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00:02 | this is lecture 12 of neuroscience and third lecture on neuro transmission neuro transmission |
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00:09 | . So we will follow the materials chapter five and six today. Uh |
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00:17 | we look back at some of the that we've discussed uh last lecture we |
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00:26 | in great detail about the colon ergic and that is the synthesis of acetylcholine |
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00:32 | of acetylcholine and breakdown of acetylcholine. we discussed basically how you have synthesis |
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00:41 | acetylcholine when you have choline and acetyl a the chat form acetylcholine gets loaded |
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00:49 | through acetylcholine transporters into vesicles gets released the C. N. S. |
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00:54 | can target both nicotine IHC receptor acetylcholine receptor channels and most chronic g |
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01:02 | coupled receptors that we mentioned in the . And when it exerts its effect |
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01:08 | the sell through the activation of these synaptic receptors. Acetylcholine molecule doesn't stay |
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01:14 | the synaptic club for a long It gets broken down by Seattle tell |
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01:19 | grace into Colin and acetic acid clothing then transported to colon sodium co transported |
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01:26 | the pre synaptic terminal which re synthesized to go through the same release |
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01:32 | Uh And we also discussed how most the alzheimer's cases uh end up in |
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01:43 | loss of acetylcholine uh producing cells. that those acetylcholine producing south we are |
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01:51 | in specific nuclei within the brain and throughout the whole brain and in the |
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01:58 | of acetylcholine, one of the most and overwhelmingly mechanisms of action of alzheimer's |
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02:05 | are basically targeting the blockade of a colonist arrays and by blocking the enzyme |
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02:12 | degrades acetylcholine that prolongs the time and of by availability of that molecule and |
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02:20 | synaptic cleft. So this is also that you can add on to your |
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02:25 | box for the Alzheimer's disease. So so nerve gasses I think that |
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02:45 | that is used in safe and effective . I think that was part of |
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02:50 | theme is that you can have something nature that's poisonous. You can make |
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02:56 | into aesthetic things like Botox or that can show that that used and regulated |
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03:05 | controlled the manner can also be a for migraines, Botox injections. So |
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03:13 | yeah the mechanisms of action are similar the way you inhale or exposed to |
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03:20 | gas is is different versus how you the pill. But in my in |
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03:27 | way that I challenge you to think the system is it has pre signed |
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03:31 | the components sent out the components and out the components and actually when thinking |
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03:39 | and about new drug design that targets systems. Most of the drugs, |
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03:48 | drugs will target post synaptic receptors. be agonists or antagonists a lot of |
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03:54 | we will hear blockers so and so taking some blockers. It's usually an |
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03:59 | to certain reception. Then there are of blocking degradation of that molecule then |
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04:08 | are ways in which you can control transport or block the transport of that |
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04:15 | that will also prolong the by availability it in the synapse, there is |
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04:20 | a way in which you can control secular loading the synthesis and particular release |
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04:27 | processes that concern the secular release. are far and few in between substances |
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04:33 | can control the secular release and specifically acetylcholine without affecting the secular release for |
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04:39 | and Gaba and everything else. most of the drugs again will target |
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04:45 | receptors or will target the synapse here the transporters. And it's harder to |
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04:52 | effective drugs that will be controlling the through precursors or the release properties through |
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05:00 | control of this protein protein binding Um So you said that there is |
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05:07 | specific specific new play in the in brain that produces the neurons that go |
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05:18 | these synapses synaptic. So if Alzheimer's destroys those cells, um how does |
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05:29 | a single calling help in any The pre synaptic neuron cannot do a |
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05:36 | ? It doesn't. You answered your question. I raised the same uh |
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05:43 | last time when I said, if first of all, you're losing a |
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05:47 | cold in cells, that means you're have to increase the concentration cycle job |
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05:52 | some point. If you're increasing some and older person has to consume, |
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05:56 | have to be cognizant about destroying their and the sake of you know, |
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06:03 | their mind or curing Alzheimer's disease. there's another way that that can impact |
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06:08 | body in a negative way. So right if and there is the absence |
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06:14 | these Colin ergic neurons. What are other alternatives in in in Alzheimer's medications |
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06:22 | and there is a medication that targets glutamate receptors. We will mention it |
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06:28 | believe in the next hour or But overwhelming majority of Alzheimer's medications are |
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06:36 | race. So yeah, these are very good questions and very good thoughts |
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06:42 | thought. So in the cns acetylcholine a natural endogenous agonist to nicotine and |
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06:51 | IQ receptors. Exogenous agonists to nicotine . Nicotine too, muscular receptors must |
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07:01 | and they also have their respective an . So is an antagonist or blocker |
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07:09 | nicotine IHC receptor and atropine will inhibit receptor activation which means will inhibit the |
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07:18 | of the downstream g protein complex. So it is useful that you know |
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07:27 | nature. Again some of these substances from plants, some of these substances |
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07:33 | are are from like poisonous frogs, nature derived. And then there's also |
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07:40 | substances that are made in the lab atropine for example were found in nature |
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07:46 | then synthesized in the lab. And theme that we're talking about that it's |
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07:53 | the cycling of these molecules is And also I mentioned already that a |
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07:59 | of these molecules are precursors to I mean so for example, time |
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08:06 | seen as a precursor to l dopa dopa is a precursor to dopamine dopamine |
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08:13 | a precursor to north norepinephrine is a to a and they're separated by single |
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08:23 | reaction. Dopamine to norepinephrine. Just beta hydroxy Alice. Just putting a |
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08:31 | group here. That's the only change this here. You have and metal |
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08:37 | race. So you're transferring CH three here. I have here dopo decoder |
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08:46 | list, you're taking away the acid here. So if you're into |
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08:51 | organic chemistry you can remember some of things. These are all cata cola |
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08:59 | and cata cola means are different. is very important for motor functions. |
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09:07 | Dopamine is also involved in the reward . Norepinephrine and epinephrine. You can |
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09:15 | of them as adrenaline of the So those molecules will be released and |
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09:21 | . Their synthesis will be accelerated accelerated the fight of flight or stressful |
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09:28 | Cata cola means when they get released they will have the boston optic |
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09:33 | mostly metabolic tropic receptors to act on . They'll be transported back again and |
