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00:00 | Start. Uh It's our lecture 12 neuroscience and we're talking about synaptic transmission |
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00:09 | we're talking about some important concepts where compared what is happening at the neuro |
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00:15 | junction where you only have excitation and only have one type of acetylcholine receptor |
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00:21 | is nicotine, nick, Ryan, tropic acetylcholine receptor channel and where the |
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00:27 | plate potential is approximately 70 million. change in E. P. |
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00:34 | And that is different from the N. S. Components that we |
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00:39 | . We discussed different classes of these . We distinguish between amino acid neurotransmitters |
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00:46 | are widely distributed and expressed throughout the . N. S. And the |
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00:50 | cord mean neurotransmitters that are confined their and synthesis within certain nuclei of the |
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00:59 | . N. S. But they have a widespread release throughout the CNS |
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01:04 | the referee as well as the The differences in the peptides and release |
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01:09 | the peptide molecules compared to the The things that are necessary for the |
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01:16 | fusion to take place and cause neurotransmitter . And if it is glued in |
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01:22 | that gets released and there's an influx positive charge it will cause austin optically |
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01:28 | graded potential which is E. S. P. Excitatory post synaptic |
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01:33 | . Excitatory post synaptic potential E. . S. P. And if |
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01:37 | excitatory post synaptic potential reaches the threshold the action potential generation, it will |
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01:45 | all or non event action potential that produced. So you need deep polarization |
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01:52 | once the action potential arrives, influx calcium fusion of the vesicles vesicles. |
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01:58 | complex and release of the neurotransmitter. Some of the techniques that we discussed |
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02:04 | study membrane components which fractured technique as as to look at the morphological distribution |
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02:12 | let's say vesicles at the doctor and zones and correlation to both executed calcium |
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02:18 | which are necessary as well as imaging the calcium spatial temporal dynamics of calcium |
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02:26 | and the pre synaptic terminals with calcium dyes. So tracing dies essentially. |
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02:32 | also partial neurotransmitter release. There is a tropic versus metabolic tropic signaling that |
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02:40 | discussed already. And continue discussing further the next lecture two, we looked |
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02:45 | at the neuro pharmacology gee of So we started developing this land which |
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02:50 | an endogenous agonist endogenous or something produced the body. What is a natural |
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02:58 | that comes from animal. What is the vital molecule that comes from the |
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03:04 | ? What is humanly synthesized chemicals. so we talked about a single colon |
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03:09 | endogenous agonist for both nicotine acetylcholine receptor and most chronic medical tropics protein coupled |
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03:17 | here. And they have their own curare is found in nature. Atropine |
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03:22 | be synthesized in the lab and a of these can then be re synthesized |
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03:26 | they're found in nature but they will two types of receptors in the cns |
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03:31 | that's different from the neuro muscular Oh so we looked at the acetylcholine |
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03:39 | you should know everything that's on here your quiz next friday and also for |
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03:45 | midterm to acetylcholine synthesis release degradation uh that are involved in synthesis and degradation |
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03:54 | well as the fact that we discuss most of the alzheimer's medications are cyclical |
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03:59 | necessaries inhibitors. And if you inhibit nestor rate, which is an acetylcholine |
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04:06 | enzyme, if you block this enzyme basically choose up acetylcholine molecule into Colin |
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04:14 | acetic acid and you prolong the by of these molecules and you'll see that |
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04:19 | can control Alzheimer's disease. Just slow the progression. But you can control |
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04:26 | amount of acetylcholine. It's still available prolonging its by availability by blocking its |
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04:34 | . And you will see other examples other I mean neurotransmitter systems where common |
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04:42 | drugs of action and also illicit drugs the market affect neural transmission within the |
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04:50 | transport of molecules into the pre synaptic or uploading them into the vesicles prison |
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05:00 | . Then we talked about how you some molecules that are present in |
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05:05 | They can cause some disease like uh by clostridium botulinum botulinum toxins but you |
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05:13 | also adapt it for your own And for beauty uses it can block |
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05:18 | transmission and reduce the wrinkle appearance on the skin, basically by blocking the |
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05:26 | of acetylcholine vesicles and release of acetylcholine reduced and it is also being used |
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05:33 | FDA approved medication for treatment of So different purposes by which these molecules |
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05:40 | be used. We discussed organophosphates or gasses and we said that nerve gasses |
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05:47 | in a similar fashion to the Alzheimer's medications in the in the sense that |
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05:53 | are several colonist Aries inhibitors. The that C H E S. It'll |
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05:58 | er is inhibitors. So you'll say then they should be all famous |
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06:02 | but when they used as a war as a lethal tool, illegally learned |
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06:09 | are illegal for for warfare, but they're used, so they affect acetylcholine |
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06:16 | contract and signaling of these locally, only in the brain, and it |
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06:21 | cause seizures but that may not kill , but it can affect your breathing |
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06:26 | diaphragm. And if there's too much and the muscle gets stimulated when the |
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06:31 | is stimulated nonstop, it goes into tannic a state which means that just |
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06:37 | permanently contract and cannot relax. And do you do when you breathe? |
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06:43 | do. But you're contracting muscles and you relax and you contract them and |
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06:47 | relax them. And if you can them, you stop breathing. So |
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06:52 | lethal effects of the North gasses would be through the cns effects, but |
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06:57 | through affecting muscles and tissues that are the diaphragm into breathing, which is |
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07:05 | for living and for her brain. , so we learned a lot of |
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07:12 | stuff, There's a little bit overlap the next two lectures, but I |
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07:17 | wanted to remind you that when we about the system a little uh acetylcholine |
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07:23 | or a mean system or norepinephrine system serotonin system, they're different from amino |
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07:32 | neurotransmitters which would be widely distributed and in different cells. But as you |
