cert gets reuptake back, remember all of |
|
| 56:20 | molecules get released, get reuptake back serotonin gets reuptake back into the pre |
|
| 56:27 | terminal, it gets metabolized by MA and it gets broken down. So |
|
| 56:35 | you inhibit MA L, right, you inhibit MA L, you inhibit |
|
| 56:42 | metabolism, that means that, that that gets transported into pre synoptic terminal |
|
| 56:49 | get broken down. But now it be re uploaded in B to repeat |
|
| 56:54 | release cycle. OK. That's the O inhibitors. So we now have |
|
| 57:03 | ways of regulating reuptake reuptake inhibition. can regulate breakdown of these amines. |
|
| 57:13 | ? We can also target the postsynaptic receptors. Uh cholinergic uh more anergic |
|
| 57:23 | others. So it's allergic receptors. . So, on this slide, |
|
| 57:30 | also have psilocybin or psilocybin mushrooms, and coyote that are interacting with uh |
|
| 57:41 | signal. And several states in this have recently legalized what is called psychedelic |
|
| 57:50 | that is a therapist assisted therapy. It's according to FDA PRO protocols and |
|
| 57:57 | some really interesting studies that are addressing role of the psychedelic substances in control |
|
| 58:07 | addiction. In particular, there are studies that are looking at how people |
|
| 58:13 | on the supervised psychedelic trips and quit uh heroin studies with animals or opioid |
|
| 58:23 | that are ongoing now with humans when is strong addiction to opioids. So |
|
| 58:28 | is an emerging field, these most of them, if you |
|
| 58:32 | they're still listed on schedule one of , which means in schedule one for |
|
| 58:38 | drug, it has no medicinal it has uh addictive properties and it |
|
| 58:46 | be dangerous. But as we're learning lot about what's on schedule one. |
|
| 58:51 | marijuana and cannabis is on schedule heroin is on schedule one and the |
|
| 58:58 | and mushrooms are a schedule aren't. you heard of these medical cannabis programs |
|
| 59:05 | are maybe in like over 40 different in this country. In Germany, |
|
| 59:11 | medical cannabis and pharmacies. So people white lab coats will give you your |
|
| 59:17 | cannabis that is subsidized with health So what is on schedule one? |
|
| 59:23 | what is in reality are two different ? And we've seen a lot of |
|
| 59:28 | since the nineties and the acceptance of as medicinal uh preparations and medicinal use |
|
| 59:36 | cannabis and physicians uh prescribing cannabis within medical state programs. And politicians deciding |
|
| 59:44 | there's over 100 and 20 different neurological even here in the state of Texas |
|
| 59:48 | which you can have medical cannabis But it's still on schedule one, |
|
| 59:54 | says it has no medicinal value and status. And when we talk about |
|
| 59:58 | the cannabinoid system, we'll come back talk about cannabis and the fact that |
|
| 60:03 | probably will witness the rescheduling of Canada this semester, maybe by the end |
|
| 60:08 | the semester, it will no longer in schedule one, but we will |
|
| 60:12 | on schedule three, but it's been schedule one since the seventies. Uh |
|
| 60:18 | these substances are also on schedule but now we're learning things about them |
|
| 60:23 | is wowing a lot of uh physicians medical practitioners. So for example, |
|
| 60:32 | you take these antidepressant drugs, especially ma O inhibitors that are now interfering |
|
| 60:39 | the metabolism of serotonin, for and a person that is having severe |
|
| 60:45 | , severe anxiety, suicidal thoughts can't the house. Some of these medications |
|
| 60:52 | take 2 to 3 weeks to see effect. That's not really fast |
|
| 60:57 | It takes time to change the the reuptake cycle or the metabolism |
|
| 61:04 | And what's really interesting that's emerging with uh psilocybin therapy. A single use |
|
| 61:11 | these psychedelics can change people's addiction to , for example. So, and |
|
| 61:22 | happens within a day or two, doesn't happen within 23 weeks. |
|
| 61:28 | with a lot of pharmaceuticals, if not working for you, if it's |
|
| 61:33 | working effectively enough, that may be too many side effects. And the |
|
| 61:38 | of those side effects are worse than with your, with your condition that |
|
| 61:43 | drug is prescribed for. So if stop taking some drug and these particular |
|
| 61:50 | antidepressants, uh substances, I also two or three weeks for the system |
|
| 61:57 | rebuild itself to recover the metabolism, reuptake dynamics that was there before, |
|
| 62:04 | and now after the drug has been . And so that's what's interesting about |
|
| 62:10 | of these new emergent therapies is that may be acting much faster, having |
|
| 62:17 | significant effect after a single therapy session then not having to take two or |
|
| 62:24 | pills or five pills every day. the time period between the sessions and |
|
| 62:31 | for how long does it help? hasn't been determined very well, the |
|
| 62:37 | for therapeutic uh uh uh applications of Coyote, MD ma other substances that |
|
| 62:46 | still under investigation. We all also slightly different individual sensitivities to different substances |
|
| 62:54 | that is also still being determined. There's this thing coming out in the |
|
| 63:00 | market says micro dosing, that means you take very small amounts so that |
|
| 63:05 | OK, just take very small amounts that take this uh cide and very |
|
| 63:09 | amounts. So then people spraying themselves day. We also don't know, |
|
| 63:14 | does it add up to if this dosing continues for 23 weeks? What |
|
| 63:19 | it add up to? We no, we haven't done a lot |
|
| 63:22 | these studies. So something to keep eye on, something that is exciting |
|
| 63:26 | something that directly acts on the serotonergic antidepressant uh uh systems that we're discussing |
|
| 63:33 | respect to the means. Ok, gonna end it here today and we'll |
|
| 63:37 | back. We're gonna have a few , very interesting slides and we'll finish |
|
| 63:42 | monogen |
|