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09:42 | into the catacombs. Mean vesicles with cata cola mean transporters here. So |
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09:46 | a similar theme as we saw with cedar cove in system. Uh Cata |
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09:54 | mean update can be blocked by amphetamines illicit drugs street drugs like cocaine and |
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10:02 | will prolong the bio availability. So can think of it will prolong the |
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10:06 | availability of reward feeling good active brain stress response. Almost like that's induced |
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10:19 | blockade the transporters. Uh Mono I M. A. O. A's |
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10:31 | amine acid inhibitors also will inhibit the of mono amine molecules. And so |
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10:40 | is another target for medication is Ml . Mon amine oxidase inhibitors, that's |
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10:50 | A. O. Stands for. amine oxidase inhibitors. And once again |
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10:57 | can think of. While in the slide we talked about medications and the |
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11:04 | of the molecule here, we're talking medications and also illicit drugs that control |
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11:12 | re uptake of that molecule. You the transporter, You prolong the by |
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11:18 | of cata colonies in the synapse. serotonin will come back to Gaba and |
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11:28 | serotonin is another important molecule and I that serotonin is known to control mood |
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11:36 | , sleep learning. So I asked from the very beginning to start forming |
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11:44 | understanding of these neurotransmitter systems as they responsible for different functions. Different state |
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11:50 | being different behaviors, mood and appetite different from appetite as you don't get |
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11:58 | when you in a fight or flight typically because norepinephrine takes over. So |
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12:05 | have to have serotonin, you have certain state of relaxation. There are |
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12:09 | pathetic systems serotonin takeover to stimulate some this appetite. So serotonin is made |
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12:17 | tryptophan is the precursor five HtP and from five HtP you make serotonin which |
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12:25 | five HT and uh serotonin systems because a mood regulating neurotransmitter serotonin systems and |
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12:37 | ergic controlling drugs are typically associated with and mental disorders. So depression um |
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12:49 | . T. S. D. a very common this is a brand |
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12:53 | PROzac but a lot of antidepressants are S. S. R. |
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12:58 | Serotonin re uptake inhibitors that's what S. R. I. Stands |
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13:04 | . Re uptake inhibitors inhibits re update prolongs the availability of serotonin in the |
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13:12 | cleft. That's just the same kind a pattern that we see and adenoids |
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13:21 | different. We already alluded to under . Under cannabinoids are not stored in |
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13:26 | vesicles. When there is a lot pre synaptic activity of this can be |
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13:31 | either excited or inhibitory. There will post synaptic activation, there will be |
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13:38 | of calcium and the enzymes that synthesize cannabinoids will produce under cannabinoids and the |
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13:45 | will cross the plasma membranes will travel retrograde fashion from post synaptic side. |
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13:52 | pre synaptic side where they will buy medical tropic on your on CB one |
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13:59 | receptor, one that is linked to protein complex and that activation of cannabinoid |
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14:06 | will shut down will inhibit both educated channels and you need calcium in order |
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14:13 | continue the secular release. So when and the cannabinoids block the calcium, |
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14:19 | regulated the secular release. If there's lot of excitation then the cannabinoids will |
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14:28 | this inhibitor response and excited to in transmitter release. When there is a |
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14:33 | of inhibition from inhibitory cells. Then cannabinoid activation will inhibit inhibitor and their |
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14:40 | release. It's really very well positioned a balancing molecule from pasta synaptic side |
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14:48 | retrograde communication and balancing the pre synaptic , really coordinating the pre synaptic release |
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14:55 | the levels of the post synaptic The side stands for deep polarization induced |
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15:02 | of inhibition and originally endocannabinoid actions and actions where discovered in the brain by |
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15:13 | because there was an interest why does plant make you feel high and it's |
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15:19 | typically coming from your toe or your That feeling it's coming from your |
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15:24 | So the original thrust was well let's for this system in the head and |
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15:29 | brain and it turns out the system everywhere in the body but in the |
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15:33 | it plays this role deep polarization and a lot of deep polarization, pre |
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15:38 | quickly there's going to be suppression of because it was originally discovered in the |
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15:45 | synopses later it was also discovered in synopsis. So we also have |
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15:50 | S. C. Which is deep excitatory synapses going to lead to suppression |
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15:56 | excitation. So D. S. . Or D. S. I |
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16:00 | . The endocrine avenue is that we're about our anandamide And what I alluded |
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16:06 | earlier as to a G. Which for two or O'donnell glycerol and you |
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16:11 | see that this signaling is very different the secular packet release of neurotransmitter here |
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16:17 | generate molecules post synaptic li and yue pre synaptic sides and target particular |
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16:24 | And so when we talk about the also nitrous oxide, carbon monoxide, |
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16:29 | also function in a similar retrograde like . And they will have their respective |
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16:35 | oxide g burden coupled receptors and These are endogenous substances that their endocrine |
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16:43 | substances. Delta nine THC which comes from Canada's plant is a phyto can |
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16:51 | phyto anything is derived from the Delta nine THC is a natural cannabinoid |
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16:58 | comes from Canada's plant. And we'll about cannabis plants a little bit later |
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17:03 | the scores. But we have really types of cannabis plants that are regulated |
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17:10 | different ways. There's a hemp that plant and it will contain very low |
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17:16 | of DELTA nine THC. And it's called industrial hemp a lot of times |
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17:21 | will have industrial applications. But you'll see that there's a lot of CBD |
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17:27 | is another cannabinoid which is phyto cannabinoid is not like Delta nine THC. |
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17:34 | also later in the course you learn about DELTA eight THC because in your |
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17:40 | life and you're surrounded by some smoke in the neighborhoods or gas stations where |
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17:46 | go by and you see this DELTA THC salt over here. Delta eight |
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17:51 | is a synthetic in adenoid that is from C. D. D. |
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17:56 | from delta nine THC. So we know as much about DELTA eight |
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18:01 | But it is really not found in cannabis plant. So then what we |
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18:05 | with endogenous substances, exogenous substances that naturally in the plans. And then |
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18:13 | substances that can be altered and synthesized still interact with these receptors and with |
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18:18 | systems that we're talking about. Okay thing before I move on to |
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18:26 | I want to mention that we've covered means let's go back and look at |
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18:31 | . You know, assets amino glutamate and Gaba. And Gaba is |
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18:37 | from glutamate. So this is how brain functions. It makes the major |