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07:37 | see and I'd like for you to with the exam that the seat of |
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07:42 | for norepinephrine in the C. S. Is local cyril ius or |
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07:47 | cyril yous locus is an area So really this is blue because when |
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07:52 | cut the brain tissue, the neurons and turn blue in this area. |
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07:57 | this is a nucleus which will be of cells. Hundreds of thousands of |
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08:01 | that synthesize norepinephrine and then they supply through their very disk used projections into |
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08:08 | C. N. S. Are and also to the spinal cord wrapping |
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08:14 | are responsible for serotonin production. And can see that sometimes there's more than |
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08:18 | nucleus, there's one more than one where serotonin is produced. So you |
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08:25 | to wrapping nuclei that supply centrally serotonin to wrapping nuclei located deeper within brainstem |
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08:34 | into medulla oblon gata here that they're the spinal cord. So this is |
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08:40 | nuclei and this is serotonin. If look at these two green nuclei, |
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08:47 | cellular basal forebrain and this green I hear the dunkel, Aponte ein |
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08:54 | lateral dorsal to dismantle nuclear here. are the two nuclei that will be |
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09:00 | a single colon. Okay and so when we talk about Alzheimer's disease in |
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09:07 | to acetylcholine. The reason why a colonist or ace inhibitors of common medications |
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09:15 | because there is a decrease and loss a proper amount of acetylcholine because there |
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09:22 | degeneration and loss of these what we Colin ergic neurons, neurons that sid |
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09:30 | are called Colin urgent. The ones have glutamate glutamate ergic, the ones |
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09:36 | have Gaba gaba ergic, the ones have serotonin serotonin ergic uh norepinephrine on |
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09:46 | under energetic. Okay, so there's little bit of a vocabulary there around |
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09:51 | these these things that we're discussing. uh I'm gonna go back to where |
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09:58 | kind of left off here talking, described E. P. S. |
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10:02 | . S. And I PS PS greater potentials will come back and talk |
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10:06 | them. But the idea that will is and C. N. |
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10:13 | If you're looking at E P. . P. S. Or I |
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10:17 | PS. And E. P. . P. And I PSP is |
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10:24 | 0.5 mil of all deep polarization. it's an E. P. |
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10:30 | P. So change single ep sp in the post synaptic membrane potential. |
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10:38 | guys understand all of this. The post synaptic membrane potential is about |
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10:44 | million balls. Okay and in this it is E. P. |
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10:49 | B. It's excitatory excitatory post synaptic . Okay. Alright. And this |
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11:00 | deep polarization in post synaptic cell. . This is about E. |
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11:10 | S. P. And we're talking I PS. P. Okay I |
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11:16 | PS are inhibitory boston opic potential and per polarization and posson optic cell. |
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11:33 | is a change in the membrane potential about half a melon ball. Okay |
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11:39 | this is in the C. S. And you remember in the |
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11:43 | muscular junction here in the skeletal muscles had potential and that employed potential was |
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11:53 | . That means that activation of axon a single synapse is sufficient to cause |
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12:00 | contraction of the muscle. The post very large potential that will generate action |
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12:07 | . Now you have this neuron that lingering around -65 area here. |
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12:16 | And it's changing its number and So if it receives excitation and |
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12:23 | P. S. P. From single synapse it may cause a small |
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12:27 | polarization but it may also receive an input and it will cause a small |
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12:33 | polarization and maybe even a stronger hyper and then a stronger deep polarization. |
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12:39 | if you activate 46 synopsis eight if you start some mating excited current |
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12:48 | And each one of these synopses or one of the ep sp activation from |
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12:54 | single synapse 0.5 million volts. That you have to have at least 40 |
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13:01 | excitatory synopsis or maybe even more because the same time the cell might be |
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13:07 | inhibitory but so these are great and they can be half a mil of |
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13:11 | . They can be one mil of the typical, they're about the same |
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13:15 | because of the number of molecules that released from the vesicles, typically about |
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13:20 | same quanta. We talked about molecules small variations known how it gets released |
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13:26 | some of them may be released So some of these are maybe partial |
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13:31 | and full releases a neurotransmitter. But it reaches the threshold for action potential |
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13:37 | when it's going to generate this all non response. And uh this is |
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13:44 | I'm gonna do this because the action compared to the E. P. |
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13:49 | . P. S are actually very fast responses. Right? So if |
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13:56 | timescale here is about one millisecond and other second and the timescale here or |
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14:09 | . P. S. P. about five milliseconds. Okay, this |
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14:24 | my time bar another seconds. And then again, you know, |
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14:29 | the cell gets hyper polarized for a and then another excited the barrage of |
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14:35 | comes in that this one goes this and it never reaches the threshold. |
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14:40 | the cell never fires an action So this is really explaining the |
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14:47 | P. S. P. And I. P. S. |
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14:49 | . S. I was so good carrying like a number of colorful markers |
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14:52 | my left them, another classroom So this is good though, |
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15:00 | And everybody can draw with me and reminds you about all of these time |
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15:04 | . All of these potentials. You take notes E. P. |
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15:07 | P. S. You know. deep polarization here will be an ep |
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15:11 | hyper polarization from resting membrane potential is I. P. S. |
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15:16 | E. P. S. Is my ma. Is produced by |
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15:23 | is produced by glutamate and I. . S. P. S produced |
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15:29 | Gaba. So glutamate causes influx of and that's what causes the deep |
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15:38 | So when glutamate binds to glutamate receptors we'll start talking about them today all |
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15:42 | the glutamate receptors in the cNS. when gaba binds to gaba receptor |
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15:48 | So it allows them to influx of which is negative charge going in and |
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15:52 | an I. P. S. . Because direct versus indirect ion a |
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15:59 | versus medical tropic. So medical tropic where you don't have a channel. |
