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00:00 | So this is electric 12 of neuroscience we have covered quite a bit of |
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00:09 | information may be new for you because you didn't hear it in other courses |
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00:15 | we talked about the differences between neuro junction in the central nervous synapses and |
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00:22 | had these things written out on the . So for those that are not |
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00:27 | up to class, it doesn't show always the best on the board. |
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00:31 | you kind of lose out or information directly conveyed to you and I |
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00:39 | everyone to be attending in person, before spring break, it's really just |
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00:44 | lectures left and then a spring break you know, so you have a |
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00:49 | um then you could work a little harder and show up to class before |
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00:54 | also work with the material. So you are not certain, like what |
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01:00 | did you talk about neuro muscular junction central nervous system synopsis. If you |
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01:06 | recall any of that information, you go back open the video, points |
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01:12 | and watch those sections because even if doesn't show up clearly what I have |
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01:17 | or written on the board, especially I make it drunk on that side |
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01:20 | the board. If it doesn't show clearly, I'm speaking about it, |
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01:25 | can still take notes, you can remind yourselves and compare if you're in |
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01:29 | the most effective way. If you're class and took notes and you have |
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01:34 | questions, I have some doubts about your understanding about subject matter, Go |
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01:39 | that subject matter, look at what have in your nose. Listen take |
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01:45 | notes, compare what you have in notes and then you're gonna be |
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01:50 | So I highly recommend for you to that. Now. We're going to |
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01:55 | our quiz next week on friday. on monday I will have casas start |
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02:01 | the scheduling okay And it's gonna cover transmission and one lecture of the of |
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02:09 | C. N. S not the one. So all of the material |
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02:13 | next Tuesday were recovered through next Tuesday be on next friday's quiz. So |
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02:21 | that's also a good time. If are not certain about some terminology or |
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02:29 | the difference between nicotine nick almost Then it's a good time to review |
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02:35 | material this week, this weekend and week going into friday to take the |
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02:42 | . So you can ace the quiz then if you ace the quiz it's |
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02:46 | your points. You get as many as you want And that really depends |
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02:51 | how well you study. So if want to bunk yourself up by eight |
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02:54 | 10 points, you know study really and get a perfect score. And |
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03:01 | what happens to your exam. Score Goes up by eight or 10 |
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03:07 | That's a lot. So that's that's . Great. I can't just add |
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03:12 | and curve the average is fairly high advanced level undergraduate course but I can |
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03:18 | you an opportunity to curve yourselves and yourselves better for the exam. Okay |
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03:25 | last lecture we talked uh a lot a seed alkaline in particular and you |
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03:33 | be able to recite and know everything acetylcholine synthesis, how it gets uploaded |
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03:42 | the vesicles, how it gets how in the cns neurons it can |
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03:49 | nicotine acetylcholine receptors and Mascarenas, acetylcholine . So we started looking at this |
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03:55 | of uh neuro pharmacology. Okay, concept of neuro pharmacology where neural pharmacology |
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04:10 | this case for acetylcholine, it's what the agonists? What are the |
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04:16 | What are endogenous or naturally by our bodies produced agonists was a natural other |
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04:24 | in nature, or agonists or antagonists could be produced. We talked about |
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04:28 | and spiders and and snakes and what the, you know, what are |
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04:33 | human synthesized chemicals agonist antagonists? What the action of Alzheimer's medication? What |
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04:44 | the action of the nerve gasses? . There's all questions that can show |
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04:50 | on the quiz and on the exam it's really important to know and understand |
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04:56 | system because the system for seed locally the basis for other systems that we're |
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05:01 | about. There is release of glutamate glutamate will bind to iron. A |
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05:05 | and metal tropic receptors in the There's release of gaba and gaba, |
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05:10 | learn will buy into ion a tropic metabolic tropic receptors for gaba in the |
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05:17 | . So we'll talk about other And if you look at other means |
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05:23 | example, cata cola means class of or tyrosine is a precursor to L |
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05:32 | . L dopa is a precursor to . Dopamine is a precursor to |
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05:38 | Norepinephrine is a precursor to reference. lot of these molecules are actually precursors |
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05:44 | each other. I don't want you know the enzyme times that you know |
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05:49 | our box late things like take ceo group or hydroxy delays which add an |
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05:55 | age group which you should already I'm not gonna ask you for specifics |
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05:59 | what enzymes are responsible for converting a precursor into a molecule like dopamine. |
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06:07 | the principle is the same. And cola means and in fact cata cola |
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06:11 | will purely actor medical tropical storms. this is this is the difference |
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06:17 | as I discussed between acetylcholine and this here of all of the neurotransmitter types |
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06:24 | that acetylcholine has ion a tropic receptor and metadata tropic G protein coupled receptors |
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06:32 | it can target. But all the means are acting through G protein coupled |
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06:41 | . So if you have cattle colony release you also have a breakdown and |
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06:47 | talked about how you have a breakdown acetylcholine in the synapse or cata cola |
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06:53 | they can be transported back into the synaptic terminal terminal and there is mono |
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07:01 | mono amine oxidase and this mono amine is will be responsible for the breakdown |
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07:10 | cata cola mean like molecules and the synaptic terminals. So you can also |
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07:18 | basically not only synthesis but degradation of neurotransmitters at the level of the synaptic |
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07:26 | , pre synaptic aly and uh streets illicit drugs a lot of times they |
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07:36 | targets in the brain also. So uh for cocaine, the illicit drugs |