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18:44 | neurotransmitter from the major excited third That means that if you don't have |
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18:51 | of excited to a neurotransmitter right, cannot make enough of the inhibitor in |
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18:56 | transmitter. So it's dependent on And also all of the cells that |
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19:02 | release Gaba will contain tannic acid, box Alice or God. So all |
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19:09 | the cells that basically release Gaba, have to synthesize Gaba according to our |
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19:16 | for neurotransmitter systems and they will contain this deco box allays. Again we |
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19:24 | this car boxes group the Citigroup off cielo HD car box elated and you |
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19:31 | the major inhibitor neurotransmitter. So and are expressed everywhere. So all of |
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19:38 | means that we talked about until Cata cola means we talked about acetylcholine |
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19:45 | . They have specific nuclear in the where they're expressed while the amino acid |
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19:51 | are widely expressed throughout the brain and way that you can search and find |
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19:58 | identify and studying neurotransmitters and different cells express these neurotransmitters are pretty standard techniques |
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20:06 | are being used in you know history is one of them you can take |
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20:10 | example a mouse, identify some candidate from a mouse injected into a |
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20:19 | A rabbit will produce an antibody because a foreign substance coming into the rabbit |
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20:28 | a rat or from a mouse. then you will withdraw the specific antibodies |
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20:34 | will draw the fluids and you will the antibodies that were made against that |
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20:39 | substance. So now you have an that looks like this why this black |
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20:45 | particle, this is the antibody and antibody is chemically tagged with the visible |
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20:52 | and these are typically fluorescent markers. now you have an antibody for a |
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20:57 | of interest and that neurotransmitter of interest a specific binding side on this wide |
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21:05 | is neurotransmitter. And if this antibody to the neurotransmitter and stays inside the |
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21:12 | then that visible marker will show Then you will be able to see |
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21:18 | cell glowing and adjacent cell that doesn't this neurotransmitter molecule. The antibodies are |
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21:26 | going to stay in that cell. certain, pardon me, there are |
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21:31 | steps in the immune in history chemistry . One of these steps is employing |
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21:38 | detergent that detergent will break up the and allow for the antibodies to |
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21:46 | So actually during the uh procedure those may enter into all the cells and |
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21:54 | you do several washes and only the that have the target neurotransmitter to which |
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22:01 | antibody can stick or a protein to an antibody can sleep. Only those |
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22:06 | retain the antibody will retain the visible and the ones that don't have anything |
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22:12 | bind to, they will simply get away during the procedure. So I |
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22:17 | it is the chemistry is one way can you can ask which cells express |
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22:23 | and take large parts of the brain and say aha. I can only |
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22:27 | this patch of the brain expressing serotonin situ hybridization. It's essentially a strand |
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22:35 | M. R. N. That neuron will contain. So neuron |
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22:41 | have a message for that neurotransmitter or message for protein or something else. |
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22:46 | in this case for neurotransmitter and you these sequences of complementary Nuk lake assets |
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22:54 | it's post genomic air. So we what sequences of these new clinic assets |
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23:00 | you can radioactively label them. So build this very sophisticated piece of |
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23:05 | you synthesize it. You will actually advertisements and some departments hey we can |
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23:11 | you a sequence of so many killer pairs for like you know something like |
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23:16 | cents before inflation for 200 base pairs something like that. You know. |
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23:22 | they will design these for you and can say okay I want to see |
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23:26 | serotonin, this is my serotonin sequence labeled. So if there is a |
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23:32 | RNA for serotonin and those neurons it stick like sophisticated velcro pieces one to |
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23:39 | and the ones that don't they will show any presence of that molecule. |
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23:45 | in situ hybridization, the difference here that you're using radioactively labeled probe with |
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23:52 | sequence of the assets here using an that has a visible market that's targeting |
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23:57 | specific molecule of interest. Uh There other ways that we can study |
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24:05 | It's referred to as neurotransmitter mimicry. you have that neurotransmitter and up ipad |
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24:11 | glutamate, you can stimulate a dramaturgical synaptic terminal and record a |
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24:18 | If this is glutamate being released here will see an E. P. |
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24:22 | . P. Or you can take and you can squirt the glutamate onto |
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24:27 | piece of den dry. And you also record an ep sp Okay, |
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24:33 | that E. P. S. . S in the C. |
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24:36 | S are small and they have to in order to reach the threshold for |
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24:45 | potential. Okay that is not the in the neuro muscular junction but this |
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24:53 | the case in the cns it this has to summit so many excitatory synapses |
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25:01 | to be activated in order to reach threshold value for the action potential. |
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25:08 | and now you can think of, so this is I'm stimulating here. |
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25:12 | , a possum haptic response. I this type had applied glutamate, I |
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25:17 | post synaptic response to. And when think about this technique it is that |
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25:24 | older technique? It's been around for long time. But what happens when |
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25:28 | apply anything from the ipad onto anything is surrounded by fluids, is there's |
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25:35 | to be diffusion. So if this single pre synaptic terminal will activate one |
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25:42 | synapse here in the den drive. you release your neurotransmitter from the pipe |
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25:47 | , you can activate that synapse or adjacent or maybe two or three more |
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25:52 | once in this direction or maybe two more in this direction. Because the |
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25:59 | going to be a diffusion of the is going to be diffusion of the |
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26:03 | molecule and it's going to buy into locations along the BEN drives. |
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26:09 | in your class supporting materials, if of you are into microscopy, if |
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26:14 | of you are to uh visualization of release and wondering more about these |
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26:24 | there's a very cool technique where you actually take the molecules like and you |
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26:31 | place them in the cage and that that when they're sitting in the |
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26:38 | these legitimate molecules, they're not And what what what your class supporting |
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26:47 | talks about is these dendritic spines and the UNQ aging is is you can |
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26:56 | break the cages for glutamate with photo , which means you use a little |
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27:05 | that breaks these cages and releases glutamate specifically in the area where you point |
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27:12 | the laser. So you can point laser here and you can point the |
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27:16 | here and now you can make sure you're releasing glutamate from the cages just |