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16:05 | when neurotransmitter binds to this receptor, receptor is coupled to G protein and |
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16:10 | protein can have an effect on the channels in the plasma membrane so they |
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16:17 | regulate other ion channels through the jew complex. And if you're talking about |
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16:24 | on a tropic activation so the release the bicycle of the neurotransmitter crossing of |
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16:32 | synapse binding to the receptor and influx chloride. This is what we call |
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16:39 | synaptic delay. This takes about few from the time there is a pre |
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16:45 | action potential to the time when you a post synaptic response. Either |
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16:50 | P. S. P. I. P. S. |
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16:51 | There's typically a few millisecond delay and a synaptic delay. Now remember gap |
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16:58 | or electrical junctions don't have that That's why when we talked about gap |
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17:03 | or electrical junctions we said that they the passage of all ions. But |
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17:07 | immediate and it's really good for fast and engaging networks of cells interconnected cells |
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17:15 | a very fast fashion with chemical You have these delays. So you |
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17:21 | this delay here of 5 to 10 . Well guess what? You also |
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17:26 | even a longer delay here because this one advise the G protein coupled receptor |
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17:32 | has to catalyze activate this G protein . G protein complex has to move |
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17:38 | distance within the south to either before late for example an ion channel or |
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17:45 | an enzyme that will induce the production the secondary messenger and that secondary messenger |
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17:51 | have an effect. And these are may take time. So from the |
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17:58 | this neurotransmitter binds the G protein coupled at the time it modulates an ion |
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18:05 | nearby. There can be 20 milliseconds time, 50 milliseconds in some instances |
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18:12 | or 200 milliseconds that pass. And when we talk about this kind of |
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18:19 | neural transmission. The release of the binding of that neurotransmitter to the |
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18:26 | synaptic receptor channel the post synaptic E. P. S. |
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18:30 | S. I. P. Pieces they're strong enough. E |
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18:33 | S. P. Post synaptic cell also generate an action potential. Okay |
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18:42 | but this is not generating an P. S. P. |
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18:47 | I. P. S. If metabolic tropic channels are affected ion |
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18:53 | it may have a small influence on membrane potential charge because it is regulating |
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18:59 | ion channel will see that meadow tropic is regulating potassium ion channels. What |
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19:08 | this effect through secondary messengers? That's that's going to cause a deep |
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19:13 | And E. P. S. . No so notable tropic signaling is |
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19:17 | little bit different. It might involve ionic change of the number and potential |
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19:24 | is acting on the ionic channels. if it is acting on the secondary |
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19:30 | and those secondary messengers potentially could even going all the way to the nucleus |
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19:37 | the transcription factors that's not really gonna the membrane potential. It's gonna change |
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19:43 | cellular signal. And those changes can impactful and longer lasting too. So |
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19:52 | general think about this. Just think the brain which you've learned so |
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19:58 | It is pretty complicated but you have and neurons are fast and produce fast |
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20:04 | potentials and E. P. P. S. Are a little |
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20:06 | slower and these medical tropic effects if throughout the tropic channels are even slower |
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20:13 | the cellular facts are even slower and longer lasting. You have real |
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20:19 | Well, cells are slow in they're not involved in producing fast action |
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20:24 | that produce low calcium waves. Slow waves, it's a different temporal scale |
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20:30 | operation. We will also be involved micro glia in cytokine release and inflammation |
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20:38 | . It's a slower temporal scale. taking days and weeks. It's not |
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20:44 | fast action potential, It's not an . P. S. P that |
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20:47 | a duration of 10 or so milliseconds five millisecond synaptic delay. It's different |
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20:53 | scales. So put these things in for two cells communicating if it's gap |
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21:01 | it's immediate. So you don't have synaptic transmission delay. If it's |
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21:06 | you inevitably have that synaptic transmission Okay, so review the acetylcholine and |
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21:15 | you recall, acetylcholine will bind to IQ. And most sarinic. So |
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21:23 | is a natural agonist to both types nicotine and and muscular nick. Acetylcholine |
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21:31 | . Nicotine comes from tobacco plants uh it is an exogenous Fido molecule but |
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21:41 | also an agonist to nicotine, acetylcholine must corinne is an agonist, musk |
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21:49 | IQ. And then they have antagonists is something that opens or activists channel |
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21:56 | activist. The receptor for do protein antagonist is something that inactivated blocks the |
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22:05 | or blocks the G program complex So they have their respective agonists and |
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22:14 | uh chemical and natural and endogenous neurotransmitter a pseudo code and what you learned |
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22:21 | acetylcholine also uh is kind of a to other systems. So the cat |
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22:30 | colony in class of the means where have tyrosine as precursor to L |
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22:37 | which is a precursor to dopamine, to norepinephrine and the precursor to the |
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22:45 | . So what does that tell you tells you that release of one |
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22:49 | One neurotransmitter can be a precursor to neurotransmitter. Right? Some of some |
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22:55 | some of these get generated depending on behavioral states. For example, cata |
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23:04 | means when they get released they will only on medical tropic receptors and here |
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23:10 | will be transported. Or we have back and when they're we have taken |
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23:16 | there will be will be degraded by amine oxide. Asus. So there's |
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23:25 | enzyme that degrees in here it's Mon oxidation and uh drugs illicit drugs like |
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23:36 | and cocaine. So methamphetamine, meth crystal math would have a significant effect |
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23:44 | blocking the re uptake of cata cola stimulating and increasing dopamine and also consequentially |
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23:57 | too. So some of these drugs have multiple targets in the brain. |
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24:04 | now there are also pharmaceutical drugs that control Mon ami Mon ami knocks ID |
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24:12 | and they would be mono amine oxidase of pharmaceutical drugs and if they inhibit |
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24:18 | oxidation of the means. That means prolong the availability of the means to |
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24:24 | re uploaded. They're not getting degraded they're cycling faster. They're more available |