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07:44 | also molecules that would be medications We talking about how you have something natural |
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07:50 | is produced in the body. You something that is natural, can be |
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07:53 | and used as medication. We talked Botox. Can you be used for |
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07:57 | purposes but then it can be used FDA approved medication. And the targets |
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08:04 | , you know are the receptors in case the target is the re uptake |
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08:10 | cata cola means. So you can target and block the re uptake and |
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08:16 | you do. For example, if block the reuptake of norepinephrine and epinephrine |
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08:22 | is kind of like adrenaline of the , something that engages you or the |
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08:30 | , then blocking the re uptake again the by availability the presence of that |
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08:38 | within the synapse, it's a common . So you can do it by |
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08:42 | acetylcholine nestor race in the city alkaline pathway which is in the synapse or |
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08:49 | exam or you can be blocking the uptake or you could also be blocking |
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08:55 | oxidize here. Mono amine oxides prison which will also not degrade the molecule |
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09:03 | synaptic list, it would increase the of that molecule being transported and uploaded |
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09:09 | its appropriate class vehicles. So, acid neurotransmitters in general, what we |
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09:16 | about is that they're widely distributed uh expressed by south throughout the brain. |
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09:24 | so I drew this diagram here where can imagine that all of the blue |
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09:32 | is inhibition, whether it's Gaba, for amino acids, neurotransmitters and the |
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09:39 | dots are widely distributed self that are cells. And then these black nuclei |
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09:48 | the collections of cells that will be the means. And so they are |
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09:54 | limited and confined spatially. But they very broad projections that will go cortical |
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10:00 | as well as sub cortical lee and the peripherally on a lot of |
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10:05 | That will be central and peripheral outputs out from these nuclei innovating different centers |
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10:11 | the brain stem and the brain and the spinal cord amino acids. When |
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10:17 | talk about amino acids, Glutamate is precursor to Gaba. So the major |
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10:23 | neurotransmitter in the brain. Glutamate is precursor to the major inhibitory neurotransmitter here |
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10:30 | the CMS in the brain and I want you to know that the |
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10:36 | that converts glutamate into Gaba is atomic dicker box or God. And that |
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10:44 | important because if you were doing certain on tissue or cell subtypes. This |
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10:52 | one of the markers that all of inhibitory cells would be expressing. Remember |
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10:57 | talked about how the different subtypes of cells in hippocampus, They express different |
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11:03 | specific markers. Some expressed so matter , others expressed peru albumin that all |
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11:10 | the inhibitory cells will be expressing. . Because if you are inhibitory cell |
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11:16 | you're synthesizing Gaba and releasing Gaba, going to have God, this enzyme |
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11:24 | do the work for you now, uh going back to this uh to |
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11:33 | uh to this diagram and it's it's again, the expressions are different, |
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11:38 | precursors are different. Now serotonin here put mood, appetite, sleep |
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11:46 | So the common theme that I'm trying convey is these neurotransmitter molecules, These |
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11:53 | that are expressed in certain parts of brain and have the projections and interconnected |
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12:00 | different parts of the brain are responsible different states, different behavioral states. |
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12:07 | if you are in a fight or response, we will have a pen |
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12:12 | , norepinephrine on on demand being being released from these nuclei to react |
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12:17 | that situation. If you think about , you're talking about mood and you're |
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12:23 | about here release of serotonin which will through medical tropic receptors. Re uptake |
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12:29 | serotonin can be blocked with brand name called PROzac which is a very common |
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12:38 | and anti anxiety medication. What it it prolongs availability of serotonin molecule and |
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12:46 | means that serotonin is intricately involved in of mood and normal mental state such |
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12:54 | you know, if you have abnormal state like clinical depression uh you will |
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13:01 | treated with serotonin re uptake inhibitors. you will hear us S. S |
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13:07 | so serotonin re uptake inhibitors, serotonin uptake of serotonin re uptake inhibitors. |
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13:16 | doesn't get re up taken just like and blocks the re uptake prolongs the |
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13:22 | of this molecule. A lot of um uh precursor for serotonin we actually |
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13:34 | during thanksgiving when we typically in this but not in Canada interestingly. Uh |
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13:43 | Turkey which contains uh trip to fan tryptophan is a precursor to Five |
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13:54 | which is a precursor to serotonin You can see these are the structures |
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14:00 | they're very structurally just slightly different. have the pro boxing group or the |
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14:05 | box elated. Uh they have the group uh hydroxy will add a hydroxyl |
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14:16 | . A lot of the medications that on the market that target like reacting |
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14:21 | or antidepressants. They take a while start taking a significant effect on the |
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14:31 | . This is one of the problems serotonin reuptake inhibitors is lately being called |
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14:37 | question of how effective they are for of mood, anxiety and depression |
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14:45 | It's being called into question, why it taking three weeks at least to |
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14:50 | of see the fact. And there's search for alternatives. Alternative treatments and |
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14:57 | enough psilocybin and the molecule that comes what is called magic mushrooms psilocybin has |
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15:09 | shown to act against depression very And it's not completely known the exact |
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15:19 | of different active ingredients in those in mushrooms. But very serious schools like |
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15:27 | stanford, they're doing research where these like psilocybin are being used. Instead |
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15:36 | reuptake inhibitors to treat mood disorders and treat addiction as well. So that's |
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15:42 | interesting. Okay, so maybe that's you get sleepy, it regulates |
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15:48 | Start coming in the park when you a lot of turkey, not just |
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15:51 | your stuff but you also intake a of tryptophan during the thanksgiving. If |
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15:58 | if you partake in turkey. The other molecules that we already |