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27:22 | these two synopsis. So it's a more spatially specific. The lasers are |
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27:28 | fast these days the lasers are moving the santo second speeds, which means |
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27:36 | you can actually within a millisecond activate if you have fast enough of the |
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27:45 | or maybe even thousands but hundreds of within millisecond in different spatial locations. |
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27:52 | that is a lot more representative of is happening in the brain, meaning |
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27:57 | synapses and activities spatially localized. If applied from this pipette here is gonna |
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28:04 | . This is going to be like cloud more concentration in the middle and |
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28:08 | concentration on the side. This makes a lot more specific. And also |
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28:14 | article that I have in the class lecture materials, talks about doing this |
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28:18 | four dimensions. So you have three with space and times and you can |
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28:27 | in three dimensions in space with lasers different focal planes. So you can |
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28:32 | build a four dimensional model of the activation by using the cages in this |
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28:39 | aging technique where you're breaking the cages with little lasers with little beams of |
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28:46 | . So uh look it up, can show you where it is or |
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28:51 | can just look it up on your . This is uh sagittal section through |
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28:56 | embryo that's labeled all of the truck bean coding, neurotrophic tyrosine kinase |
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29:04 | and TR K. Two. So you're seeing dark stains is that's where |
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29:10 | particular receptor is going to be located least or is located at this embryonic |
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29:17 | . So this is immune, artistic but you can also do this with |
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29:21 | hybridization uh to visualize how these molecules how the receptors for different molecules like |
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29:30 | molecules change with age with maturity and their spatial distribution changes as an animal |
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29:38 | and enters into adulthood. Okay, because we don't have very reliable synopsis |
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29:47 | the C. N. S. because uh single synapse will produce a |
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29:53 | deep polarization underwater of half a mil bowl in order for us to get |
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29:59 | cell to properly respond with an action , we have to summit the |
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30:06 | And so there are two types of that ensures that we can produce activity |
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30:11 | our brain. So we don't fail of the time. Even if we |
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30:15 | these partial fusions in the brain and of calcium sometimes here and there that |
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30:20 | have the way to engage new neurons to have them respond and you do |
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30:26 | through spatial summation or temporal summation in summation. If you just have activated |
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30:33 | synapse you will see a small deep but if you activated three inputs at |
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30:40 | same time you will see three times size of the response. So its |
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30:47 | , one synapse half a million If you activate three synopsis at the |
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30:51 | time, 1.5 million goals. So you have the ability to spatially summit |
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30:58 | you can activate tens and hundreds of at the same time by making sure |
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31:03 | all of these accents are activated at same time. In temporal summation you |
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31:09 | summing instead of here you're summing over , adding all the inputs here. |
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31:17 | summing over time. So if that axon produce three consecutive action potentials, |
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31:24 | will also get much larger response than by activating one synapse release of |
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31:30 | interested in vesicles with one action potential notice that you will not reach the |
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31:36 | peak as with the spatial summation This this response. This G. |
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31:43 | . S. P. It's growing size over time but it doesn't get |
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31:48 | as large as this one because as time transpires the PSP starts re |
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31:55 | re polarizing again. So this will much depend on frequency. The closer |
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32:01 | time the stimulus happening, the larger the summation than the response. If |
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32:08 | immediately at the same time from three you get the maximum response Now when |
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32:15 | talked about axons and action potential we talked about regenerative processes that the |
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32:22 | of Ron beer and the fact that potential is the same amplitude attacks an |
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32:27 | segment as it is. That the terminal where it's releasing the neurotransmitter. |
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32:34 | are not my eliminated. So that that there's going to be leakage when |
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32:39 | post synaptic receptors get activated when you the flux of cars, some of |
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32:45 | currents are going to leak out through down drives. They're not going to |
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32:50 | regenerated. And this is what we to as a dendritic cable concept that |
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33:00 | a certain length constant. So this lambda refers to a length constant and |
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33:10 | is a life constant. So if inject current in this location here, |
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33:15 | of it is going to leak out the way. And by the time |
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33:19 | recording the current in the second electrode only going to see a fraction of |
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33:24 | deep polarization that was created by the electorate. And so the distance that |
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33:30 | takes for the signal from the 100 percent input the distance that it takes |
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33:36 | the signal to die down to decay 37% of its maximum 0.37 of |
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33:45 | O. Which is D. At the initial point basically maximum |
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33:52 | 100% initial point. This distance is length constant. So the cells that |
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33:57 | long length constant are going to be to conduct the signal further distances because |
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34:05 | is the distance along the dendrite. is the distance. And v lambda |
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34:12 | is the voltage of 37% of the of the initial voltage. So now |
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34:21 | cells that have long led constant, going to be able to sustain the |
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34:27 | over longer distances. The cells that short length constant, they're going to |
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34:33 | it out much faster and this is to drop much faster and lambda value |
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34:38 | gonna be smaller. So this is for these types of summations. So |
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34:48 | if you have a longer length constant you can some age over space much |
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34:56 | because this signal will travel almost in because you have a long length |
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35:01 | add on to this signal. Both them will travel with long length |
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35:06 | The third one I think both of all three will travel to make sure |
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35:11 | excite that post synaptic cell. There's concept of shunting inhibition. So you |
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35:23 | if you are stimulating here at the and at the level of the soma |
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35:31 | of the current is going to leak . You're gonna record some current smaller |
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35:37 | and that's why you need to activate many synapses and dendrites and selma's in |
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35:41 | for this current to still be strong in the selma to generate the action |
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35:46 | in the accident initial segment here. then. What happens if you activate |
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35:52 | synapse. So some of the rules the brain circuits are such that the |
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35:58 | synapses are distal and more approximately to soma. You have more inhibitors |
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36:06 | That's just the way the neuron oh hippocampal circuits are built. Is that |