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24:30 | this neurotransmitter system to cycle through. I don't want you to know that |
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24:38 | synthesizing enzymes so that it's pretty easy have deco box analysis. The decoder |
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24:44 | silica molecules you have hydroxy analysis that an O. H. Group. |
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24:52 | what you're seeing here is that they are structurally similar. These molecules chemically |
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25:01 | similar molecules. They'll have their own receptors and they all have different subtypes |
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25:07 | receptors and norepinephrine through the tropics signaling target multiple different receptors and processing optic |
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25:15 | serotonin but here mood appetite sleep So serotonin and serotonin dysfunctions. Here |
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25:29 | have the PROzac is a serotonin re inhibitor. This is a re uptake |
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25:38 | . When serotonin gets released it gets up taken and then it gets degraded |
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25:44 | mono monoxide Asus. Okay but if block again re uptake, this is |
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25:50 | a pharmaceutical medication brand name pros that it is a serotonin re uptake inhibitor |
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25:57 | you hear you will hear people use re uptake inhibitors or S. |
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26:02 | I. S. Somebody in the or somebody in from pharmacological Wardlaw. |
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26:07 | taking sRS and things like that. guess what it is for mood mental |
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26:13 | . Distort is depression, anxiety which all interrelated with with sleep too because |
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26:19 | you're in a bad mood, you sleep and if you don't sleep you |
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26:22 | learn well in a bad mood. don't learn well either. So it's |
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26:27 | interrelated now serotonin has a precursor of . There's a lot of tryptophan in |
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26:34 | uh stripped of time goes into five which is a dropsy trip to fan |
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26:40 | five HTP car box elated and makes serotonin or five hydroxy trip to |
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26:48 | So once again no transmitters, these transmitters who are studying if you're talking |
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26:56 | excitation and inhibition that's uh switch on off now this means they're all of |
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27:02 | different behavioral states. So dope. mean a lot of dope. I |
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27:07 | a lot of norepinephrine, you're in upstate, you engage statement gets released |
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27:13 | the big bears running at you, don't get typically sleepy and say oh |
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27:19 | really entertaining, I'm gonna relax. bear is coming to take my head |
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27:24 | and loving to do so now when are going to be in a different |
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27:31 | , the appetite, different neurotransmitters are to be activated different states that sometimes |
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27:39 | imposed on us extra cellular uh cellular externally right different environments and it dictates |
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27:50 | mood and it changes the production and release of these different molecules. So |
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27:56 | you walk in in a dim lit that has com music playing and candles |
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28:03 | aromatherapy, you probably get relaxed and levels go down serotonin levels go up |
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28:13 | denison levels go up. Then you into the gym where everybody's pumped up |
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28:19 | running and jumping. You know different different mood kicks in different neurotransmitters now |
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28:28 | different behavior. Now they have these upset. So if you have a |
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28:34 | system upset then you have dysfunctions like , clinical depression, anxiety associated with |
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28:43 | elements PROzac and srs would be treatment depression and anxiety. If you have |
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28:49 | system upset and motor disorders like uh disease for example. Okay, so |
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28:57 | associated with different states but also with neurological conditions. Okay now in the |
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29:07 | we already discuss them and they're somewhat to the gasses that we mentioned. |
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29:14 | oxide and carbon monoxide. Not because their function but because of how they |
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29:21 | in the synopsis and in the But the end of cannabinoids are endogenous |
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29:28 | molecules. You don't have to eat gummy or anything it's inside of |
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29:33 | This production of endocannabinoid that goes up the stress levels and activity levels in |
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29:39 | south and the body go up where of the neurotransmitters we're discussing here such |
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29:46 | for example, glutamate gets released prison and advised to the receptors post synaptic |
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29:54 | and causes post synaptic in fact. this is referred as anterograde signaling for |
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30:00 | synaptic synaptic and other South and other but ended up in adenoids and the |
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30:07 | nitrous oxide and carbon monoxide. Both and retrograde fashion. And what can |
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30:15 | of cannabinoids do is they serve as feedback molecules. So the endocannabinoid system |
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30:25 | this type of signaling is relatively new our understanding in neuroscience We've just really |
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30:34 | then the cannabinoid system, mostly the scientists in Czech scientists in 1990s. |
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30:42 | some of these things we know less 30 years about. But the initial |
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30:48 | of Anandamide and to a geo to phenomenal glycerol is the end of Canavan |
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30:57 | molecules happened in the early nineties. there, we have to have the |
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31:03 | system, right? So if you a neurotransmitter, this is under cannabinoids |
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31:08 | enzymes that synthesize right have to release they're not stored in the vesicles the |
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31:16 | there is heightened levels of activity pre lee there is deep polarization process in |
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31:22 | they're hyper polarization. Either one so can be with glutamate or Gaba. |
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31:28 | increased productions of these other cannabinoid person optically the lipid soluble, so |
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31:35 | cross the plasma membranes and they travel the retrograde fashion to the pre synaptic |
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31:41 | where they bind to cannabinoid sectors. they have their target receptors as part |
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31:46 | the system. CB one receptors cannabinoid one which is expressed ubiquitously on most |
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31:53 | of the neurons CB one receptor is jeffersonian coupled receptor an activation of CB |
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32:01 | receptor and this jeopardy in complex will the closure of voltage gated calcium |
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32:09 | Remember that voltage gated calcium channels and so that the vesicles confuse and cause |
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32:16 | release. So if you block the gated calcium channels prison optically you block |
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32:24 | release and that's why it's a negative system. Too much excitation. And |
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32:32 | cannabinoids kick in retrograde lee, activate protein complex here and shut down the |
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32:40 | . Too much inhibition. And the activate retrograde lee travel and regulate the |
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32:47 | molecule release. So it places under in this situation where they control both |
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32:56 | and inhibitory molecule released at the pre level but from past synaptic side not |