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16:03 | our endocannabinoid and the endocannabinoid, Czar cannabinoids that are produced austin optically and |
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16:13 | there is heightened levels of activity prison inhibitory cells are excited to ourselves is |
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16:19 | to be released. Another phenomenal uh if the cell has significant possum attic |
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16:28 | , it's typically going to be mediated influx of calcium. And the mechanism |
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16:35 | that when there's a lot of activity with these neurotransmitters like glutamate, this |
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16:41 | starts producing under anonymous and anonymous. not stored in the vesicles, their |
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16:48 | soluble. So they exit out of cells and they travel retro greatly to |
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16:56 | pre synaptic terminals with a bind to cannabinoid receptors. This is CB one |
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17:03 | cannabinoid receptor one which is predominantly expressed neurons and activation of CB one receptor |
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17:10 | is G protein coupled receptor will activate G. Protium and this G protein |
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17:17 | actually close the voltage gated calcium channel synaptic, what do we use? |
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17:24 | gated calcium channels Before there are two that are necessary to release the |
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17:31 | neurotransmitters and the vesicles. The deep and the actual potential. And the |
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17:36 | thing is influx of calcium and calcium of protein protein complex fusion between the |
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17:43 | and the plasma membrane, correct two . So if we block calcium, |
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17:48 | what happens there is no particular So this is a retrograde negative feedback |
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17:58 | . So imagine glutamate a lot of , a lot of excitability. The |
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18:03 | feedback the air conditioning kicks in and cooling by sending and the cannabinoids retrograde |
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18:10 | to prism optics sides and regulating the of neurotransmitters. So it stands for |
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18:17 | . S. I. Stands for polarization D. S. I. |
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18:23 | deep polarization induced suppression, pass And that is because endocannabinoid signaling was |
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18:45 | in the brain. Uh And when was discovered it was first discovered in |
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18:51 | inhibitory synopsis. So it was thought oh it regulates gaba release only that's |
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18:57 | it was called deep polarization and do of an ambition. But we now |
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19:02 | that endocannabinoid receptors will regulate both inhibition excitation. So there is D. |
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19:12 | . I. And D. E. Which is deep polarization induced |
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19:18 | of excitation. What that means is polarization where there is a lot of |
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19:25 | apostle active activity, it will induce suppression of even inhibition or excitation. |
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19:35 | by this virtue in the cannabinoids are well positioned in regulating and balancing the |
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19:43 | and inhibitory signaling in the branch. you. The two major in the |
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19:49 | on molecules that we know and we learned a lot about them and the |
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19:55 | 1990s when they were discovered. So is in the cannabinoid system. You'll |
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20:01 | a couple of pages in your book that but it was discovered only about |
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20:06 | years ago. So things take time get into the textbook but it's slowly |
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20:12 | its way the whole endocannabinoid system which of enzymes that synthesizing the phenomenons their |
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20:22 | to which these under Canaveral molecules bind then any degradation enzymes again. So |
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20:30 | the Simula theme that you saw with neurotransmitters. The classical neurotransmitters right at |
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20:36 | synthesized release the greatest and what's emerging is anandamide and two A. |
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20:43 | Or to our katana glycerol. The major in economics of the brain emerging |
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20:49 | one of some of the major a static regulatory functions in the brain |
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20:56 | the body. So keeping up the and regulation of synaptic transmission now fit |
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21:06 | with delta nine THC. Delta nine is a phyto cannabinoid. Anything that's |
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21:12 | , it comes from the plant to nine THC is a phyto cannabinoids. |
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21:17 | this is the most famous active ingredient the cannabis plant or marijuana plant, |
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21:26 | it's cannabis plant. So Delta nine comes from Canada's plants and DELTA nine |
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21:33 | although it looks different from anandamide and A. G. Has a binding |
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21:39 | and interact with CB one receptors. nine THC is now an exogenous molecules |
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21:46 | this plan derived non animal. So molecule that acts on the same receptor |
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21:53 | the brain as in the cannabinoid molecules . Delta nine THC O. Is |
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21:59 | known to cause and be responsible for high effect or euphoria effect. When |
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22:06 | consume Canada's, it contains delta nine . You also know now because everywhere |
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22:13 | gas stations and everywhere you see CBD here. So this is the second |
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22:18 | famous cannabinoid after DELTA nine THC. we will address some of these differences |
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22:25 | in the course, when we look the endocannabinoid system and interactions with these |
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22:29 | . And my last comment to make that you also will see things like |
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22:34 | eight and Delta 10 THC. And and Delta 10 THC is a derivative |
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22:44 | either delta non or CVD CVD s dial Delta nine THC stands for tetrahydrocannabinol |
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22:53 | Delta and Delta Town a synthetic derivatives these active molecules. And so as |
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23:02 | learn things in the scores, be of things that are around, you |
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23:06 | aware of things that you may be in consuming your friends are consuming because |
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23:11 | a wild wild west of legal and cannabinoids. Fidel and synthetic cannabinoids and |
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23:20 | of them can be quite dangerous. um Typically naturally derived by the cannabinoids |
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23:28 | shown significant safety issues, dangers or apart from poisoning for kids and things |
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23:35 | that. But with the recovery, other synthetic molecules, that's where there |
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23:40 | a lot of unknowns and there are lot of unknown ways in which they |
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23:44 | be prepared that concerns all of the drugs, cocaine have a huge problem |
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23:51 | fentaNYL, which is opioid. And problem with fentaNYL is because it's a |
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23:58 | dose is so small. And in for opiates and opiate medications when people |
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24:07 | opiates, there's an effective dose. do people take? Opiates for |
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24:13 | What is effective dose, Pain goes or pain is reduced. What is |
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24:18 | ? Does you die? So, opioids, the effective dose is |
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24:27 | The order of milligram or two And the lethal dose can be just |