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36:12 | inhibitory south will target mostly around the . And so what happens? You |
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36:19 | a pretty strong stimulation here you of recording a very largely at PSP here |
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36:25 | like you did in the previous Now this current is leaking out and |
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36:30 | what happens you actually inhibit activate inhibit synapse and the rest of the current |
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36:36 | leaks out. It gets inhibited and also leaks out. It does both |
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36:43 | . So that's why it's called It shunts the travel of the signal |
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36:48 | it leak out. And also inhibits South. Okay so now you have |
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36:53 | sorts of combinations where in order to the self to respond you have to |
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36:59 | spatially submit excitatory inputs. Make sure overcome the shunting and they overcome the |
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37:05 | inhibitory neurotransmitter release and acted hyper polarization that this neuron can still produce an |
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37:12 | potential when we talk about metabolic tropic . We talk about modulation of by |
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37:25 | response at the level of the And so when you activate for example |
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37:30 | norepinephrine when you activate norepinephrine receptor it activate G protein complex which can activate |
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37:39 | in a little cyclist produce cyclic GMP the production of protein kindnesses and it |
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37:48 | control this potassium channel. It can this potassium channel. So this protein |
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37:55 | . We have kindnesses and phosphate. kindnesses. Ad appeal for group |
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38:07 | Asus takes away the peel for group . And there's a fine balance of |
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38:20 | this nearby potassium channel activity. You like wait a second potassium channel. |
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38:26 | potassium channel activity. So there's a balance now between these kindnesses and prosthesis |
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38:33 | the area. Some of them by being activated. They will try to |
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38:37 | the channel open and prosper related others depose correlated with hospital Asus and try |
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38:43 | keep that channel closed. So this what we would refer to as a |
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38:49 | tropical modular Torey response. And we're come back to this and uh one |
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38:59 | move on to the next slides next . So the reminder how you study |
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39:14 | neurotransmitter systems. This is another way thinking about the major systems that we're |
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39:24 | about. You have communal assets, have acetylcholine that we've studied in great |
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39:33 | . Have serotonin system. Uh And you have the cattle colony in |
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39:39 | . So these are you can say major systems although each one of the |
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39:44 | means neurotransmitters like dopamine or norepinephrine is a chemical of its own with its |
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39:52 | actions and and target receptors and But that's another good way to visualize |
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40:00 | and think about that amino acids are everywhere throughout the C. N. |
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40:06 | . Uh That a means that we're about mono means we're talking about |
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40:13 | They expressed in specific nuclei in specific in the brain. So their expression |
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40:20 | is different. We know very The acetylcholine system, the two post |
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40:28 | target receptors, nicotine and muscular What do they do in the |
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40:35 | N. S. We know in neuro muscular junction nicotine, acetylcholine receptor |
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40:41 | contraction of the muscle. What does do here? It actually causes small |
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40:48 | polarization but masculine IHC receptor causes a hyper polarization. So they're opposing |
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40:56 | nicotine and masculinity receptors in the This is a shortcut pathway of how |
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41:05 | IQ receptor. Actually these metabolic tropic cannot on this muskrat receptor can catalyze |
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41:14 | jeep podium complex. One of the units either alpha in this case, |
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41:19 | can immediately open potassium channel nearby. if you activate nicotine after sodium will |
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41:31 | in, you'll have deep polarization But if you activate metabolic trophic masculinity |
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41:38 | steel cone receptor, you're gonna open channel, you open potassium channel potassium |
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41:45 | going to start leaving the cell positive . The manufacture is going to be |
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41:50 | polarization. No, you're not saying . So here's our software, it's |
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42:02 | center channel. So see what will it. And so you will come |
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42:09 | and it's gonna cause positive charge build will also later allow for the influx |
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42:16 | potassium but initially it's gonna de polarize . Yeah. And nearby. You |
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42:25 | medical tropics mask theoretic receptor and you channel and when this acetylcholine binds to |
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42:39 | casino Colin this chapter it acted as complex and complex opens this potassium |
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42:49 | And when potassium channel is open, lines are going to leave, this |
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42:54 | inside of the south, this is of the cell is going to leave |
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42:59 | so positive charge is going to be the south here. That effect here |
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43:06 | deep polarization. That effect here is polarization, your positive charges coming in |
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43:14 | do your positive charges leaving. So it's the same substance to receptors. |
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43:22 | eye on a tropic one miserable tropic can cause small deep polarization in the |
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43:27 | . N. S. Can cause large deep polarization in the neuromuscular |
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43:32 | Small deep polarization in the C. . S. And the opposing action |
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43:39 | mascara. Nick little code in the this uh zoom was trying to keep |
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43:49 | actually but maybe the racing is this . Mhm. Alright so glutamate and |
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44:05 | fact that glutamate and Gaba is synthesized the C. N. S. |
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44:10 | interesting is that you have the synaptic that is using glue laminates and is |
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44:16 | glutamate glutamate okay from glutamine is making inside neurons that is releasing the glutamate |
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44:26 | glutamate will also have on a tropic channels and miserable tropic receptors you put |
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44:35 | a couple of receptors. So glutamate like the southern molecules we talked about |
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44:41 | will also have its own cycle when gets released? Interesting glutamate has its |
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44:56 | cycle and when it's released it has transporters. Okay glutamate transporters and that |
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45:05 | will get re up taken back into and then you'll have the secular glutamate |
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45:11 | is gonna be uploaded back into the reposition back for release. But notice |
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45:19 | happens here. First of all the of the slightest tripartite synapse. So |
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45:25 | it was pre synaptic and possibly not by partite but we have glia involved |
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45:33 | and in particular these are astra sites this is the third party of the |
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45:39 | synapse in controlling glued inabilities or glutamate and metabolism. So glutamate has glial |
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45:48 | transporter. This is G. And neuronal glutamate transporters. And neurons |
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45:55 | pump it back into the prison optic . Glutamate transporters will take it up |
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46:02 | glia and there they will use glue and turn it into G. |
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46:12 | N. Which stands for glutamine. then leo will give this glutamine two |
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46:23 | also through some transport mechanism and then can take this glutamine with the help |
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46:31 | glue laminates and some energy converted into and loaded up into vesicles. So |