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33:03 | in vesicles lipid soluble and function retrograde and so do the gasses and now |
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33:12 | cl mhm delta nine THC is the here on top. And you can |
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33:20 | there's some structural similarities between anandamide and glycerol. Delta nine THC is a |
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33:27 | cannabinoid molecule that comes from the from cannabis plant and you can see |
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33:33 | a different structure. But a lot these receptors will have multiple binding sites |
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33:39 | multiple molecules endogenous and exogenous can bind these receptors. And so th |
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33:48 | That the line THC will buy two one this afternoon mimic the activity of |
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33:59 | . Yeah, so the blocks the one receptor activates CB one receptor. |
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34:12 | good question. The agonist of CB receptor. But in which case the |
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34:17 | of the CB one receptor is to down the calcium signal the agonist because |
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34:25 | activate this g protein complex, that of that g protein complex doesn't mean |
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34:30 | polarization of positive effect. It can multiple times control of iron channels into |
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34:36 | or messengers and such. But this the mechanism also uh uh dennison is |
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34:43 | molecule from A. T. We discussed will be exerting a similar |
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34:48 | through different different koppel receptor also regulating channels. There's several molecules in the |
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34:56 | that will be doing the same function controlling their transmitter release. You're |
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35:03 | Okay so we'll come back and talk this a little bit more. We'll |
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35:08 | talk about this uh later later in course also. Uh yeah now a |
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35:17 | way to study neurotransmitters. So now are a scientist, a neuroscientist and |
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35:23 | in the lab and you learn how make brain slices. And you're gonna |
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35:28 | the question, I want to know cells in the hippocampus are inhibitory, |
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35:33 | ones are excited during And uh so you look for example in a nina |
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35:42 | , major inhibitory neurotransmitter Gaba is actually from the major excitatory neurotransmitter glutamate and |
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35:50 | is done with atomic is God. means that all of the South that |
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35:57 | releasing Gaba are gonna have God um all of the cells that carry glutamate |
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36:04 | gonna have glutamate or they're gonna have other synthesizing molecules for glutamate. Remember |
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36:12 | was for sale locally called transfer is that that that synthesizes see locally. |
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36:21 | there are two techniques that are commonly for detecting neurotransmitter expression and different cell |
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36:27 | and that's immune system chemistry and in hybridization and um you know is the |
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36:33 | immuno it's an immune response to actually the candidate molecule of interest from let's |
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36:39 | a mouse injected into rabbit. That will have an immune response to. |
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36:44 | . Will generate antibodies to it which can isolate them. And these antibodies |
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36:50 | pictured as wise here can be tagged visible markers so that you can see |
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36:58 | in color and typically in fluorescent And these antibodies will be specific to |
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37:03 | neurotransmitter of interest that that you've isolated now you've isolated the antibodies for |
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37:09 | So you know it's the chemistry is technique where you apply the antibodies on |
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37:15 | slides and the slides here it says shows two cells that will have let's |
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37:19 | thousands of cells. But let's say cells. And there's a little bit |
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37:22 | techniques. So you introduce detergent, wash the membranes to allow for this |
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37:28 | to come inside the cells binds to target interest molecule neurotransmitter protein, you |
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37:36 | it. Okay. And then you a number of washes. So the |
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37:42 | that the antibody doesn't bind to, will not show anything All this antibody |
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37:47 | gonna get washed away from that. the cells that express that neurotransmitter, |
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37:52 | protein and enzyme of interest. They light up and it will all be |
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37:56 | . So out of these two cells all of them they have been exposed |
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38:00 | the same antibody with a fluorescent Only one of them is expressing a |
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38:06 | americans that have interest and only one them will show a visible marker visual |
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38:13 | . Insider hybridization is different there you're strands of messenger and neurons by radio |
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38:22 | labeled probes that have proper sequences of nucleic acids. So you make the |
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38:29 | because you know what economic era, genes code for, what proteins or |
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38:37 | enzymes. And so you have a that you're targeting now for that specific |
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38:44 | it's radioactively labeled. And again you apply it and only the cells that |
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38:50 | a complementary strand of messenger RNA will bound up like that. I call |
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38:56 | a sophisticated velcro will get bound up complementary nucleic acids and you will see |
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39:03 | only these cells are expressing that messenger specific molecule of interest. So it |
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39:09 | be done in a single cell sub early cell circuits on network uh it |
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39:18 | also be done on the whole animal for example in the embryo. This |
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39:23 | just an example of expression of the Truck B, which encodes neurotrophic tires |
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39:30 | two receptor no widespread but specific expression brain and spinal cord in various cranial |
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39:38 | axial skeletal structures. And then spinal tail region. So wherever you're seeing |
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39:44 | dark darker areas. Okay darker that's where you have an expression of |
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39:51 | molecule of interest in this case it's receptor but you can track expression of |
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39:57 | and this says this is embryo sagittal through 14.5 day old mouse embryo. |
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40:07 | this is really very valuable because a of different expression of chemicals in the |
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40:15 | in the cns and the body expression receptor channels subunits of these receptor |
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40:24 | They don't all happen all at The brain just formed like this. |
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40:28 | takes time. There's sometimes a sequential and you want to for example now |
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40:35 | is the earliest appearance of that receptor the embryo? And what do you |
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40:43 | then as a graduate student? Your embryo at five days old, six |
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40:47 | old, 10 days old, 12 old, 14 days old and then |
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40:52 | don't see anything and you're at your end and then you section it at |
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40:56 | days old and boom it lights up it shows you so it tells you |
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41:01 | this is an expression of that protein started at a certain time. It |
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41:07 | change its spatial expression over development and aging and it may change expression of |