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24:32 | or three times of that effective And you see that patients overdosing when |
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24:38 | using medications and that's why we see lot of fentaNYL deaths. Two because |
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24:44 | it's extremely potent b it's a lot unknowns. It's illegal. There's no |
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24:52 | process that regulated in any way. and that's why it is so |
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24:59 | So the more you learn about these and the pharmacology in the brain and |
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25:04 | pharmacological substances out in the world and know pharmaceutical cabinets and things like |
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25:11 | Just be more aware about things that out are available and be smart about |
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25:19 | . Now there's ways that we can neurotransmitters, a good way to study |
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25:24 | as immuno chemistry in other ways in hybridization with immuno chemistry, you're using |
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25:31 | , you create antibodies. So for you can take a mouse molecule neurotransmitter |
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25:36 | interest and inject it into a And this rabbit is going to recognize |
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25:41 | foreign molecule found from a mouse. it's going to start generating antibodies for |
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25:46 | . So you can extract the You can isolate the antibodies. These |
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25:50 | the wide looking wide structures under those could be tagged with the visible marker |
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25:57 | as colored marker fluorescent market, that image under a microscope. And those |
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26:03 | are going to be specific to that of interest that you isolated and injected |
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26:08 | another animal to generate the antibodies. now what you do is you want |
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26:14 | ask a question, which ones are cells here are God positive. So |
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26:20 | have a slice and looking at the of the Hippocampus which sells the Gods |
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26:26 | . How many are looking at 100 going to be five cells out of |
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26:31 | . Where are they located? So would use them, you know history |
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26:35 | and you would apply that antibody typically procedure is I'm in a slice brain |
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26:43 | and you add a little bit of that detergent breaks the walls of the |
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26:47 | a little bit allows for the antibody go into the cells. And then |
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26:52 | wash it several washes and the municipal procedure. And you know because it's |
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26:57 | on the immune reaction antibody. you wash the slides really well. |
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27:04 | so the cells that don't express there's nothing for that antibody to stick |
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27:09 | and bind. So they get washed . And the cells that contain the |
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27:16 | that we looked at before the sauce will be inhibitory cells. They'll all |
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27:20 | the antibody stock to them when you it under the microscope. The south |
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27:25 | positive will light up with some visible color marker. Typically fluorescent market and |
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27:31 | can do dual triple quadruple some some some labs and some um uh The |
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27:39 | and clinics are very sophisticated. They do 678 antibody. And you notice |
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27:45 | chemist to confirm staining and there's a of details about these antibodies. But |
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27:52 | is a good way to visualize. are the cells that are expressing a |
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27:58 | or an enzyme will use God you do equivalent for God. And you |
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28:02 | do it for neurotransmitter. Hybridization is different technique here. You have radioactively |
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28:09 | probe that has the proper sequence which the known sequence of complementary nucleic |
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28:15 | The non sequences because we know what genes code for. So you can |
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28:21 | a certain sequence to be prepared for radioactivity label and sent to you that |
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28:27 | target a specific strand of messenger RNA Euro. And the cells that will |
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28:33 | that messenger RNA, which means that cell of interest that's a messenger for |
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28:39 | will show a radioactive label and themselves like the wood wood. So the |
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28:46 | antibodies versus radioactively labeled strands target RNA antibodies bind directly to enzymes or |
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28:59 | of of of interest mimicry. We know about this. If I stimulated |
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29:06 | cell we learned that this is excited itself is going to excite. This |
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29:12 | is going to be deep polarization And so if I uh isolated glutamate |
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29:18 | the Saxon or this neuron and uh glutamate here would also excite this den |
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29:25 | and I would see a deep polarization we also talked about in Cajun |
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29:30 | So this is the original kind of neurotransmitter of mimicry and application of the |
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29:36 | that we talked about how to be from the to have a lot of |
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29:40 | and especially non specific spread of the and that using uncaged of neurotransmitters |
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29:47 | Just reminding you with photo lice, you remember in the cage neurotransmitters occasion |
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29:52 | chemical cages and those cages are broken very fast lasers. So we discuss |
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29:58 | briefly before two and immunize the chemistry cdo hybridization. Either one of these |
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30:05 | could be used not only to study small circuit but look at for |
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30:09 | the whole expression of a molecule of in this case it's an expression of |
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30:15 | drug B I was ST chinese type receptor and R. T. |
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30:20 | Two and it's in the embryo. this is uh an important slide because |
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30:27 | tells you so does that mean that molecules and expression of these molecules is |
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30:33 | same throughout life. Is the expression different receptors and different chemicals change as |
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30:42 | develop. Of course it does. about the location where they located? |
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30:48 | did they start first? Uh showing with the chemistry? It's uh 12 |
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30:54 | of age or 20 days of That tells you something about the |
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30:58 | If you catch one of the first for a specific receptor. So you |
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31:03 | that this is 14.5 day miles What if you stand at 12 |
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31:09 | 12.5 days and you saw nothing 13.5 and you didn't see any stain |
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31:16 | The stain is everywhere. You see is this receptor, you didn't see |
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31:20 | . And then on day 14.5 you saw this? What does that |
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31:25 | you? That's when maybe the expression that molecule started. It doesn't all |
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31:31 | at the same time or maybe that's you located the final in the in |
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31:35 | tissue or brain area of interest that looking at and now you're have a |
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31:41 | . So you can look at the expression of these molecules. You can |