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46:38 | has a say of how much glutamate neuron releases and how much glutamate this |
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46:43 | has available. Glia has a lot say. So when we talked about |
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46:51 | I said that they control synaptic Well this is a way in which |
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46:56 | control synaptic activity. They can limit increase the production of glutamine, they |
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47:05 | increase the transport of glutamate or decrease transport of glutamine and make it more |
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47:10 | less available for neurons. Uh They can regulate it through their |
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47:17 | So if there is a very large increase and they get overburdened, they |
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47:23 | use the gap junctions, they will their processes to buffer these neurotransmitters. |
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47:30 | now it's it's not only involved in communication, it's also involved in neurotransmitter |
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47:38 | and neurotransmitter spatial distribution if you may their networks. But this is what |
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47:46 | is happening. So when we think neurons and most of the time, |
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47:52 | of the neuroscience books, it's about communication and neuronal neuronal communication, what |
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47:58 | discovering is that glia very intricately involved regulating how much neurons can communicate with |
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48:04 | other. And the most recent news year show that we actually have some |
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48:08 | of way of separate way of communicating neurons and that's something that's just emerging |
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48:14 | brand new neuroscience this year. It's . This is just some of the |
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48:26 | of the molecules that we talked about when these slides actually refer that they |
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48:33 | movement, mood, attention, visceral , they all have different ones slightly |
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48:40 | ones, mood, appetite, sleep . If you don't if you're in |
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48:44 | bad mood, you don't eat you don't sleep well, you don't |
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48:50 | . So all of these things are of interrelated. Uh second messenger |
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49:01 | This is another interesting situation. So just looked at nicotine versus Rennick nicotine |
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49:08 | is excitatory inhibitor, the same same neurotransmitter, two different post synaptic |
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49:17 | here we have an example of what called and and that kind of this |
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49:23 | of activation receptor channel, no intermediaries and channels A lot of times referred |
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49:33 | shortcut, there's no other intermediary because some instances there are other intermediary chemicals |
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49:41 | chemical reactions to generate secondary messengers that either have an effect at the level |
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49:47 | the membrane or downstream and other organized even inside the nucleus. Uh This |
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49:56 | the secondary messenger cascade that we're talking . Let's look now in a situation |
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50:03 | norepinephrine receptors are all G protein coupled . There's no norepinephrine receptor channel. |
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50:16 | is all metal tropic. North in is all metal tropic signaling all that |
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50:24 | molecules also dopamine all of that means exception of acetylcholine and the C. |
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50:32 | . S. All medical tropic signaling protein complexes. So if here we |
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50:39 | that iron a tropic has a positive Ization met over tropic has a negative |
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50:47 | on the south member and potential hyper Here we have norepinephrine and beta and |
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50:54 | α two same molecules but the different of g protein coupled receptors. So |
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51:02 | you have a situation where a molecule acting through G protein coupled receptors and |
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51:08 | through either channel or the receptor, these two receptors may have opposing action |
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51:16 | the outfit and the secondary messenger cascades and beta will stimulate the production of |
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51:23 | GMP from a dental cyclist will produce cyclic GMP will produce more protein |
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51:29 | Say will produce more kindness and more . But if that same norepinephrine |
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51:38 | activists, alpha two receptor nearby the and complex here will inhibit them alongside |
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51:46 | and will reduce the amount of cycling and will reduce the amount of available |
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51:53 | tiny essay. And so this is to as push pull mechanism from one |
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52:00 | . You're pushing the system to produce protein kind and say from this side |
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52:06 | actually pulling the system away from producing kind and say so you have here |
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52:13 | actions the same molecule but through two subtypes of metal tropic receptors. So |
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52:24 | the cell express both types of great . The cells can co express |
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52:32 | They can express them in different locations the membrane And they can have more |
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52:39 | one versus another. And this is of the mystery and part of the |
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52:46 | and part of the individualism I think we have in our in our brains |
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52:51 | brain functions. Yeah. So you co express nicotine nick and masculine IQ |
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52:58 | they will compete against each other if right there next to each other. |
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53:03 | can co express this alpha data and also cells that will just contain alpha |
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53:11 | just will contain beta and therefore norepinephrine have a stimulatory effect on certain type |
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53:16 | the cell and inhibitory effect on another of the cell. But through these |
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53:21 | protein mechanisms and their longer mechanisms. if you think about this we talked |
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53:29 | gap junctions seven fastest, then we synoptic chemical in our transmission item A |
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53:36 | receptors. Because you bind the molecule opens collapsed, then minimal, tropical |
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53:43 | slower. So from the town MRS binds to the receptor, this receptor |
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53:51 | almost instantaneously within a millisecond Michelle. there's a single column and by some |
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|
53:56 | book tropic catalyze the G program G will have to move activate this. |
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|
54:03 | talking about 2050 sometimes even 100 millisecond . So the tropic versus medical tropic |
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|
54:12 | tropic is faster. Medical tropic systems slower, slower fact, delay the |
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|
54:19 | . But you know when you say one second just passed. You |
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|
54:25 | I can't say even two words in second. One second, one |
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|
54:29 | That's 1000 milliseconds. So if you do this within 20 milliseconds you're still |
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54:36 | about very fast activity but it's still than one or two milliseconds glia are |
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|
54:45 | than neurons. So you have to and spatial scales there as well. |
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|
54:52 | I should have showed you the slide instead of drawing it. But I |
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|
54:56 | you to draw the slide and this the nuclei that are expressing the molecules |
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|
55:04 | interest for us. So in the locust, cyril ius the blue nucleus |
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55:10 | ius locus from location Cyril uses blue you cut the brain. Actually these |
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55:17 | the cells get oxidized and the turns blue on the on the tissue. |
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|
55:21 | pretty cold. That's what it's Locus Aurelius produces nora ephron and all |
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55:28 | these arrows. It's the norepinephrine sprinkler . It gets sprinkled throughout the projections |
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|
55:35 | the cortex and into the bathroom and spinal cord us kids. Oh somebody's |
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55:46 | late than never. Um nuclei are here. The green ones and then |
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55:55 | purple ones and these nuclear I basically is the south, this is the |
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56:02 | that will produce serotonin. There is so much that will produce their tone |