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41:15 | levels and sometimes spatial expression as a of aging process. Also not just |
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41:23 | but also aging. We talked about neurotransmitter mimicry. So that's on a |
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41:31 | level. So when you look at chemistry and cd hybridization you can visualize |
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41:35 | cells have what but if you want study the E. P. |
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41:38 | P. S. The I PS . What is application of acetylcholine has |
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41:43 | do with deep realization hyper polarization. want to do neurotransmitter mimicry. And |
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41:48 | talked about it. You can apply through the pipe that you will be |
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41:52 | a significant amount of diffusion here. if you stimulate it this is glutamate |
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41:57 | neuron. You will record your If you isolated the glutamate and applied |
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42:02 | here, you will recording PSP. we talked about in caging of |
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42:07 | Use the neurotransmitters that are caged and cages. And breaking these cages with |
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42:13 | or with lasers can be a useful to study very spatially specific activation along |
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42:20 | dendrite. And even are they? has a message that you that you |
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42:42 | you uh express. Yeah. So cells that have cata cola means they |
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42:50 | bind to messenger RNA. The radioactive . Nearby cells don't have cata cola |
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42:56 | they will not show it. If can target an enzyme to you can |
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43:00 | God for example, Time capacity per ladies. So, all right. |
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43:08 | now, what happens in in in Denver. Right. And what we |
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43:15 | about here in this example, we talked about how if you activate |
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43:22 | one or few excited synapses, this is not going to reach the threshold |
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43:28 | action potential. So you have to many synapses. And so the brain |
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43:34 | strategy of how to do that and does sell through a couple of |
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43:40 | One of them is called spatial So one synapse, one action potential |
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43:47 | in one synapse produces a small E . S. P. Small p |
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43:52 | , then three of them that are very close in space near each other |
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43:59 | produce a much larger maybe even three the amplitude of that U. |
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44:04 | S. P. So this is summation. You have temporal summation. |
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44:10 | one action potential produces a small T. S. P. If |
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44:16 | cell repeats action potentials produces a small to action potentials to each is gonna |
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44:28 | with an E P S. Foss. In optical you're gonna record |
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44:31 | pasta E P S. P. this is called temporal information. You |
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44:36 | see that the maximum altitude is reached spatial information, temporal summation will cause |
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44:45 | larger ups. But you can see with on the PSP starts the |
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44:50 | So that's why this temporarily some Adedy from a single axon is not as |
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44:58 | of an aptitude as the Ep sp gets produced with spatially sublimated inputs and |
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45:06 | done drive if you remember this is patch of been really cable. And |
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45:12 | we talked about how there is no regeneration of that signal. It's only |
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45:20 | potentials that regenerated each note of round but the deep realizations and then drives |
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45:26 | capitalizations actually leak out the cable is insulated. And if you have a |
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45:34 | amount of current injected in this location causes a certain change in the number |
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45:39 | potential here positive change only a small or a fraction of that change is |
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45:46 | to be recorded some distance away so not going to be like an action |
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45:52 | . An axon where action potential is to be the same amplitude when it |
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45:56 | an action initial segment and when it the external terminal you have a decay |
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46:01 | the signal here over distance and we calculate what is called the length constant |
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|
46:10 | v lambda or lambda V. Either which is V lambda is the 37% |
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46:19 | this location here in the denver you the voltage by 100% which is |
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46:26 | L the maximum year 100% over some . This very strong deep polarization is |
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46:36 | to decrease decrease, decrease decrease until reaches 37% value. So 37% of |
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|
46:47 | maximum value. The distance Along the ride that it takes story to go |
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|
46:54 | 100% to 37% is the λ And this is the λ is the |
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47:01 | constant. So you can measure the and the longer the length constant the |
|
|
47:10 | it is for the temporal summation in . So the longer the length |
|
|
47:20 | Do something here, one count. . Look at the length constant |
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|
48:00 | this is what we're talking about. in some instances this length constant can |
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48:08 | longer and it can take like a this window come back to it. |
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|
48:29 | is short length constant. This is short length constant. This is very |
|
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48:34 | length constant. So the shorter the , that means that if you had |
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48:41 | that were specially some mated we better in temporarily sublimated, especially temporally submitted |
|
|
48:48 | data. Be better be very very fast summation here you provide a |
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48:55 | more opportunity for for for spatial summation you have this long length constant which |
|
|
49:01 | more of the deep polarization over So you can build on and build |
|
|
49:05 | and build on it and reach the for the action potential. Okay uh |
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|
49:13 | you can see here that if you any PSP which is a lot of |
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49:19 | inputs will be coming in distantly. you have excitatory synapse here generate C |
|
|
49:26 | and there's no inhibition in the system at the level of the summer you're |
|
|
49:30 | to record a small E. S. P. If you have |
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|
49:35 | excitatory synapse activated but quite often you'll inhibitors synapses that are located around the |
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49:42 | here. Remember the closer to the closer to the action initial |
|
|
49:47 | the more influence you have on the properties of the cell influencing whether the |
|
|
49:53 | is going to produce an action potential or not. While you have |
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|
49:57 | S. P. Here distilling the right and it's traveling down. You |
|
|
50:03 | activate inhibitory synapse. A lot of current is going to shout and escape |
|
|
50:09 | here. And the end result at level of the soma is that there's |
|
|
50:15 | no change in the membrane potential. what happened here? Inhibition canceled out |
|
|
50:21 | excitation. So the excitation has a job cut out for it. You |
|
|
50:27 | tens to hundreds of thousands sometimes active synapses that are dis delete to overcome |
|
|
50:34 | much smaller percentage of 10 or 20% inhibitory synapses that are formed here |
|
|
50:41 | But they have a very strong effect basically um influencing the final response from |
|
|
50:49 | cell and it now in modulation. I said neural transmission. And I |
|
|
50:59 | neural transmission you release neurotransmitter. You the PSP neuromodulation, secondary messengers coding |
|
|
51:06 | . Highnesses can add P. 04 and phosphorus channels. They're also molecules |
|
|
51:12 | called phosphate. Asus and they'll just the opposite. That will take away |
|
|
51:16 | P. 04 group. Okay, this is happening on the intracellular uh |
|
|
51:23 | signaling, cellular signaling cascade level and different iterations. There is a little |