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31:47 | at the temporal expression of these molecules as a function of development, as |
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31:52 | function of aging. They can be as well. Now when we talked |
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32:01 | neurons, we said that neurons receive and inhibitory inputs and we also talked |
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32:12 | how excited they inhibit the inputs. inputs are small. So we talked |
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32:19 | in the neuro muscular junction, we inflate potential. So typically a change |
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32:24 | about 70 million volts and numbering And in the C. N. |
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32:31 | we have E. P. P. S which are excitatory synaptic |
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32:36 | and I. P. S. . S. And those are approximately |
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32:42 | mill ball change. Right? So E P. S. P, |
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32:47 | would be a deep polarization and for . P. S. P. |
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32:50 | going to be hyper polarization. And we talked about how if you have |
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32:56 | threshold for action potential generation at -45 bowls and you have the cell resting |
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33:05 | potential, Resting membrane potential of -65 balls action potential gets generated only if |
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33:14 | member and potential reaches this threshold So the cell, as we talked |
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33:19 | could be receiving small excitatory inputs, inhibitor inputs, stronger excited for an |
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33:28 | inhibitory inputs. And finally if it this threshold, these are graded potentials |
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33:37 | . P. S. P. . I. P. S. |
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33:39 | . The graded potentials. The synaptic are for graded and then it will |
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33:44 | an all or non action potential. what needs to happen in order for |
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33:52 | change of 20 million balls to take , you have to engage a lot |
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33:57 | excited synopsis. This excitatory synopsis may counteracted by the inhibitory synopsis. So |
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34:05 | you have one excited tourists in apps and at the same time you have |
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34:12 | inhibitory synapse activated on the same neuron at the same time what is going |
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34:18 | be the average response? Virtually no . Okay, maybe even inhibition could |
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34:25 | stronger and it could be biased or . In addition maybe in addition was |
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34:29 | and excitation was 0.37 million rolls because slightly different. Uh number 2.5 the |
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34:37 | and slightly different. Number 72 notable the neuro muscular junction. So there |
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34:42 | a strategy. Now if you I to cause a strong polarization you can |
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34:50 | multiple neurons and synopsis in the same similar region. And this is called |
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34:57 | summation. And if you activate multiple at the same time you will see |
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35:02 | instead of the small deep polarization from synapse from many synopsis you can get |
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35:08 | larger depersonalization. So it's a spatial . What happens if you have one |
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35:15 | but instead of producing one action potential from one neuron to get a Smalley |
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35:24 | you send a train of action repeating action potentials, what you're seeing |
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35:31 | that there is a summation over Which is temporal summation. You can |
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35:39 | see that the summation over space is than information over time. Because over |
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35:47 | as you reach the peak of the it also starts decaying. So it |
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35:53 | on the frequency of the stimulation will the amplitude of the final complete |
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36:04 | And as we talked about when you polarize dendrites, dendrites are not |
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36:10 | So there's going to be leakage of from the cable. So you inject |
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36:17 | strong current here at this location with electrodes and distance away you can record |
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36:23 | see what is the attitude of that which we've injected. And you'll see |
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36:28 | it dies down the voltage that you the DM. Change it dies down |
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36:34 | distance. So if you injected here the electorate is 100% maximum change in |
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36:43 | you cause with that electrode here you the maximum. Change 100%. And |
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36:49 | electrode actually is located here and when reaches the 37% of central very |
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36:57 | 37% value of the maximum which is . O. Value. That's what |
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37:04 | call the lambda or the length, voltage. How far can this voltage |
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37:14 | before it decays to 37% of its allowing how far can this current without |
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37:21 | out travel. And what is going be evolved and changed from the original |
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37:26 | to the location from distance away. some cells have varies uh length |
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37:36 | So if it's a long length constant ? If it's a really long lambda |
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37:44 | means that there's decay can take a time. So this is A short |
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37:54 | from 100 here. 2 37%. you can have a long lander here |
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38:09 | it reaches 37%. But this specialty mean a difference of five micrometers along |
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38:19 | dendrite longer length concept. That means longer length constant, the voltage change |
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38:24 | the current changes sustained and preserved longer length, longer length, longer |
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38:34 | Now this is what's happening excitation. excitation is active. You can cause |
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38:40 | E. P. S. In the done drive. And that |
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38:44 | that only a fraction of that polarization gonna be. And that's only if |
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38:50 | no inhibition. But now you have . When we discussed this in many |
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38:55 | there's a lesser number of inhibit ourselves the CMS in hippocampus. 10 to |
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39:01 | of all the cell population. Very with lesser number. But we also |
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39:06 | that inhibit ourselves will target these proximal . They're just strategically located to target |
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39:12 | proximal areas around the selma. Why is important because you can really influence |
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39:17 | integration properties of the cell. Whether cell you can affect whether the cell |
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39:22 | going to be inhibited or in this you have a lot of times distal |
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39:29 | . You have excitation of this P. S. D. In |
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39:33 | absence of inhibition is small in the in the selma but in the presence |
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39:39 | inhibition it's also referred to a lot fans as shunting inhibition and channels are |
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39:45 | and more current cell. Even when inhibitor synapses are activated, what happens |
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39:50 | the level of the soma. You see any response. So this one |
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39:58 | here excited to input distantly was completely by a proximal inhibitory input. And |
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40:06 | does it mean for the boss that action potential or no it means nothing |