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|
56:07 | the pharma world. But for frontal lobe, occipital lobe brain |
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56:16 | This is a part of the brainstem , these amino amino amino nuclei. |
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56:23 | so you can see that Raffy nuclear a sprinkler system going down the spinal |
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|
56:28 | has a sprinkler system projecting very broadly the cortex and sub cortical areas. |
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|
56:37 | when you're talking about acetylcholine, there's nucleus here which is magnus cellular basal |
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|
56:47 | . The basal forebrain here and this right here which is did uncle upon |
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|
56:54 | and ladder of dorsal take mental I don't want you to remember the |
|
|
57:01 | . But the principle that you have locations where acetylcholine is produced in the |
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|
57:09 | and these, the ones that are prefrontal er also more vulnerable in Alzheimer's |
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|
57:17 | . And as far as loss of particular prefrontal nuclei that produces molecules. |
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|
57:24 | is there any, is it a system where they transported from the |
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|
57:35 | I remember that most of that will at the level of the synapse with |
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|
57:41 | means to it's the baptized in europe , the ones that have to come |
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|
57:46 | from the soma and organelles closer to soma. Like the Golgi apparatus if |
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|
57:52 | is recycling of these. Yeah, you have to have the selma's have |
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|
57:57 | code what it produces when it produces has a things in the external terminals |
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58:05 | can control it in the external terminals or less. But the code for |
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58:10 | to actually synthesize that. And the much for this neurons that synthesize will |
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|
58:16 | be only be located here actually the day I was walking in and I |
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|
58:22 | I actually don't know how many serotonin neurons there are in the brand. |
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|
58:28 | was gonna look it up and Just I don't know, there's like three |
|
|
58:33 | or 20 million would be interesting to if anybody has uh I'm sure somebody |
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|
58:40 | counted, not like one by but by taking the size of an |
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|
58:45 | cell and the size of an average and deriving of how many of |
|
|
58:49 | you know, certain ergic cells will packed in there. So yeah, |
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|
58:56 | very good questions. Can I ask question. These arrows? The blue |
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59:02 | purple arrows are those axons for example from cell bodies in the locus Aurelius |
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|
59:08 | their synapses onto a bunch of different everywhere. Exactly. Um when I |
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|
59:14 | the sprinkler systems, that's exactly what meant is they have these external projections |
|
|
59:19 | distribute themselves very widely and distribute themselves widely throughout the cortex and sub cortical |
|
|
59:27 | and cerebellum as you can see. . So these would be very long |
|
|
59:32 | projections coming from from those nuclei that the so Mazz that can synthesize the |
|
|
59:40 | that can synthesize these molecules 502,000. serotonin producing cells 300,000. So it's |
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|
60:01 | basically if you have billions of neurons the brain it's like a whole earth |
|
|
60:08 | 300,000 is like a small town that that that has to supply the whole |
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|
60:15 | with the mood, Sleeping happy uh interesting. Huh? I wonder what |
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|
60:23 | colon ergic number as and uh and they're distributed if there's more uh basal |
|
|
60:32 | or not but we can look that offline but it's that's that gives you |
|
|
60:37 | perspective. Right? It's not that . 300,000, wow I have to |
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|
60:45 | up that alone. So here I dispelled for you one more time. |
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|
60:49 | deep polarization induced depression of in addition the deep polarization induced suppression of excitation |
|
|
60:57 | teach C stands for tetrahydrocannabinol which is fighter phenomenon. So T Tetra H |
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|
61:07 | seek a nominal in in in our there are two major under economic noise |
|
|
61:13 | in the brain but there's really potentially six or seven of them molecules that |
|
|
61:19 | is under economic lloyds. And in plan there's over 120 different phyto |
|
|
61:26 | uh THC CBD delta nine and so and so forth amino acids, |
|
|
61:37 | all of the neurons. And if use them you know history chemistry and |
|
|
61:41 | said which cells are inhibitory cells said I'm gonna use God antibody or God |
|
|
61:50 | RNA a radioactively labeled sequence and all this is also gonna be inhibitory. |
|
|
61:58 | will show up and that is So all of the cns cells that |
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|
62:01 | Gaba will contain God because they have synthesize. And you have the same |
|
|
62:08 | in the sense that both Glutamate and cells will have the co transporters into |
|
|
62:14 | mystical transporters as well. So when thinking about drugs, you know again |
|
|
62:21 | of the drugs, when you think these two systems, glutamate excitatory system |
|
|
62:27 | inhibitory system. Most of the pharmaceutical are directed towards Gaba system to increase |
|
|
62:34 | and a lot of neurological disorders. seems to be a loss of control |
|
|
62:38 | excitation and so a lot of the of the brain activity will be by |
|
|
62:45 | inhibition. But then you have the for different transporters into the cell, |
|
|
62:50 | the vesicles and such and the rest the Time which we will not have |
|
|
62:59 | time today. So we will have new transmission lecture four on Wednesday. |
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|
63:07 | following that I will give you guys quiz and I'll think it's going to |
|
|
63:15 | most likely on monday. So a from today so that we finished the |
|
|
63:20 | transmission on Wednesday and you guys have on the weekend to study and take |
|
|
63:25 | on monday. I haven't confronted with . Yes I'll let you know for |
|
|
63:30 | on Wednesday but so we'll finish up of it today and some of it |
|
|
63:37 | Wednesday. But glutamate has three distinct targets in the brain. It has |
|
|
63:42 | receptors and NBA receptors and receptors. is an endogenous neurotransmitter agonist. And |
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|
63:51 | are synthetic chemical agonists and that will specifically part of the example receptor and |
|
|
63:58 | specifically the M. D. Receptor and kind the chemical that will |
|
|
64:03 | specifically to kinase receptors. So remember the beginning of this course we talked |
|
|
64:12 | how this action potential is produced and and some some some folks asked me |
|
|
64:18 | what does the deep polarization come And deep polarization comes from the the |
|
|
64:27 | release with binds to glutamate receptors. . That produced E. P. |
|
|
64:38 | . P. Okay and if this . P. S. B. |
|
|
64:44 | strong enough this is the summer here will produce an action potential. So |
|
|
64:54 | is supposed to be like dendrite inputs whatever. It's kind of funny anyway |
|
|
65:00 | this is E. P. P. S. If you have |
|
|
65:02 | enough post synaptic responses of where do C. P. S. |
|
|
65:05 | S come from? And I said come from glutamate receptor channels. And |
|
|
65:09 | turns out that there are two major classes and is grouped together and then |
|
|
65:16 | . A receptor is group separately when is glutamate release Glutamate molecules will bind |
|
|
65:23 | both ample receptor shown here in blue an M. B. A receptor |
|
|
65:29 | . And as soon as advised the receptor receptor will allow for influx of |
|
|
65:35 | and you will get the initial P of this E. P. |
|
|
65:40 | P. Coming through the reception and through this blue receptor. And then |
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|
65:46 | interceptor even if it gets bound, receptor gets bound by glutamate molecules, |
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|
65:53 | still doesn't open an M. A receptor at wrestling number and potential |
|
|
65:59 | a magnesium that's blocking an M. . A receptor. And even if |
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|
66:04 | binds if it's a minus 65 there's binding to this receptor, this an |
|
|
66:09 | . D. A receptor is going stay closed. But this initial deep |
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|
66:16 | through ample receptor is what's needed. change in the voltage from -652 more |
|
|
66:24 | polarized potentials is what's needed to open M. D. A receptor. |
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|
66:29 | this initial deep polarization on flocks of ions sodium ions into the south Tampa |
|
|
66:39 | removes the magnesium block and allows for N. M. D. |
|
|
66:43 | Channel to be open. And this M. D. A receptor channel |
|
|
66:47 | responsible for the late phase of the . P. S. P. |
|
|
66:53 | you can basically take the E. . S. P. That looks |
|
|
66:57 | this and divided into early phase here late phase here in the early phases |
|
|
67:10 | receptors and delayed phases mm. A. This flux through an |
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|
67:14 | D. A. Receptor channels a of students that say that oh an |
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67:20 | is a memorable tropic receptor and it not a metal tropic receptor, it |
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|
67:25 | just how to locate by magnesium. actually a receptor channel. So it |
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67:30 | an anna tropic receptor so ample opens , ample doesn't need deep polarization and |
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67:39 | . D. A. Needs deep and M. D. A. |
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67:42 | slower kinetics. Uh And also the thing is ample receptor will allow the |