|
|
51:31 | of overlap here. There's different presentations these systems. A single Colin |
|
|
51:37 | Serotonin cata cola mean systems you're responsible everything in Alzheimer's I mean sorry on |
|
|
51:46 | including the alzheimer's medications functions. Uh this is how masculinity or metaphor |
|
|
51:54 | Acetylcholine receptor works when you bind the into little tropic receptor. It will |
|
|
52:01 | potassium channel and it will allow for flux of potassium through nicotine. It |
|
|
52:11 | allow equal influx of sodium suicidal Wanted boston academic it promotes deep polarization |
|
|
52:20 | mascara nick with some delay. It opening of potassium and hyper polarization. |
|
|
52:28 | they're opposing actions the same molecule but different nicotine IQ tropic versus madavo |
|
|
52:37 | They have a different effect at the of the member and potential here. |
|
|
52:47 | ? Oh now let's talk about if have a competition between Iowa tropic and |
|
|
52:54 | tropic I just said nicotine increases mascara and you have the competition at the |
|
|
53:00 | of medical tropic on the cellular targets cellular cascade. So here you have |
|
|
53:07 | . Norepinephrine can buy into beta receptors is like here it doesn't show up |
|
|
53:12 | G protein or G. S. stimulant or a protean will push the |
|
|
53:17 | to produce more activated in a little produce more cycling. Campion produce more |
|
|
53:23 | chains which can force correlate channels and same molecule can activate another metal tropic |
|
|
53:30 | . Beta alpha which is linked to . I. The inhibitory G. |
|
|
53:37 | which will inhibit the. Dental cyclists the production cycle can be reduced the |
|
|
53:42 | of program guidance systems called push pull This beta receptors pushing the system activation |
|
|
53:50 | beta, pushing to produce more cycle . And this system is pulling it |
|
|
53:55 | from producing more cycle K. And according to chinese says an enzyme and |
|
|
54:02 | are capable of plus for leading Again. So this is a lot |
|
|
54:08 | men of the tropics signaling. Don't that amino acids are everywhere and the |
|
|
54:17 | are in these nuclei. Uh If talking about cata cola mean movement, |
|
|
54:24 | , attention, visceral function, appetite, sleep learning, do they |
|
|
54:27 | overlapping functions? Sure. Couple of can control different different functions or similar |
|
|
54:34 | behaviors. Similar responses in the body the end of cannabinoids a little bit |
|
|
54:41 | . I guess this mechanism, I mention that because they didn't have written |
|
|
54:46 | in the bigger slide. This mechanism signaling and suppression of neurotransmitter release is |
|
|
54:54 | deep polarization induced suppression of the condition deep polarization induced suppression of sanitation. |
|
|
55:01 | realization because there's going to be pre deep polarization which is going to |
|
|
55:06 | let's say gluten. Maker rules and Blue to maple cause influx of calcium |
|
|
55:13 | africa lee ji memoranda. Cannabinoids, polarization induced suppression of excitation. If |
|
|
55:21 | inhibition, there's going to be deep of inhibitory synaptic terminals, there's going |
|
|
55:27 | be post synaptic activity influx of calcium different levels. Production of other phenomenons |
|
|
55:33 | control of inhibition. The suppression of and suppression of excitation. Delta |
|
|
55:40 | I wanted to mention that. I haven't written out Delta nine THC or |
|
|
55:46 | was a fighter. Cannabinoid. It's most famous fighter can adam. It |
|
|
55:51 | uh cabinet that was isolated in 1960 only It was banned in about |
|
|
55:59 | So Canada's altogether the prohibition of Canada over 100 years ago. But delta |
|
|
56:07 | is a naturally occurring molecule. Another phyto cannabinoid is CBD, which is |
|
|
56:18 | and you will see almost everybody from shops to gas stations to clinics selling |
|
|
56:24 | creams and oils. And CBD does cause the same effect as THC |
|
|
56:32 | When it binds to CB one it's responsible for causing the high or |
|
|
56:38 | euphoria in effect when you consume delta THC. So does that mean under |
|
|
56:47 | ? Get you high if you produce of these, they're responsible for good |
|
|
56:53 | and they're responsible for protecting cells and neural transmission. So yeah, under |
|
|
57:00 | in a way give people what is the runner's high. It's not equated |
|
|
57:06 | getting high with Canada's development nine But this is the fact that it |
|
|
57:12 | exert and it will exert in the . The CB one receptor that THC |
|
|
57:16 | also an agonist that will regulate the . But you have to be careful |
|
|
57:24 | aware of is there are derivatives of natural phyto cannabinoids like delta nine THC |
|
|
57:31 | CBD. They're called delta eight You'll also see it on every gas |
|
|
57:37 | delta 10 th C. You will things like acetate delta eight. |
|
|
57:45 | delta 10 acetate all those are a bit a lot unknown molecules. And |
|
|
57:57 | not super dangerous but a little bit because we don't know enough about Delta |
|
|
58:02 | and delta 10 th C. It's anecdotally that it comes from the |
|
|
58:07 | In fact most of the Delta And Delta 10 th C. That |
|
|
58:11 | on the market in these gas stations produced from other phyto cannabinoid CBD and |
|
|
58:18 | nine THC from hemp plants typically. the process by which is converted into |
|
|
58:26 | Delta 10, there's no standard So a lot of synthetic phenomenons and |
|
|
58:32 | is delta and delta 10, a synthetic phenomenons because they synthesized from a |
|
|
58:38 | that's a natural precursor. And then we talk about later in the course |
|
|
58:42 | also tell you about synthetic phenomenon which be very dangerous. Uh and they |
|
|
58:50 | are acting on the brain and the in a very different way from the |
|
|
58:57 | or natural phenomenons. Okay, so aware of all of these things because |
|
|
59:02 | surrounding you every day and you have know what they are and with these |
|
|
59:12 | , unfortunately, especially in the gas and Vape shops and such. You |
|
|
59:18 | , people take advice of a person the counter and they take all sorts |
|
|
59:23 | advice, you know, will make yeah good you sleep. It's like |
|
|
59:28 | , I can't feel my legs for hours, great. You know, |
|
|
59:31 | in the middle of the highway, . You know, you didn't tell |
|
|
59:34 | that part, you know, so aware of these things. We'll talk |
|
|
59:39 | about this because it's a change that happening as you're growing up your generation |
|
|
59:45 | cannabis globally with medicinal applications of there's gonna be huge pharmaceutical breakthroughs with |
|
|
59:55 | . We already have some that are medications. There will be even more |
|
|
60:00 | also more natural molecules are coming into world. So when we talk about |
|
|
60:06 | for example, and we talk about treatment of depression, treatment of |
|
|
60:14 | which is post traumatic stress disorder, are new emergent uh molecules such as |
|
|
60:26 | from magic mushrooms or psychedelic mushrooms that currently in clinical studies and are being |
|
|
60:35 | in different locations around the world for to treat depression and to treat anxiety |
|
|
60:41 | treat addiction. Some drugs are very and we're now learning that there are |
|
|
60:48 | other drugs that are described as psychedelics have anti addictive properties and some of |
|
|
60:59 | will mimic again some of the actions antidepressants. I think maybe I lost |
|
|
61:15 | recording and we'll see what happens. no, it's maybe recording recording |
|
|
61:30 | Okay, hopefully it picks it So the the issue with somebody having |
|
|
61:38 | depression anxiety is it can be It's not, I'm just anxious to |
|
|
61:44 | an exam. People have so much . Are you nervous? Yeah, |
|
|
61:48 | have butterflies, You don't have a condition of anxiety. You know, |
|
|
61:52 | you have a chronic condition, if totally anxious, you may not want |
|
|
61:55 | come outside and talk to people may to go through your day and |
|
|
61:59 | you know, so you are assess their eyes so totally we have |
|
|
62:05 | inhibitors. Is it like you take and the pain goes away. So |
|
|
62:11 | take a. S. R. no longer depressed. I have no |
|
|
62:14 | or laughing, you know, know is the typical effect? Three |
|
|
62:21 | maybe sometimes longer. Alright, so have to wait, imagine waiting through |
|
|
62:29 | for three weeks that is debilitating to mentally. Very, very difficult. |
|
|
62:36 | ? The surprising thing that we're learning about psilocybin from mushrooms is a single |
|
|
62:43 | of these molecules can drive people to smoking and nicotine use that they've done |
|
|
62:50 | decades. Single use can improve their for a long time. And the |
|
|
62:57 | that people are seeing are within hours a day or two and a lot |
|
|
63:03 | times with a lot of pharmaceutical This is another thing. You guys |
|
|
63:07 | the future of neuro pharmacology. Hopefully of you in this world and creating |
|
|
63:12 | smart and interesting drugs. Right? of these uh drugs don't kick in |
|
|
63:21 | a while and then what do you to do but to keep taking them |
|
|
63:27 | sometimes you have to increase the dose of one tablet. Now you're into |
|
|
63:31 | , you're taking it three times a . 10 mg is not enough. |
|
|
63:34 | mg, increase the dose. I'll you a cocktail, maybe that will |
|
|
63:37 | now you're in two medications, three that's not working. Let's wean you |
|
|
63:41 | one. It's for for neurologists or , for people in medical field, |
|
|
63:50 | are solving a problem. They don't a given solution to each one of |
|
|
63:53 | As individuals. Each one of us a different foe different than the stony |
|
|
63:58 | these chemicals floating around and different. know, you move one piece of |
|
|
64:03 | in the soup and then, you , your beef is floating around |
|
|
64:06 | So it's changing things. That's one , changing the activity of another chemical |
|
|
64:12 | . And so it's difficult for a of times for medical doctors and |
|
|
64:17 | especially with mental conditions to come up a effective treatment. Okay. And |
|
|
64:25 | these turning out the natural ones that turning out one use and you have |