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40:13 | change. And that's why you have engage multiple synopses et spes in order |
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40:20 | reach the threshold for action potential generation the in the C. N. |
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40:26 | . When we talk about medical tropic transmission, you'll also see a lot |
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40:31 | times neuromodulation and this is another way talking about modulation while in the brain |
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40:39 | neuromodulation neuromodulation. What is the difference neural transmission? The neuromodulation neuro transmission |
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40:50 | you have a release of neurotransmitter that binds post synaptic receptors and it generates |
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40:57 | pure I PSP through ion a tropic but you also have medical tropic signaling |
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41:05 | in the case of medical tropic You are affecting downstream targets through this |
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41:12 | protein complex are affecting nearby receptor channels can cause they're possible relation adding a |
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41:18 | . 04 group which can change the of the channel for a longer period |
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41:25 | time. You can also activate secondary and even the transcription factors in the |
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41:33 | of the cell which will exert long effects on the system. So it's |
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41:38 | the quick neuro transmission and generation of P. An I. P. |
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41:42 | . P. D. Polarization and polarization or actual potential. But it's |
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41:46 | the cellular mechanisms that are typically longer and typically needed nuclear mechanisms to be |
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41:54 | if you want to have really significant long lasting changes in the brain |
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42:04 | Alright, so these are all of good ways that we can study. |
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42:07 | is another way of thinking about amina . Acetylcholine serotonin like molecules cata cola |
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42:18 | like molecules uh And this is what been discussing. Um The last couple |
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42:27 | lectures so review all of the information acetylcholine synthesis, neural pharmacology of acetylcholine |
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42:38 | metabolic tropic signaling. Most suffer will G protein complex and this g protein |
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42:49 | will target potassium channel which will open passing show. Hmm. So neuro |
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43:01 | junction. We have only nicotine in . Yeah. Thank you. Thank |
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43:14 | . So we only have nicotine building happens in the C. N. |
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43:23 | . We have an academic calling receptors are channels right. We already talked |
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43:34 | how they will allow for the influx sodium and also the flux of potassium |
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43:42 | initially the influx of sodium is gonna small deep polarization to these cns narrows |
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43:51 | not talk about neuromuscular junction cns well us now. So the same molecule |
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44:01 | gets released as little Colin nearby may a G protein coupled mascara Mick acetyl |
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44:11 | suffer and that muscular acetylcholine receptor through jew protium is going to open potassium |
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44:22 | and it's going to cause costume and what happens when positive charges leaving it |
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|
44:34 | hyper polarization. So this is where the same molecule on the same |
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44:40 | the same neuron Mako express nicotine, and metra tropic masculinity receptors. Same |
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44:46 | will bind, causing small deep polarization nicotine And through medical tropic with some |
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44:52 | it will cause a small hyper So in the end the effect on |
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44:59 | cell is very different and the effect the cell depends on what it doesn't |
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45:04 | on the chemical, it depends on post synaptic receptor. It's a receptor |
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45:09 | nicotine. It does one thing if most chronic it does another thing, |
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45:24 | , it's called shortcut catholic because there no chemical intermediaries there sometimes chemical intermediaries |
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45:30 | this case there's no chemical intermediary, one of the accomplish that catalyzed and |
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45:35 | targeting this potassium channel and opening the channel causing the hyper polarization. Uh |
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45:49 | that's great, still Killeen cata colon serotonin cattle colonies, movement, |
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45:58 | attention, visceral function, mood appetite , learning g proteins. Let's look |
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46:04 | these g proteins before we come back talk about the glutamate synapse. Uh |
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46:10 | talk about glutamate synapse. I'll come to that image. So we have |
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46:18 | messengers and this is another example of and effort molecules. Now here I |
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|
46:26 | you an example where the same chemical activate basically opposing action receptors. One |
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46:36 | the receptor channel, Another one is protein complex. Can you have opposing |
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46:41 | through medical tropic interactions? This is opposing action of iron A tropic versus |
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|
46:46 | tropic. This shows the north another and it binds to the beta, |
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46:53 | and beta beta receptor that catalyze is it's linked to the G stimulatory GS |
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47:03 | which stimulates the production of cyclo PNP the expression and production of protein kindness |
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47:11 | . And kindnesses or molecules kindnesses of that add field for group Okay, |
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47:21 | are kind nations as opposed to foster sis which removed Phosphate Group P |
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47:40 | Uh so this pathway through beta nor is stimulating P. K. |
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47:47 | And it's pushing the system to produce of this podium. Finance a PK |
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47:53 | same there on may also to express to binding on north into the alpha |
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48:04 | stimulates G. I. To inhibit inhibits the production of cycling campy and |
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48:14 | china's essentially pulling the system away from more P P. A. So |
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48:20 | is opposing actions the same chemical but alpha versus beta receptor exerts opposing actions |
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48:32 | early on the same target which converge the same target, regulate the same |
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48:37 | . One of them is pushing to more P. K. I don't |
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48:41 | us pulling the system away from producing PK. Mhm. All right. |
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48:48 | is a in the image that I drawing because uh I don't have color |
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48:55 | so I can draw in colors but can also draw. And I always |
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49:01 | that the best way to learn is only to see but also to |
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|
49:06 | I want to replicate something. So the exam I would like for you |
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|
49:12 | know that norepinephrine is produced in the nucleus called locus Aurelius, locus or |
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|
49:24 | lo sai locus cerulean stands for Does it cut the brain tissue this |
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|
49:32 | and it oxidizes in terms of So it's local civilians. And that's |
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|
49:38 | you have expression of norepinephrine. And can see that you have diffused projections |
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|
49:43 | these neurons throughout the C. S. And into the spinal |