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67:49 | of sodium and potassium and M. . A receptor in addition allows the |
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67:54 | of calcium. So all an D. A receptors will allow for |
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67:59 | of calcium which is significant because remember acts as a secondary messenger inside the |
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68:08 | there's the differences. Again, non receptors which is an are always permeable |
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68:20 | sodium potassium only but there are some where they can be permissible to calcium |
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68:26 | M. D. A receptor is permissible to sodium potassium and calcium. |
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68:33 | ample receptors conduct about 20 PICO seaman's this conductance thing and M. |
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68:39 | A. Receptor is conduct about 50 seamans of current. So once you |
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68:43 | an M. D. A receptor get 2.5 times as much current flux |
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68:47 | M. D. A reception, have their own distinct blockers. So |
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68:55 | receptor has an antagonist that's called N. Q. X. And |
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69:00 | M. D. A receptor has antagonist that is called AP. |
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69:03 | or 85. These are distinct agonists antagonists. And M. D. |
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69:10 | receptor is referred to as coincident detector it coincidentally has to detect glutamate and |
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69:20 | attic deep polarization in order to be . So if there's just glutamate but |
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69:26 | enough personality polarization, it's not coincidentally pre synaptic neurotransmitter and personality polarization, |
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69:35 | doesn't budge, it doesn't get So small deep polarization. Just open |
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69:40 | little bit of ample channels and cost deep polarization is they may not lead |
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69:45 | the opening of an M. A. They may not lead to |
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69:48 | E. P. S. And they may not promote the cell |
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69:53 | d polarizing to the threshold for the potential. Uh So am pi is |
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70:00 | and it's the early phase and D. A. Is late. |
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70:05 | has slow kinetics and is responsible for late portion of the E. |
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70:10 | S. T. Glutamate can also into medical tropical receptors. So don't |
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70:18 | an M. D. A Medical tropic glutamate has medical tropical automate |
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70:23 | but it's probably about 12 different cell of medical tropic glutamate receptors and we're |
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70:28 | gonna look at them a little bit we study the visual system. But |
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70:33 | than that we will talk much about function of medical tropic glutamate receptors. |
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70:38 | will focus on the island of So here you have an M. |
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70:43 | . A. Receptor and you have glue as a binding side and also |
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70:52 | have glide which is glycerine. glycerine and C. N. |
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70:57 | Is a co factor of an NBA something. Is that funny? And |
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71:03 | spinal cord glycerine is the major inhibitor and here is a co factor for |
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71:08 | excitatory post synaptic receptor signal depends again it binds to what it binds. |
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71:16 | fact is going to happen. So you have glycerine, pardon me as |
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71:22 | co factor glutamate will bind blasting will and you need you know deep polarization |
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71:28 | the channel is active. You remove of this girl I seen the channel |
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71:32 | not going to open as readily. has a binding side in there. |
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71:41 | he's um actually has two binding So you can see it's sort of |
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71:46 | a key into the keyhole. Each of these molecules have different binding |
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71:52 | Each agonists and antagonists can target different of the channel or they can compete |
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72:00 | the same site. And so you'll a term competitive agonists or competitive antagonists |
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72:05 | means that something is competing with slicing to fit right here and it's opening |
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72:13 | here. So the two molecules are then you may hear a term binding |
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72:20 | Which means which is more likely to license has higher binding affinity than some |
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72:26 | competing with it. But slicing takes of the place is taken by licensing |
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72:33 | molecule can only get 30% and if need to increase the concentration of the |
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72:38 | molecules to bind up as many places license. You know it doesn't have |
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72:43 | good of an affinity binding affinity to molecules. Uh you have sodium potassium |
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72:52 | calcium crossing through an M. D . As I said it requires deep |
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72:59 | licensing as a co factor to remove magnesium block to be functional. There |
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73:05 | drugs M. K. A. is an antagonist that targets only active |
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73:11 | M. D. D. What does that mean? And |
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73:18 | Because remember that when receptors active that that this three dimensional structure changed its |
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73:27 | all properties. So as it changes conformational properties, it opens up new |
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73:33 | cyst for molecules to bind and some bind to these receptors channels only when |
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73:40 | active and only when these new conformational in the amino acid structures form okay |
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73:49 | you can have a receptor that's activated only bound by uh by this |
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73:56 | And on PC PS mentioned here is in your book is an angel |
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74:03 | A lot of process an illicit street . It can cause hallucinations and very |
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74:13 | single doses of some of these drugs drugs like PCP and strong hallucinogenic drugs |
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74:21 | induce schizophrenia too and not just uh episode of schizophrenia but potentially an onset |
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74:31 | a chronic problem. So PCP is chemical substance that has binding affinity to |
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74:42 | M. D. A. Receptors it's known to to provoke these mental |
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74:51 | and not just a single episode and open up the door for chronic mental |
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74:56 | by activating certain parts of the receptor really not supposed to be activated because |
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75:02 | an exogenous substance like an illicit drug some of these exogenous substances can be |
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75:12 | . We have uh opioid epidemic for these are pharmaceutical drugs that are prescribed |
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75:21 | people are dying from them because just little bit of that drug can overload |
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75:26 | system and and kill you just like PCP a single use can overload the |
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75:33 | and destroy the system like an NBA . And there are other substances that |
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75:39 | plant based and botanical based that people lived with for thousands of years and |
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75:44 | interact with our systems and don't seem be as harmful. So it's all |
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75:49 | what you know really really what you and what you really know. Um |
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75:59 | is uh actually I'm gonna if you don't mind I'm gonna end the lecture |
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76:05 | . I'm running a little bit out time. So please let's save your |
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76:09 | for next lecture. And we're gonna up on a few slides on an |
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76:14 | . D. A receptor in gabba , medical tropic signaling and put it |
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76:20 | within the context of this pretty interesting which will give you an understanding and |
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76:26 | of how complex cns synapses are. thank you very much for being here |
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76:31 | it's beautiful weather outside. We'll see again on Wednesday and then I'll let |
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76:36 | guys know about the quiz and whoever on zoom. Please hang on to |
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76:40 | question for the next lecture. Thank |
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