|
|
64:31 | effect that potentially last for one or years. That's great. It's not |
|
|
64:36 | great for pharmaceutical industry because you it's not much sale uh repeating selling |
|
|
64:44 | pill that you have to take over over and over and over over every |
|
|
64:48 | . So this is these are the of treatments were looking, I'm not |
|
|
64:51 | that everybody should do self outside. I'm telling you that these are the |
|
|
64:56 | of treatments that we're looking for. we affect the condition within hours rather |
|
|
65:02 | weeks. Can we cause a change you take the pill? You take |
|
|
65:08 | injection, you take some treatment. is long lasting, so you don't |
|
|
65:13 | to do it every day. you don't have to carry, you |
|
|
65:17 | , a bag of prescription pills and to treat a certain condition. So |
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65:23 | the future. You know? And learning a lot of it from |
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65:27 | We're learning a lot of it from the chemistry in the brain and |
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65:30 | also have to be very, very because the biggest problem right now with |
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65:36 | drugs in this country is fentaNYL. the reason why you don't hear |
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65:46 | Oh this uh this person they uh our endocannabinoid? Is this person smoked |
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65:54 | and they died. How many states adult use of legal use of marijuana |
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66:03 | cannabis? Legally, millions of people this country. So you'd be reporting |
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66:09 | every day. There's something about certain . There are non non lethal. |
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66:15 | sure they can intoxicate you. Gonna you, it can cause psychosis. |
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66:20 | not all beneficial effects of cannabinoids. negative effects. Also, it can |
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66:25 | Children, send them to toxicology. those same kids will go to school |
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66:29 | , once they ate their parents their stomachs get washed out and then |
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66:33 | back to school day later. It's lethal. The problem with sentimental is |
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66:40 | it's so lethal. With such small , it's powder, it's synthetic, |
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66:46 | derivatives of it. So you don't , I'll give you any white powder |
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66:49 | Alaska what it is and you won't what it is. You know, |
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66:53 | if it is an illicit drug it be almost anything and you don't know |
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66:58 | there's no regulatory system behind it. no lab measuring results or anything like |
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67:04 | . The other problem with the opiates the sentinel. So only a couple |
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67:08 | milligrams will kill you opioid drugs that prescription medications to treat pain. We |
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67:16 | also overdoses and deaths from pharmaceutical We have a lot of thousands of |
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67:21 | dying in the United States from treating from pain from opiates. Why are |
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67:26 | many people dying from those molecules? effective does is small couple of |
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67:34 | But a lethal does from pharmaceutical drugs opiates can be just three or four |
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67:39 | of an effective dose. It's the as if to add val's take away |
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67:43 | headache. Eight Advil will kill That's the analogy with the opiates, |
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67:49 | turns out that with a lot of molecules and fentaNYL, it's even worse |
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67:54 | derivatives of it, it's even worse with natural molecules you don't always get |
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68:00 | same effect and that is very much on how they will bind and the |
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68:06 | that receptors it delta nine THC will to the CB one receptor, it |
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68:11 | cause a person to get a high for 34 hours. That's it. |
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68:16 | it's a synthetic cannabinoid advise the seaview the stop it may stick to it |
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68:21 | two weeks and may cause acute psychosis to chronic psychosis leading to chronic disabilities |
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68:31 | things like cash. Because they're synthetic are known their full agonists versus partial |
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68:38 | . So when we talk about agonist of the molecules will be partial agonists |
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68:43 | changed the bond to that receptor. only partially influenced the podium so there's |
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68:49 | dynamic range there or they're full and like maximally activate the system and stick |
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68:55 | these different receptors in the brain. done. But we're a little bit |
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69:05 | so I'm gonna talk a little bit glutamate. We'll start talking about |
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69:09 | Glutamate is an endogenous neurotransmitter that will to three types of amyotrophic. We |
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69:14 | accept this and and in the end eight and then we'll have chemical agonists |
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69:21 | and that will have their special violence and these receptors and will basically distinguish |
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69:29 | between these three different subtypes of A tropic glutamate receptor channels and when |
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69:37 | gets released it has caused E. . S. P. And it's |
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69:41 | mostly through AMFA and NMDA receptors when gets released and advice to ankara receptors |
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69:50 | causes the initial deep polarization. I'll that these are live in gated receptor |
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69:56 | and just like we talked about nicotine will allow for influx of sodium and |
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70:02 | . You have a receptacle opera influx sodium. This is the initial d |
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70:08 | influx of potassium will be this re of the PSP and the first flu |
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70:15 | receptor channels to open our ample receptors of glutamate in NBA receptors does not |
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70:22 | an NBA receptors. There are two that are necessary for an M. |
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70:26 | . A receptor is to open. of them is the binding of glutamate |
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70:30 | the other is deep polarization because NMDA have magnesium that is blocking the |
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70:39 | And to remove this magnesium you actually to de polarize the plasma membrane. |
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70:45 | in the initial deep polarization which happens apple receptors allows for magnesium to leave |
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70:52 | NBA receptors open an NBA receptors and NBA receptors will allow for significant influx |
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70:59 | sodium calcium in potassium. So all them via receptors were allowed to put |
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71:05 | of sodium and calcium only some ample will allow for influx of calcium but |
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71:12 | will all allow for the influx of and the flux of potassium. Okay |
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71:20 | so they have distinct agonists and antagonists we we'll talk about antagonists in the |
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71:26 | selectivity. So they're selected for certain conductance and then via receptors are capable |
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71:33 | much larger conductance is ample receptor is to be responsible for the initial phase |
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71:38 | U. P. S. And M. D. A receptor |
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71:41 | going to be responsible for the late of E. S. P. |
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71:48 | um well actually end here for today when we come back we'll get in |
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71:55 | into the glue dramaturgical pharmacology. We'll about inhibition inhibitory pharmacology and we'll move |
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72:04 | the c. N. S. we have about maybe half an hour |
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72:07 | neural transmission. A lot for what be neural transmission for. Thank you |
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72:12 | . And I'll see you next |
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