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|
49:49 | The other thing I would like for to know is raph nuclei that are |
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|
49:53 | for the expression of serotonin and you the purple rafting nuclei. And the |
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|
49:59 | from these purple wrapping nuclei neurons that serotonin will target the C. |
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|
50:05 | S. The cortex of cortical areas cerebral cortex cerebellum. The green wrapping |
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50:12 | located in slightly different locations and the will send their projections into the spinal |
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50:19 | into the peripheral. In the meantime and gaba cells will be widely distributed |
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|
50:29 | expressed. Wouldn't be located in just nucleus. Like in these cases if |
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|
50:36 | look here you have magnets cellular basal is green and this another green color |
|
|
50:48 | todung killer pontin and lateral dorsal take nuclei. The green ones. Green |
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|
50:56 | are responsible for civil Colin. So we talk about alzheimer's disease, we |
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51:05 | that there is a loss of acetylcholine , you would be losing neurons in |
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|
51:14 | regions particularly here basil or brand and and having an apology associated with cool |
|
|
51:27 | the cannabinoids are different. So this just deciphering because I didn't know where |
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|
51:31 | was going to stop where it was to pick up where I was going |
|
|
51:33 | review. But THC tetrahydrocannabinol phyto endocannabinoid anandamide to a g. A |
|
|
51:42 | interesting thing. Also remember we said dennison and I said that a denison |
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51:50 | and you activated dennison receptors every morning you consume caffeine and denizen receptors would |
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52:02 | increase caffeine would increase release. So other molecules prison optically apart from other |
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|
52:11 | that can regulate and we'll see if can regulate neurotransmitter release. This is |
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|
52:17 | out polarization induced suppression of ambition, induced suppression of excitation. Okay amino |
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|
52:25 | neurotransmitters. A very important thing about being converted into gaba and glutamate control |
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|
52:34 | general. So first of all, you release either glutamate or Gaba, |
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|
52:40 | gets transported back into pre synaptic terminals it gets reloaded back into the vessels |
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|
52:47 | what's really important that emerged in the 20 or so years is this concept |
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|
52:55 | tripartite synapse um I know these slides jumping a little bit, but maybe |
|
|
53:04 | just follow the video to match the . But here, what it shows |
|
|
53:11 | the right is a glial cell and have glued in it. When it |
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|
53:18 | released will target ion a tropic and tropic glutamate receptors will get transported back |
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|
53:26 | glutamate neuronal transporters into pre synaptic terminals in the vesicles and released again. |
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|
53:34 | Julia have their own glutamate transporters and will react to glutamate will convert it |
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|
53:43 | glutamine with glutamine synthesis and this glutamine going to be given back to neurons |
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|
53:50 | into neurons and with the help of AIDS converted into glutamate and uploaded into |
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|
53:58 | vesicles. So this concept of tripartite especially with glutamate control, where the |
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|
54:08 | player number one is pre synaptic neuron two is posson optic neurons. And |
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|
54:16 | third try part. The third part this is leo sauce that are intricately |
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|
54:24 | glutamate, which means they also can the availability of glutamate. And if |
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|
54:29 | have a dysfunction and glutamate transporters in , then you can affect glutamate levels |
|
|
54:37 | the system. If they're not uh properly, there's going to be too |
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|
54:42 | glutamate here, there's going to be much excitability between neurons because of glia |
|
|
54:49 | leah cannot transport the from the same or vice versa. Maybe it's up |
|
|
54:56 | expression of glutamate transporters. And now much of glutamate is being sucked out |
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|
55:02 | the synapse too fast by glia. affecting how much of this glutamate is |
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|
55:08 | for neuronal transmission. Alright, so have their own individual transporters and for |
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|
55:20 | next hour or so we won't finish . We'll finish next lecture. We |
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|
55:28 | focus on gloomy motor GIC, neural And Gaba urging. So what is |
|
|
55:35 | ergic Lutin eight ergic gaba ergic Cerrito , under energetic and then force it |
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|
55:48 | and it's actually Colin ergic. So little bit of a vocabulary neurotransmitter, |
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|
55:55 | , endogenous agonists, everybody with me arguments. Good. Okay, chemical |
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|
56:03 | that our individual glutamate subdivide these based the pharmacology into ampara and India and |
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|
56:11 | and receptors. So that means that will bind to all three in a |
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56:16 | glutamate receptor channels but they will have specific agonists which they can be distinguished |
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|
56:24 | ecological one of them will be reactive called Tampa and therefore called receptor, |
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|
56:31 | one molecule found in the NBA that in the a receptor the third one |
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|
56:36 | kind and it was called kinase These are exogenous or chemical agonists that |
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|
56:44 | us to pharmacologically distinguish these three subtypes glutamate island A tropic channels pharmacology kinetics |
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|
56:56 | is channel opening kinetics. Remember we about kinetics of voltage gated sodium channel |
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|
57:03 | we said that that channel is much but it also closes in activates in |
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|
57:07 | very fast fashion. But we said kinetics of potassium channel is slower but |
|
|
57:12 | also prolonged opening of that channel. what are the kinetics and when glutamate |
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|
57:19 | released? That means that glutamate combined all three subtypes ample in India and |
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|
57:26 | eight which one gets activated first if all go expressed and they can be |
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57:32 | expressed on the same patch of the membrane if all three of them get |
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57:39 | up by glutamate which one gets activated the same all at the same time |
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57:45 | they conduct the same amount of do they allow the passage of sodium |
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|
57:50 | potassium or something else? All of questions that we can ask and find |
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|
57:56 | in the slide that when glucose gets these green molecules and here for simplicity |
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|
58:04 | a lot of problems and receptors and are grouped together because they have very |
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58:10 | features and a lot of times at are going to be referred to as |
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58:16 | an M. B. A. they are not an M. |
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|
58:20 | A receptor. So for now let's about APPA in blue and an |
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58:26 | D. A receptor here in pink what it shows that once glutamate gets |
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|
58:34 | in these green molecules here it binds ample receptor and as soon as glutamate |
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58:41 | to a receptor this ample receptor or N. M. D. A |
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58:46 | starts conducting sodium inside and later potassium glutamate remember glutamate signaling through these Alpine |
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|
58:57 | . And kinda receptors are going to responsible for producing the E. |
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59:03 | S. P. The excitatory possible of the country including Mexico. |
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|
59:11 | So how what what which receptor channel to which fortune of E. |
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|
59:16 | S. P. Just like an potential which I am contributed to rising |
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|
59:20 | and following phase. So obviously when see the initial D polarization it's sodium |
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|
59:28 | in right that's deep polarization followed by flux of potassium which is going back |
|
|
59:37 | hyper polarization to the pre stimulation pre levels. And when glutamate binds to |
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|
59:46 | NMDA receptors they immediately open and start sodium and potassium. But when glutamate |
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|
59:53 | to an M. D. A they don't open immediately because they have |
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60:02 | that is blocking NMDA receptors. And is a physical blockade of the |
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|
60:11 | By dive a link a tie on . And the only way that this |
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|
60:17 | is going to be permeable to ions if you kick that magnesium out so |
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|
60:23 | remove the magnesium block, what needs happen is there has to be an |
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|
60:29 | deep polarization from the resting membrane potential about minus 65. Two more positive |
|
|
60:37 | minus 50 minus 50 minus 48 minus minus 40 to minus 30 and so |
|
|
60:45 | . And only with the initial. . Polarization will you relieve this magnesium |
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|
60:51 | And if you do you can see an M. D. A channels |
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|
60:54 | conduct not only sodium inside all an . D. A channels will conduct |
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|
60:59 | and calcium inside the south influx of and calcium and also e flux of |
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|
61:09 | . So when we talk about the first channels that open are ample |
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|
61:15 | and they cause the initial D. . The later channels that open with |
|
|
61:21 | because of magnesium block or an D. A. Receptor channels. |
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|
61:25 | ? We talk about selectivity and for typically with some exceptions impermeable to sodium |
|
|
61:33 | potassium selectivity for ion passage. Some receptor channels will be permissible to |
|
|
61:41 | You will see that the latest lines an N. D. A. |
|
|
61:45 | always a significant source of not only but also counselors and then the receptors |
|
|
61:51 | always cause the influx of calcium significant not for visualization but for the intracellular |
|
|
62:00 | synaptic signaling cellular signal conductance. So you open non NMDA ampara receptor cane |
|
|
62:12 | channels they will conduct 20 PICO PICO simmons remember that we can have |
|
|
62:20 | channel conductance is and this is PICO . So 20 PICO simmons, if |
|
|
62:25 | open an M. D. A it will conduct 50 PICO simmons. |
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|
62:32 | here what it means the conductance is strength of the amplitude of that |
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|
62:38 | How much of it it can obviously responsible for conducting a lot more ions |
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|
62:45 | an NBA receptors is significantly contributing to E. P. S. |
|
|
62:51 | They have their own blockers are So AMP kinase receptors will be blocked |
|
|
62:57 | C N. Q. X. M. D. A. Receptors |
|
|
62:59 | be blocked by another blocker. PV. And M. D. |
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|
63:04 | receptor is also referred to as coincidence coincidence detector because binding of glutamate is |
|
|
63:14 | enough to open an M. A receptor. So detecting pre synaptic |
|
|
63:21 | or release of the pre synaptic consider not enough to open an empty |
|
|
63:26 | It also has to detect the deep so it has to detect pre synaptic |
|
|
63:34 | release and fast synaptic polarization in order be functional. But say there's glutamate |
|
|
63:39 | and apple receptors are upset and there's deep polarization and a it's not going |
|
|
63:46 | detect the synaptic equalization, it's not to alleviate magnesium block. Therefore it's |
|
|
63:53 | going to to cause an opening of receptor. So it's coincidentally detecting pre |
|
|
63:59 | and post synaptic activity in a way is binding the pre synaptic neurotransmitter release |
|
|
64:08 | the post synaptic deep polarization. The thing to notice is this is lie |
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|
64:19 | just for working all of you license is licensed doing here? Didn't you |
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|
64:28 | us advising is released by inhibiting neurons the spinal cord that's a major neurotransmitter |
|
|
64:35 | the spinal cord there's some gavel a bit of Gavin spinal cord too. |
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|
64:41 | this is not an addition. this excitation and in this case by scene |
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|
64:47 | a necessary co factor that is present the CMS. So glutamate receptor NMDA |
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|
64:58 | is a co factor or the glutamate properly agonize or openness receptor channel and |
|
|
65:06 | receptor has to detect synoptic decolonization. if you have coincident detection and you |
|
|
65:12 | also a co factor here is licensed you can see that glutamate has it's |
|
|
65:18 | a little key that has its own on this receptor. It has to |
|
|
65:22 | into this law. What is this ? This lock is the three dimensional |
|
|
65:27 | of communal essence and the structures of chemicals and molecules that will bind and |
|
|
65:34 | fact that opening or closing. Now can see that license has a separate |
|
|
65:40 | size on this receptor channel. Remember very complex three dimensional structures each individual |
|
|
65:47 | that we're talking about here. So have zinc binding side, there's two |
|
|
65:53 | binding sides in an M. Receptor there's also a binding side for |
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|
66:01 | which is another very dangerous solicit uh drug that's called a popular Angel dust |
|
|
66:11 | crystal methane and it induces hallucinations. PCP by acting very strongly in an |
|
|
66:19 | receptor can cause acute psychosis. And chronic schizophrenia following a single use our |
|
|
66:32 | of uh the synthetic drug PCP. that's why these receptors are important for |
|
|
66:40 | and memory and then the receptors are for binding pre synaptic post synaptic activity |
|
|
66:48 | there are substances that can upset the and the function of these receptors. |
|
|
66:53 | sometimes these substances and chemicals especially synthetic can be so powerful. I'm not |
|
|
66:58 | about pharmaceutical. I'm talking about illicit can be so powerful and dangerous that |
|
|
67:03 | can cause a permanent effect following a use. Okay um knowing that these |
|
|
67:17 | not for M. P. Or ones like for the denuclearization. |
|
|
67:30 | the initial D. Polarization happens to because glutamate is enough to open up |
|
|
67:36 | receptors and conduct sodium. And then later part of the PSP we're gonna |
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67:42 | it a little bit in the next . But if you took E. |
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67:46 | . S. P. Which is E PSP and you broke down this |
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67:52 | part of the PSP is mostly due ample receptor and this late part of |
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67:58 | PSP is due to an M. . A receptor activation. And we'll |
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68:04 | look at some studies or out of today but we're gonna look at some |
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68:10 | I. V. Curves and pharmacological that address exactly this in the next |
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68:16 | . So what we'll do on Thursdays finish neuro transmission which will be neuro |
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68:23 | for and we'll start C. S. Yes for which molecules uh |
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68:38 | there something endogenous li that mimics said there an endogenous molecule like it depends |
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68:56 | how strongly advised this is uh this yeah this is what we call uh |
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69:05 | versus partial. So a lot of are reversible partial agonists, uh or |
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69:15 | they're full agonists, they're reversible sword . Like. Yeah. And then |
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69:22 | are others that are chemicals that will stick to that it's too long to |
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69:29 | it, like two hours, which is significant, the fact that the |
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69:33 | Republic, so Longan |
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